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Sunday, December 7, 2025

g factor (psychometrics)

From Wikipedia, the free encyclopedia
 

The g factor is a construct developed in psychometric investigations of cognitive abilities and human intelligence. It is a variable that summarizes positive correlations among different cognitive tasks, reflecting the assertion that an individual's performance on one type of cognitive task tends to be comparable to that person's performance on other kinds of cognitive tasks. The g factor typically accounts for 40 to 50 percent of the between-individual performance differences on a given cognitive test, and composite scores ("IQ scores") based on many tests are frequently regarded as estimates of individuals' standing on the g factor. The terms IQ, general intelligence, general cognitive ability, general mental ability, and simply intelligence are often used interchangeably to refer to this common core shared by cognitive tests. However, the g factor itself is a mathematical construct indicating the level of observed correlation between cognitive tasks. The measured value of this construct depends on the cognitive tasks that are used, and little is known about the underlying causes of the observed correlations.

The existence of the g factor was originally proposed by the English psychologist Charles Spearman in the early years of the 20th century. He observed that children's performance ratings, across seemingly unrelated school subjects, were positively correlated, and reasoned that these correlations reflected the influence of an underlying general mental ability that entered into performance on all kinds of mental tests. Spearman suggested that all mental performance could be conceptualized in terms of a single general ability factor, which he labeled g, and many narrow task-specific ability factors. Soon after Spearman proposed the existence of g, it was challenged by Godfrey Thomson, who presented evidence that such intercorrelations among test results could arise even if no g-factor existed.

Traditionally, research on g has concentrated on psychometric investigations of test data, with a special emphasis on factor analytic approaches. However, empirical research on the nature of g has also drawn upon experimental cognitive psychology and mental chronometry, brain anatomy and physiology, quantitative and molecular genetics, and primate evolution. Research in the field of behavioral genetics has shown that the construct of g is heritable in measured populations. It has a number of other biological correlates, including brain size. It is also a significant predictor of individual differences in many social outcomes, particularly in education and employment.

Critics have contended that an emphasis on g is misplaced and entails a devaluation of other important abilities. Some scientists, including Stephen J. Gould, have argued that the concept of g is a merely reified construct rather than a valid measure of human intelligence.

Concept

Spearman's correlation matrix for six measures of school performance. All the correlations are positive, the positive manifold phenomenon. The bottom row shows the g loadings of each performance measure.

Classics French English Math Pitch Music
Classics




French .83



English .78 .67


Math .70 .67 .64

Pitch discrimination .66 .65 .54 .45
Music .63 .57 .51 .51 .40
g .958 .882 .803 .750 .673 .646
Subtest intercorrelations in a sample of Scottish subjects who completed the WAIS-R battery. The subtests are Vocabulary, Similarities, Information, Comprehension, Picture arrangement, Block design, Arithmetic, Picture completion, Digit span, Object assembly, and Digit symbol. The bottom row shows the g loadings of each subtest.

V S I C PA BD A PC DSp OA DS
V









S .67 -








I .72 .59 -







C .70 .58 .59 -






PA .51 .53 .50 .42 -





BD .45 .46 .45 .39 .43 -




A .48 .43 .55 .45 .41 .44



PC .49 .52 .52 .46 .48 .45 .30 -


DSp .46 .40 .36 .36 .31 .32 .47 .23 -

OA .32 .40 .32 .29 .36 .58 .33 .41 .14 -
DS .32 .33 .26 .30 .28 .36 .28 .26 .27 .25 -
g .83 .80 .80 .75 .70 .70 .68 .68 .56 .56 .48
Heat-map of mental test from the above given data
Correlations between mental tests

In a famous research paper published in 1904, English psychologist Charles Spearman observed that children's performance measures across seemingly unrelated school subjects were positively correlated. The consistent finding of universally positive correlation matrices of mental test results (or the "positive manifold"), despite large differences in tests' contents, has been described as "arguably the most replicated result in all psychology".

Using factor analysis or related statistical methods, it is possible to identify a single common factor that can be regarded as a summary variable characterizing the correlations between all the different tests in a test battery. Spearman referred to this common factor as the general factor, or simply g. (By convention, g is always printed as a lower case italic.) Mathematically, the g factor is a source of variance among individuals, which means that one cannot meaningfully speak of any one individual's mental abilities consisting of g or other factors to any specified degree. One can only speak of an individual's standing on g (or other factors) compared to other individuals in a relevant population.

Different tests in a test battery may correlate with (or "load onto") the g factor of the battery to different degrees. These correlations are known as g loadings. An individual test taker's g factor score, representing their relative standing on the g factor in the total group of individuals, can be estimated using the g loadings. Full-scale IQ scores from a test battery will usually be highly correlated with g factor scores, and they are often regarded as estimates of g. For example, the correlations between g factor scores and full-scale IQ scores from David Wechsler's tests have been found to be greater than .95. The terms IQ, general intelligence, general cognitive ability, general mental ability, or simply intelligence are frequently used interchangeably to refer to the common core shared by cognitive tests.

The g loadings of mental tests are always positive and usually range between .10 and .90, with a mean of about .60 and a standard deviation of about .15. Raven's Progressive Matrices is among the tests with the highest g loadings, around .80. Tests of vocabulary and general information are also typically found to have high g loadings. However, the g loading of the same test may vary somewhat depending on the composition of the test battery.

The complexity of tests and the demands they place on mental manipulation are related to the tests' g loadings. For example, in the forward digit span test the subject is asked to repeat a sequence of digits in the order of their presentation after hearing them once at a rate of one digit per second. The backward digit span test is otherwise the same except that the subject is asked to repeat the digits in the reverse order to that in which they were presented. The backward digit span test is more complex than the forward digit span test, and it has a significantly higher g loading. Similarly, the g loadings of arithmetic computation, spelling, and word reading tests are lower than those of arithmetic problem solving, text composition, and reading comprehension tests, respectively.

Test difficulty and g loadings are distinct concepts that may or may not be empirically related in any specific situation. Tests that have the same difficulty level, as indexed by the proportion of test items that are failed by test takers, may exhibit a wide range of g loadings. For example, tests of rote memory have been shown to have the same level of difficulty but considerably lower g loadings than many tests that involve reasoning.

History

Spearman's early research

Spearman's research on intelligence originated from his research on measurement. He studied Francis Galton's theories of intelligence and was intriuged by why Galton failed to find associations between different performance metrics and common indicators of intelligence. Spearman posited that the tests Galton used contained substantial measurement error and were unreliable–the same person obtained a different score upon being tested again. Spearman developed procedures to correct correlation coefficients for various influences to estimate the "true relationship", including a procedure to disattenuate correlations. These ideas regarding true scores, measurement error and procedures for correcting correlations form the basis for what is now known as classical test theory. When he applied these procedures to the data he had gathered for measures of intelligence and what he called sensory discrimination ability, he obtained correlations approaching 1.

The concept of "general intelligence" first arose from Spearman's 1904 paper "'General Intelligence', Objectively Determined and Measured", where he applied his new statistical methods for correcting correlations to tests of ability to propose a two-factor theory of intelligence. Based on the observation that tests of ability typically positively correlate with each other, he proposed that these tests all measure the same thing—general intelligence—and that individual tests measure a combination of two factors: 'general intelligence' (g), common to all tests, and a 'specific ability' (s), specific to one test. This concept of "general intelligence" was supposed to provide an undisputed definition of intelligence which could be described as "objectively determined and measured". There were several corollaries of his theory, such as the claim that it is "possible to rank order the measures in terms of their g-to-s ratio". The most important was Spearman's law of tetrad differences, demonstrated by Spearman in 1924. It states that the pairwise products of two sets of correlations are equal–that is, their difference is zero. For four traits labeled 1, 2, 3, 4, this is r13⋅r24-r23r14=0. This is equivalent to the prediction that for a correlation matrix statistically removing the common factor "g" would yield a matrix of partial correlations that are all 0.

Early critics

The first psychologist to raise problems with Spearman's work was Cyril Burt, who noted that mental effort was not factored into his analysis. Burt marshalled a larger set of data and showed that more factors than a single general factor were required to explain the correlations: the law of tetrad differences was not satisfied by the data. It was shown that correlations between certain pairs of tests were much higher than expected on Spearman's theory that their only common factor was general intelligence. Spearman knew about these problems as early as 1906, but attempted to dismiss the criticism by proposing that these higher than expected correlations were because the tests weren't meaningfully distinct. In subsequent years, many other psychologists showed a wider array of factors was needed to explain various sets of data: Spearman's two-factory theory didn't explain the correlations.

Other psychologists like Thomson provided alternative explanations for the same phenomena that he used to support the concept with what is now known as sampling theory. Thomson accepted Spearman's data and methodology of factor analysis, but interpreted the results differently. He proposed that the mind was composed of innumerable independent bonds or units and any test sampled some subset of these bonds. Simultaneous to Spearman's development of his theory of g was an alternative theory from Godfrey Thomson and Edward Thorndike who proposed that the positive intercorrelation of tests (positive manifold) was compatible with a theory of many common factors. Thorndike argued that performance on cognitive tests drew from numerous cognitive processes and that different cognitive tests draw from these different processes and can produce positive correlations as observed in test batteries.

Despite these issues, Spearman's theory garnered early support. Lewis Terman, Stanford professor of psychology, drew upon Spearman's "general intelligence factor" when he revised Alfred Binet's intelligence scales to develop the Stanford-Binet Scales for American children.

The Abilities of Man

Spearman's 1927 book The Abilities of Man attempted to provide a comprehensive account of human intelligence, responding to his critics and compiling evidence in favor of his theory. He now argued that general intelligence was a reflection of "mental energy" that flowed throughout the brain, but different neural systems served as "mental engines" that explain the specific factors. He also refined his concept of "g", not as equivalent to as concrete entity or synonym for intelligence, but as a magnitude that is identified as the common factor that underlies all mental abilities, and could be identified with tests of the tetrad equation. By now, he reluctantly accepted the existence of group factors in addition to his general factor and specific factors. Following recognition that the arguments in his book did not sufficiently respond to critics evidence that not all data satisfied the tetrad condition, he put forth a different theory: that g was reflected in every ability measure and that this was proven by the positive correlations between tests of abilities, known as the "indifference of the indicator". This shift between theories has been noted as transforming "g" from a falsifiable hypothesis to an unfalsifiable result of mathematical necessity.

Another early criticism raised of the g theory was factor indeterminacy. In a review of Spearman's Ability of Man, Edwin Wilson pointed out that Spearman's theory did not define g uniquely because it proposed more independent factors than observed psychological tests. and it was possible to generate a different set of factor scores for a set of students that reproduces the same correlation matrix.

In response to these criticisms, some psychologists tried to rescue Spearman's theory by producing batteries of tests that would reflect g without introducing specific factor overlap that produces common factors other than g. Invariably these attempts failed and psychologists acknowledged that many common factors were needed to explain correlations between tests, as many as one third as many factors as tests in a battery.

Later theories

In 1938, Louis Thurstone developed a theory of intelligence contrary to both Spearman and Thomson. He, like Thomson, proposed that there were separate factors that were unrelated to each other, but he proposed a smaller set of just seven primary mental abilities. Thurstone developed the method of multiple factor analysis to identify the number of factors needed to explain a matrix of observed correlations. His early results using orthogonal factors identified as many as 13 factors, which he believed conclusively refuted Spearman's theory, though a reanalysis of his results showed that Spearman's g theory could explain the data as well. Later Thurstone abandoned the idea of completely independent factors and posited correlated factors, analyzing test data using oblique factor analysis but left him without a strong criticism of Spearman's theory. After the 1940s, studies using Thurstone's methods proliferated, identifying increasing numbers of mental abilities. One example was Joy Paul Guilford's "Structure-of-Intellectual" model which proposed 3 facets of ability - contents, products, operations - that can be composed in different ways to obtain 150 different abilities. Lloyd Humphries argued that following Thurstone's publications, "psychometrists and factor analysts have tended to lose sight of the general factor in intelligence".

By 1941, Raymond Cattell, who had worked with Spearman, proposed a two common factor theory of intelligence. Cattell's theory proposed two high level factors: Gc (crystallized intelligence) that reflected learned knowledge and general information and Gf (fluid intelligence) that closely resembled Spearman's conceptualization of g. Since proposing these factors, Cattell and his student John Horn proposed a number of other 'general factors' or 'broad factors' like Gs (visual inspection speed), Ga (auditory thinking), Gv (visual-spatial reasoning), Gq (quantitative reasoning), Gr (fluency in recall). Their theory is what Arthur Jensen calls a "truncated hierarchy", as it extracts many factors but not one unitary "general" factor on top of the hierarchy.

Jensen

Jensen mounted defenses of the g-factor from its many critics over the course of his career. His first major work How Much Can We Boost IQ and Scholastic Achievement? described Spearman's development of the concept of "general intelligence" in support of what Urbach calls the "hard core of the hereditarian program". In the dispute among psychometricians over general intelligence, Jensen fiercely argued for its existence, presenting it as a fact that no self-respecting psychometrician could deny. In that article, Jensen presented a hierarchical model of intelligence, where abilities operate two levels: Level I and Level II. In his later work The g Factor: The Science of Mental Ability, Jensen offered an extensive synthesis of a large body of research to argue that g is a legitimate scientific construct based in human biology with far-reaching effects on human life.

In some ways, Arthur Jensen resuscitated Spearman's g theory, but his arguments reflect a marked shift from Spearman's theory of factors to its replacement with principal components.

Measurement

An illustration of Spearman's two-factor intelligence theory. Each small oval is a hypothetical mental test. The blue areas correspond to test-specific variance (s), while the purple areas represent the variance attributed to g.

Factor analysis is a family of mathematical techniques that can be used to represent correlations between intelligence tests in terms of a smaller number of variables known as factors. The purpose is to simplify the correlation matrix by using hypothetical underlying factors to explain the patterns in it. When all correlations in a matrix are positive, as they are in the case of IQ, factor analysis will yield a general factor common to all tests. The general factor of IQ tests is referred to as the g factor, and it typically accounts for 40 to 50 percent of the variance in IQ test batteries. The presence of correlations between many widely varying cognitive tests has often been taken as evidence for the existence of g, but mathematically the correlations do not provide any more or less support for the existence of g than for the existence of multiple factors of intelligence.

Charles Spearman developed factor analysis in order to study correlations between tests. Initially, he developed a model of intelligence in which variations in all intelligence test scores are explained by only two kinds of variables: first, factors that are specific to each test (denoted s); and second, a g factor that accounts for the positive correlations across tests. This is known as Spearman's two-factor theory. Later research based on more diverse test batteries than those used by Spearman demonstrated that g alone could not account for all correlations between tests. Specifically, it was found that even after controlling for g, some tests were still correlated with each other. This led to the postulation of group factors that represent variance that groups of tests with similar task demands (e.g., verbal, spatial, or numerical) have in common in addition to the shared g variance.

An illustration of John B. Carroll's three stratum theory, an influential contemporary model of cognitive abilities. The broad abilities recognized by the model are fluid intelligence (Gf), crystallized intelligence (Gc), general memory and learning (Gy), broad visual perception (Gv), broad auditory perception (Gu), broad retrieval ability (Gr), broad cognitive speediness (Gs), and processing speed (Gt). Carroll regarded the broad abilities as different "flavors" of g.

Through factor rotation, it is, in principle, possible to produce an infinite number of different factor solutions that are mathematically equivalent in their ability to account for the intercorrelations among cognitive tests. These include solutions that do not contain a g factor. Thus factor analysis alone cannot establish what the underlying structure of intelligence is. In choosing between different factor solutions, researchers have to examine the results of factor analysis together with other information about the structure of cognitive abilities.

There are many psychologically relevant reasons for preferring factor solutions that contain a g factor. These include the existence of the positive manifold, the fact that certain kinds of tests (generally the more complex ones) have consistently larger g loadings, the substantial invariance of g factors across different test batteries, the impossibility of constructing test batteries that do not yield a g factor, and the widespread practical validity of g as a predictor of individual outcomes. The g factor, together with group factors, best represents the empirically established fact that, on average, overall ability differences between individuals are greater than differences among abilities within individuals, while a factor solution with orthogonal factors without g obscures this fact. Moreover, g appears to be the most heritable component of intelligence. Research utilizing the techniques of confirmatory factor analysis has also provided support for the existence of g.

A g factor can be computed from a correlation matrix of test results using several different methods. These include exploratory factor analysis, principal components analysis (PCA), and confirmatory factor analysis. Different factor-extraction methods produce highly consistent results, although PCA has sometimes been found to produce inflated estimates of the influence of g on test scores.

Theories

While the existence of g as a statistical regularity is well-established and uncontroversial among experts, there is no consensus as to what causes the positive intercorrelations. Several explanations have been proposed.

Mental energy or efficiency

Charles Spearman reasoned that correlations between tests reflected the influence of a common causal factor, a general mental ability that enters into performance on all kinds of mental tasks. However, he thought that the best indicators of g were those tests that reflected what he called the eduction of relations and correlates, which included abilities such as deduction, induction, problem solving, grasping relationships, inferring rules, and spotting differences and similarities. Spearman hypothesized that g was equivalent with "mental energy". However, this was more of a metaphorical explanation, and he remained agnostic about the physical basis of this energy, expecting that future research would uncover the exact physiological nature of g.

Following Spearman, Arthur Jensen maintained that all mental tasks tap into g to some degree. According to Jensen, the g factor represents a "distillate" of scores on different tests rather than a summation or an average of such scores, with factor analysis acting as the distillation procedure. He argued that g cannot be described in terms of the item characteristics or information content of tests, pointing out that very dissimilar mental tasks may have nearly equal g loadings. Wechsler similarly contended that g is not an ability at all but rather some general property of the brain. Jensen hypothesized that g corresponds to individual differences in the speed or efficiency of the neural processes associated with mental abilities. He also suggested that given the associations between g and elementary cognitive tasks, it should be possible to construct a ratio scale test of g that uses time as the unit of measurement.

Sampling theory

The so-called sampling theory of g, originally developed by Edward Thorndike and Godfrey Thomson, proposes that the existence of the positive manifold can be explained without reference to a unitary underlying capacity. According to this theory, there are a number of uncorrelated mental processes, and all tests draw upon different samples of these processes. The inter correlations between tests are caused by an overlap between processes tapped by the tests. Thus, the positive manifold arises due to a measurement problem, an inability to measure more fine-grained, presumably uncorrelated mental processes.

It has been shown that it is not possible to distinguish statistically between Spearman's model of g and the sampling model; both are equally able to account for inter correlations among tests. The sampling theory is also consistent with the observation that more complex mental tasks have higher g loading, because more complex tasks are expected to involve a larger sampling of neural elements and therefore have more of them in common with other tasks.

Some researchers have argued that the sampling model invalidates g as a psychological concept, because the model suggests that g factors derived from different test batteries simply reflect the shared elements of the particular tests contained in each battery rather than a g that is common to all tests. Similarly, high correlations between different batteries could be due to them measuring the same set of abilities rather than the same ability.

Critics have argued that the sampling theory is incongruent with certain empirical findings. Based on the sampling theory, one might expect that related cognitive tests share many elements and thus be highly correlated. However, some closely related tests, such as forward and backward digit span, are only modestly correlated, while some seemingly completely dissimilar tests, such as vocabulary tests and Raven's matrices, are consistently highly correlated. Another problematic finding is that brain damage frequently leads to specific cognitive impairments rather than a general impairment one might expect based on the sampling theory.

Mutualism

The "mutualism" model of g proposes that cognitive processes are initially uncorrelated, but that the positive manifold arises during individual development due to mutual beneficial relations between cognitive processes. Thus there is no single process or capacity underlying the positive correlations between tests. During the course of development, the theory holds, any one particularly efficient process will benefit other processes, with the result that the processes will end up being correlated with one another. Thus similarly high IQs in different persons may stem from quite different initial advantages that they had. Critics have argued that the observed correlations between the g loadings and the heritability coefficients of subtests are problematic for the mutualism theory.

Gf-Gc theory

Raymond Cattell, a student of Charles Spearman's, modified the unitary g factor model and divided g into two broad, relatively independent domains: fluid intelligence (Gf) and crystallized intelligence (Gc). Gf is conceptualized as a capacity to figure out novel problems, and it is best assessed with tests with little cultural or scholastic content, such as Raven's matrices. Gc can be thought of as consolidated knowledge, reflecting the skills and information that an individual acquires and retains throughout his or her life. Gc is dependent on education and other forms of acculturation, and it is best assessed with tests that emphasize scholastic and cultural knowledge. Gf can be thought to primarily consist of current reasoning and problem solving capabilities, while Gc reflects the outcome of previously executed cognitive processes.

The rationale for the separation of Gf and Gc was to explain individuals' cognitive development over time. While Gf and Gc have been found to be highly correlated, they differ in the way they change over a lifetime. Gf tends to peak at around age 20, slowly declining thereafter. In contrast, Gc is stable or increases across adulthood. A single general factor has been criticized as obscuring this bifurcated pattern of development. Cattell argued that Gf reflected individual differences in the efficiency of the central nervous system. Gc was, in Cattell's thinking, the result of a person "investing" his or her Gf in learning experiences throughout life.

Cattell, together with John Horn, later expanded the Gf-Gc model to include a number of other broad abilities, such as Gq (quantitative reasoning) and Gv (visual-spatial reasoning). While all the broad ability factors in the extended Gf-Gc model are positively correlated and thus would enable the extraction of a higher order g factor, Cattell and Horn maintained that it would be erroneous to posit that a general factor underlies these broad abilities. They argued that g factors computed from different test batteries are not invariant and would give different values of g, and that the correlations among tests arise because it is difficult to test just one ability at a time.

However, several researchers have suggested that the Gf-Gc model is compatible with a g-centered understanding of cognitive abilities. For example, John B. Carroll's three-stratum model of intelligence includes both Gf and Gc together with a higher-order g factor. Based on factor analyses of many data sets, some researchers have also argued that Gf and g are one and the same factor and that g factors from different test batteries are substantially invariant provided that the batteries are large and diverse.

Theories of uncorrelated abilities

Several theorists have proposed that there are intellectual abilities that are uncorrelated with each other. Among the earliest was L.L. Thurstone who created a model of primary mental abilities representing supposedly independent domains of intelligence. However, Thurstone's tests of these abilities were found to produce a strong general factor. He argued that the lack of independence among his tests reflected the difficulty of constructing "factorially pure" tests that measured just one ability. Similarly, J.P. Guilford proposed a model of intelligence that comprised up to 180 distinct, uncorrelated abilities, and claimed to be able to test all of them. Later analyses have shown that the factorial procedures Guilford presented as evidence for his theory did not provide support for it, and that the test data that he claimed provided evidence against g did in fact exhibit the usual pattern of intercorrelations after correction for statistical artifacts.

Gardner's theory of multiple intelligences

More recently, Howard Gardner has developed the theory of multiple intelligences. He posits the existence of nine different and independent domains of intelligence, such as mathematical, linguistic, spatial, musical, bodily-kinesthetic, meta-cognitive, and existential intelligences, and contends that individuals who fail in some of them may excel in others. According to Gardner, tests and schools traditionally emphasize only linguistic and logical abilities while neglecting other forms of intelligence.

While popular among educationalists, Gardner's theory has been much criticized by psychologists and psychometricians. One criticism is that the theory contradicts both scientific and everyday usages of the word intelligence. Several researchers have argued that not all of Gardner's intelligences fall within the cognitive sphere. For example, Gardner contends that a successful career in professional sports or popular music reflects bodily-kinesthetic intelligence and musical intelligence, respectively, even though one might usually talk of athletic and musical skills, talents, or abilities instead.

Another criticism of Gardner's theory is that many of his purportedly independent domains of intelligence are in fact correlated with each other. Responding to empirical analyses showing correlations between the domains, Gardner has argued that the correlations exist because of the common format of tests and because all tests require linguistic and logical skills. His critics have in turn pointed out that not all IQ tests are administered in the paper-and-pencil format, that aside from linguistic and logical abilities, IQ test batteries contain also measures of, for example, spatial abilities, and that elementary cognitive tasks (for example, inspection time and reaction time) that do not involve linguistic or logical reasoning correlate with conventional IQ batteries, too.

Sternberg's three classes of intelligence

Robert Sternberg, working with various colleagues, has also suggested that intelligence has dimensions independent of g. He argues that there are three classes of intelligence: analytic, practical, and creative. According to Sternberg, traditional psychometric tests measure only analytic intelligence, and should be augmented to test creative and practical intelligence as well. He has devised several tests to this effect. Sternberg equates analytic intelligence with academic intelligence, and contrasts it with practical intelligence, defined as an ability to deal with ill-defined real-life problems. Tacit intelligence is an important component of practical intelligence, consisting of knowledge that is not explicitly taught but is required in many real-life situations. Assessing creativity independent of intelligence tests has traditionally proved difficult, but Sternberg and colleagues have claimed to have created valid tests of creativity, too.

The validation of Sternberg's theory requires that the three abilities tested are substantially uncorrelated and have independent predictive validity. Sternberg has conducted many experiments which he claims confirm the validity of his theory, but several researchers have disputed this conclusion. For example, in his reanalysis of a validation study of Sternberg's STAT test, Nathan Brody showed that the predictive validity of the STAT, a test of three allegedly independent abilities, was almost solely due to a single general factor underlying the tests, which Brody equated with the g factor.

Flynn's model

James Flynn has argued that intelligence should be conceptualized at three different levels: brain physiology, cognitive differences between individuals, and social trends in intelligence over time. According to this model, the g factor is a useful concept with respect to individual differences but its explanatory power is limited when the focus of investigation is either brain physiology, or, especially, the effect of social trends on intelligence. Flynn has criticized the notion that cognitive gains over time, or the Flynn effect, are "hollow" if they cannot be shown to be increases in g. He argues that the Flynn effect reflects shifting social priorities and individuals' adaptation to them. To apply the individual differences concept of g to the Flynn effect is to confuse different levels of analysis. On the other hand, according to Flynn, it is also fallacious to deny, by referring to trends in intelligence over time, that some individuals have "better brains and minds" to cope with the cognitive demands of their particular time. At the level of brain physiology, Flynn has emphasized both that localized neural clusters can be affected differently by cognitive exercise, and that there are important factors that affect all neural clusters.

"Indifference of the indicator"

Spearman proposed the principle of the indifference of the indicator, according to which the precise content of intelligence tests is unimportant for the purposes of identifying g, because g enters into performance on all kinds of tests. Any test can therefore be used as an indicator of g. Following Spearman, Arthur Jensen more recently argued that a g factor extracted from one test battery will always be the same, within the limits of measurement error, as that extracted from another battery, provided that the batteries are large and diverse. According to this view, every mental test, no matter how distinctive, calls on g to some extent. Thus a composite score of a number of different tests will load onto g more strongly than any of the individual test scores, because the g components cumulate into the composite score, while the uncorrelated non-g components will cancel each other out. Theoretically, the composite score of an infinitely large, diverse test battery would, then, be a perfect measure of g.

In contrast, L. L. Thurstone argued that a g factor extracted from a test battery reflects the average of all the abilities called for by the particular battery, and that g therefore varies from one battery to another and "has no fundamental psychological significance." Along similar lines, John Horn argued that g factors are meaningless because they are not invariant across test batteries, maintaining that correlations between different ability measures arise because it is difficult to define a human action that depends on just one ability.

To show that different batteries reflect the same g, one must administer several test batteries to the same individuals, extract g factors from each battery, and show that the factors are highly correlated. This can be done within a confirmatory factor analysis framework. Wendy Johnson and colleagues have published two such studies finding correlations between g factors extracted from different batteries between .95–1.00 for most batteries, while the correlations ranged from .79 to .96 for the Cattell Culture Fair Intelligence Test (the CFIT). They attributed the somewhat lower correlations with the CFIT battery to its lack of content diversity for it contains only matrix-type items, and interpreted the findings as supporting the contention that g factors derived from different test batteries are the same provided that the batteries are diverse enough. This approach has been criticized by psychologist Lazar Stankov in the Handbook of Understanding and Measuring Intelligence, who concluded "Correlations between the g factors from different test batteries are not unity."

A study authored by Scott Barry Kaufman and colleagues showed that the general factor extracted from the Woodjock-Johnson cognitive abilities test, and the general factor extracted from the Achievement test batteries are highly correlated, but not isomorphic.

Spearman's law of diminishing returns

A number of researchers have suggested that the proportion of variation accounted for by g may not be uniform across all subgroups within a population. Spearman's law of diminishing returns (SLODR), also termed the cognitive ability differentiation hypothesis, predicts that the positive correlations among different cognitive abilities are weaker among more intelligent subgroups of individuals. More specifically, SLODR predicts that the g factor will account for a smaller proportion of individual differences in cognitive tests scores at higher scores on the g factor.

SLODR was originally proposed in 1927 by Charles Spearman, who reported that the average correlation between 12 cognitive ability tests was .466 in 78 normal children, and .782 in 22 "defective" children. Detterman and Daniel rediscovered this phenomenon in 1989. They reported that for subtests of both the WAIS and the WISC, subtest intercorrelations decreased monotonically with ability group, ranging from approximately an average intercorrelation of .7 among individuals with IQs less than 78 to .4 among individuals with IQs greater than 122.

SLODR has been replicated in a variety of child and adult samples who have been measured using broad arrays of cognitive tests. The most common approach has been to divide individuals into multiple ability groups using an observable proxy for their general intellectual ability, and then to either compare the average interrelation among the subtests across the different groups, or to compare the proportion of variation accounted for by a single common factor, in the different groups. However, as both Deary et al. (1996) and Tucker-Drob (2009) have pointed out, dividing the continuous distribution of intelligence into an arbitrary number of discrete ability groups is less than ideal for examining SLODR. Tucker-Drob (2009) extensively reviewed the literature on SLODR and the various methods by which it had been previously tested, and proposed that SLODR could be most appropriately captured by fitting a common factor model that allows the relations between the factor and its indicators to be nonlinear in nature. He applied such a factor model to a nationally representative data of children and adults in the United States and found consistent evidence for SLODR. For example, Tucker-Drob (2009) found that a general factor accounted for approximately 75% of the variation in seven different cognitive abilities among very low IQ adults, but only accounted for approximately 30% of the variation in the abilities among very high IQ adults.

A recent meta-analytic study by Blum and Holling also provided support for the differentiation hypothesis. As opposed to most research on the topic, this work made it possible to study ability and age variables as continuous predictors of the g saturation, and not just to compare lower- vs. higher-skilled or younger vs. older groups of testees. Results demonstrate that the mean correlation and g loadings of cognitive ability tests decrease with increasing ability, yet increase with respondent age. SLODR, as described by Charles Spearman, could be confirmed by a g-saturation decrease as a function of IQ as well as a g-saturation increase from middle age to senescence. Specifically speaking, for samples with a mean intelligence that is two standard deviations (i.e., 30 IQ-points) higher, the mean correlation to be expected is decreased by approximately .15 points. The question remains whether a difference of this magnitude could result in a greater apparent factorial complexity when cognitive data are factored for the higher-ability sample, as opposed to the lower-ability sample. It seems likely that greater factor dimensionality should tend to be observed for the case of higher ability, but the magnitude of this effect (i.e., how much more likely and how many more factors) remains uncertain.

g in non-humans

Evidence of a general factor of intelligence has also been observed in non-human animals. Studies have shown that g is responsible for 47% of the variance at the species level in primates and around 55% of the individual variance observed in mice. A review and meta-analysis of general intelligence, however, found that the average correlation among cognitive abilities was 0.18 and suggested that overall support for g is weak in non-human animals.

Although it is not assessable using the same intelligence measures used in humans, cognitive ability can be measured with a variety of interactive and observational tools focusing on innovation, habit reversal, social learning, and responses to novelty. Non-human models of g such as mice are used to study genetic influences on intelligence and neurological developmental research into the mechanisms behind and biological correlates of g.

g (or c) in human groups

Similar to g for individuals, a new research path aims to extract a general collective intelligence factor c for groups displaying a group's general ability to perform a wide range of tasks. Definition, operationalization and statistical approach for this c factor are derived from and similar to g. Causes, predictive validity as well as additional parallels to g are investigated.

Biological correlates

Neuroscience

g has a number of correlates in the brain. Studies using magnetic resonance imaging (MRI) have established that g and total brain volume are moderately correlated (r~.3–.4). External head size has a correlation of ~.2 with g. MRI research on brain regions indicates that the volumes of frontal, parietal and temporal cortices, and the hippocampus are also correlated with g, generally at .25 or more, while the correlations, averaged over many studies, with overall grey matter and overall white matter have been found to be .31 and .27, respectively. Some but not all studies have also found positive correlations between g and cortical thickness. However, the underlying reasons for these associations between the quantity of brain tissue and differences in cognitive abilities remain largely unknown.

Most researchers believe that intelligence cannot be localized to a single brain region, such as the frontal lobe. Brain lesion studies have found small but consistent associations indicating that people with more white matter lesions tend to have lower cognitive ability. Research utilizing NMR spectroscopy has discovered somewhat inconsistent but generally positive correlations between intelligence and white matter integrity, supporting the notion that white matter is important for intelligence.

Some research suggests that aside from the integrity of white matter, also its organizational efficiency is related to intelligence. The hypothesis that brain efficiency has a role in intelligence is supported by functional MRI research showing that more intelligent people generally process information more efficiently, i.e., they use fewer brain resources for the same task than less intelligent people.

Small but relatively consistent associations with intelligence test scores include also brain activity, as measured by EEG records or event-related potentials, and nerve conduction velocity.

Genetic and environmental determinants

Heritability is the proportion of phenotypic variance in a trait in a population that can be attributed to genetic factors. The heritability of g has been estimated to fall between 40 and 80 percent using twin, adoption, and other family study designs as well as molecular genetic methods. Estimates based on the totality of evidence place the heritability of g at about 50%. It has been found to increase linearly with age.

As with heritability in general, the heritability of g can be understood in reference to a specific population at a specific place and time, and findings for one population do not apply to a different population that is exposed to different environmental factors. A population that is exposed to strong environmental factors can be expected to have a lower level of heritability than a population that is exposed to only weak environmental factors. For example, one twin study found that genotype differences almost completely explain the variance in IQ scores within affluent families, but make close to zero contribution towards explaining IQ score differences in impoverished families. Notably, heritability findings also only refer to total variation within a population and do not support a genetic explanation for differences between groups. It is theoretically possible for the differences between the average g of two groups to be 100% due to environmental factors even if the variance within each group is 100% heritable.

Much research points to g being a highly polygenic trait influenced by many common genetic variants, each having only small effects. Another possibility is that heritable differences in g are due to individuals having different "loads" of rare, deleterious mutations, with genetic variation among individuals persisting due to mutation–selection balance.

Group similarities and differences

Cross-cultural studies indicate that the g factor can be observed whenever a battery of diverse, complex cognitive tests is administered to a human sample. In some studies, the factor structure of IQ tests has also been found to be consistent across sexes and ethnic groups in the U.S. and elsewhere.

Most studies suggest that there are negligible differences in the mean level of g between the sexes, but that sex differences in cognitive abilities are to be found in more narrow domains. For example, males generally outperform females in spatial tasks, while females generally outperform males in verbal tasks. Another difference that has been found in many studies is that males show more variability in both general and specific abilities than females, with proportionately more males at both the low end and the high end of the test score distribution.

Differences in g between racial and ethnic groups have been found, particularly in the U.S. between black- and white-identifying test takers, though these differences appear to have diminished significantly over time, and to be attributable to environmental (rather than genetic) causes. Some researchers have suggested that the magnitude of the black-white gap in cognitive test results is dependent on the magnitude of the test's g loading, with tests showing higher g loading producing larger gaps (see Spearman's hypothesis), while others have criticized this view as methodologically unfounded. Still others have noted that despite the increasing g loading of IQ test batteries over time, the performance gap between racial groups continues to diminish. Comparative analysis has shown that while a gap of approximately 1.1 standard deviation in mean IQ (around 16 points) between white and black Americans existed in the late 1960s, between 1972 and 2002 black Americans gained between 4 and 7 IQ points relative to non-Hispanic Whites, and that "the g gap between Blacks and Whites declined virtually in tandem with the IQ gap." In contrast, Americans of East Asian descent generally slightly outscore white Americans. It has been claimed that racial and ethnic differences similar to those found in the U.S. can be observed globally, but the significance, methodological grounding, and truth of such claims have all been disputed.

Relation to other psychological constructs

Elementary cognitive tasks

An illustration of the Jensen box, an apparatus for measuring choice reaction time

Elementary cognitive tasks (ECTs) also correlate strongly with g. ECTs are, as the name suggests, simple tasks that apparently require very little intelligence, but still correlate strongly with more exhaustive intelligence tests. Determining whether a light is red or blue and determining whether there are four or five squares drawn on a computer screen are two examples of ECTs. The answers to such questions are usually provided by quickly pressing buttons. Often, in addition to buttons for the two options provided, a third button is held down from the start of the test. When the stimulus is given to the subject, they remove their hand from the starting button to the button of the correct answer. This allows the examiner to determine how much time was spent thinking about the answer to the question (reaction time, usually measured in small fractions of second), and how much time was spent on physical hand movement to the correct button (movement time). Reaction time correlates strongly with g, while movement time correlates less strongly. ECT testing has allowed quantitative examination of hypotheses concerning test bias, subject motivation, and group differences. By virtue of their simplicity, ECTs provide a link between classical IQ testing and biological inquiries such as fMRI studies.

Working memory

One theory holds that g is identical or nearly identical to working memory capacity. Among other evidence for this view, some studies have found factors representing g and working memory to be perfectly correlated. However, in a meta-analysis the correlation was found to be considerably lower. One criticism that has been made of studies that identify g with working memory is that "we do not advance understanding by showing that one mysterious concept is linked to another."

Piagetian tasks

Psychometric theories of intelligence aim at quantifying intellectual growth and identifying ability differences between individuals and groups. In contrast, Jean Piaget's theory of cognitive development seeks to understand qualitative changes in children's intellectual development. Piaget designed a number of tasks to verify hypotheses arising from his theory. The tasks were not intended to measure individual differences, and they have no equivalent in psychometric intelligence tests. For example, in one of the best-known Piagetian conservation tasks a child is asked if the amount of water in two identical glasses is the same. After the child agrees that the amount is the same, the investigator pours the water from one of the glasses into a glass of different shape so that the amount appears different although it remains the same. The child is then asked if the amount of water in the two glasses is the same or different.

Notwithstanding the different research traditions in which psychometric tests and Piagetian tasks were developed, the correlations between the two types of measures have been found to be consistently positive and generally moderate in magnitude. A common general factor underlies them. It has been shown that it is possible to construct a battery consisting of Piagetian tasks that is as good a measure of g as standard IQ tests.

Personality

The traditional view in psychology is that there is no meaningful relationship between personality and intelligence, and that the two should be studied separately. Intelligence can be understood in terms of what an individual can do, or what his or her maximal performance is, while personality can be thought of in terms of what an individual will typically do, or what his or her general tendencies of behavior are. Large-scale meta-analyses have found that there are hundreds of connections >.20 in magnitude between cognitive abilities and personality traits across the Big Five. This is despite the fact that correlations with the global Big Five factors themselves being small, except for Openness (.26). More interesting relations emerge at other levels (e.g., .23 for the activity facet of extraversion with general mental ability, -.29 for the uneven-tempered facet of neuroticism, .32 for the industriousness aspect of conscientiousness, .26 for the compassion aspect of agreeableness).

The associations between intelligence and personality have generally been interpreted in two main ways. The first perspective is that personality traits influence performance on intelligence tests. For example, a person may fail to perform at a maximal level on an IQ test due to his or her anxiety and stress-proneness. The second perspective considers intelligence and personality to be conceptually related, with personality traits determining how people apply and invest their cognitive abilities, leading to knowledge expansion and greater cognitive differentiation. Other theories (e.g., Cybernetic Trait Complexes Theory) view personality and cognitive ability as intertwined parameters of individuals that co-evolved and are also co-influenced during development (e.g., by early life starvation).

Creativity

Some researchers believe that there is a threshold level of g below which socially significant creativity is rare, but that otherwise there is no relationship between the two. It has been suggested that this threshold is at least one standard deviation above the population mean. Above the threshold, personality differences are believed to be important determinants of individual variation in creativity.

Others have challenged the threshold theory. While not disputing that opportunity and personal attributes other than intelligence, such as energy and commitment, are important for creativity, they argue that g is positively associated with creativity even at the high end of the ability distribution. The longitudinal Study of Mathematically Precocious Youth has provided evidence for this contention. It has shown that individuals identified by standardized tests as intellectually gifted in early adolescence accomplish creative achievements (for example, securing patents or publishing literary or scientific works) at several times the rate of the general population, and that even within the top 1 percent of cognitive ability, those with higher ability are more likely to make outstanding achievements. The study has also suggested that the level of g acts as a predictor of the level of achievement, while specific cognitive ability patterns predict the realm of achievement.

Criticism

Connection with eugenics and racialism

Research on the G-factor, as well as other psychometric values, has been widely criticized for not properly taking into account the eugenicist background of its research practices. The reductionism of the G-factor has been attributed to having evolved from pseudoscientific theories about race and intelligence. Spearman's g and the concept of inherited, immutable intelligence were a boon for eugenicists and pseudoscientists alike.

Joseph L. Graves Jr. and Amanda Johnson have argued that g "...is to the psychometricians what Huygens' ether was to early physicists: a nonentity taken as an article of faith instead of one in need of verification by real data."

Some scientists have described the g factor, and psychometrics, as forms of pseudoscience.

Conceptual critiques

Paleontologist and biologist Stephen Jay Gould presented a critique in his 1981 book The Mismeasure of Man. He argued that psychometricians fallaciously reified the g factor into an ineluctable "thing" that provided a convenient explanation for human intelligence, grounded only in mathematical theory rather than the rigorous application of mathematical theory to biological knowledge. An example is provided in the work of Cyril Burt, published posthumously in 1972: "The two main conclusions we have reached seem clear and beyond all question. The hypothesis of a general factor entering into every type of cognitive process, tentatively suggested by speculations derived from neurology and biology, is fully borne out by the statistical evidence; and the contention that differences in this general factor depend largely on the individual's genetic constitution appears incontestable.The concept of an innate, general cognitive ability, which follows from these two assumptions, though admittedly sheerly an abstraction, is thus wholly consistent with the empirical facts."

Several researchers have criticized Gould's arguments. For example, they have rejected the accusation of reification, maintaining that the use of extracted factors such as g as potential causal variables whose reality can be supported or rejected by further investigations constitutes a normal scientific practice that in no way distinguishes psychometrics from other sciences. Critics have also suggested that Gould did not understand the purpose of factor analysis, and that he was ignorant of relevant methodological advances in the field. While different factor solutions may be mathematically equivalent in their ability to account for intercorrelations among tests, solutions that yield a g factor are psychologically preferable for several reasons extrinsic to factor analysis, including the phenomenon of the positive manifold, the fact that the same g can emerge from quite different test batteries, the widespread practical validity of g, and the linkage of g to many biological variables.

There is also debate over whether g is consistent with evolutionary psychology, since the body of research in evolutionary psychology has instead established that the evolution of human intelligence shows clearer evidence for massive modularity of mind rather than a single psychological trait that facilitates content-independent domain-general learning and general-purpose reasoning. John Tooby and Leda Cosmides have consistently noted that the frame problem and combinatorial explosion in artificial intelligence would preclude a psychological trait for general-purpose problem solving and domain-general learning from being computationally capable of performing cognitive tasks necessary for survival and reproduction in an environment of evolutionary adaptedness, and that such a trait would be unlikely to evolve since adaptations require selection pressure from recurrent problems (which lead instead to a suite of cognitive modules that serve domain-specific functions and enable domain-specific learning). While acknowledging the consensus within psychometrics and differential psychology about the g factor, Steven Pinker has also argued against the construct validity of general intelligence and in favor of modularity of mind as proposed by Tooby and Cosmides and reiterated skepticism about the theoretical coherence of g when discussing artificial general intelligence.

Other critiques of g

John Horn and John McArdle have argued that the modern g theory, as espoused by, for example, Arthur Jensen, is unfalsifiable, because the existence of a common factor like g follows tautologically from positive correlations among tests. They contrasted the modern hierarchical theory of g with Spearman's original two-factor theory which was readily falsifiable (and indeed was falsified).

Enzyme

From Wikipedia, the free encyclopedia
https://en.wikipedia.org/wiki/Enzyme
Ribbon diagram of glycosidase with an arrow showing the cleavage of the maltose sugar substrate into two glucose products.
The enzyme glucosidase converts the sugar maltose into two glucose sugars. Active site residues in red, maltose substrate in black, and NAD cofactor in yellow. (PDB: 1OBB​)

An enzyme is a biological macromolecule, usually a protein, that acts as a biological catalyst, accelerating chemical reactions without being consumed in the process. The molecules on which enzymes act are called substrates, which are converted into products. Nearly all metabolic processes within a cell depend on enzyme catalysis to occur at biologically relevant rates. Metabolic pathways are typically composed of a series of enzyme-catalyzed steps. The study of enzymes is known as enzymology, and a related field focuses on pseudoenzymes—proteins that have lost catalytic activity but may retain regulatory or scaffolding functions, often indicated by alterations in their amino acid sequences or unusual 'pseudocatalytic' behavior.

Enzymes are known to catalyze over 5,000 types of biochemical reactions. Other biological catalysts include catalytic RNA molecules, or ribozymes, which are sometimes classified as enzymes despite being composed of RNA rather than protein. More recently, biomolecular condensates have been recognized as a third category of biocatalysts, capable of catalyzing reactions by creating interfaces and gradients—such as ionic gradients—that drive biochemical processes, even when their component proteins are not intrinsically catalytic.

Enzymes increase the reaction rate by lowering a reaction's activation energy, often by factors of millions. A striking example is orotidine 5'-phosphate decarboxylase, which accelerates a reaction that would otherwise take millions of years to occur in milliseconds. Like all catalysts, enzymes do not affect the overall equilibrium of a reaction and are regenerated at the end of each cycle. What distinguishes them is their high specificity, determined by their unique three-dimensional structure, and their sensitivity to factors such as temperature and pH. Enzyme activity can be enhanced by activators or diminished by inhibitors, many of which serve as drugs or poisons. Outside optimal conditions, enzymes may lose their structure through denaturation, leading to loss of function.

Enzymes have widespread practical applications. In industry, they are used to catalyze the production of antibiotics and other complex molecules. In everyday life, enzymes in biological washing powders break down protein, starch, and fat stains, enhancing cleaning performance. Papain and other proteolytic enzymes are used in meat tenderizers to hydrolyze proteins, improving texture and digestibility. Their specificity and efficiency make enzymes indispensable in both biological systems and commercial processes.

IUPAC definition for enzymes

Etymology and history

By the late 17th and early 18th centuries, the digestion of meat by stomach secretions and the conversion of starch to sugars by plant extracts and saliva were known but the mechanisms by which these occurred had not been identified.

French chemist Anselme Payen was the first to discover an enzyme, diastase, in 1833. A few decades later, when studying the fermentation of sugar to alcohol by yeast, Louis Pasteur concluded that this fermentation was caused by a vital force contained within the yeast cells called "ferments", which were thought to function only within living organisms. He wrote that "alcoholic fermentation is an act correlated with the life and organization of the yeast cells, not with the death or putrefaction of the cells."

In 1877, German physiologist Wilhelm Kühne (1837–1900) first used the term enzyme, which comes from Ancient Greek ἔνζυμον (énzymon) 'leavened, in yeast', to describe this process. The word enzyme was used later to refer to nonliving substances such as pepsin, and the word ferment was used to refer to chemical activity produced by living organisms.

Photograph of Eduard Buchner.
Eduard Buchner

Eduard Buchner submitted his first paper on the study of yeast extracts in 1897. In a series of experiments at the University of Berlin, he found that sugar was fermented by yeast extracts even when there were no living yeast cells in the mixture. He named the enzyme that brought about the fermentation of sucrose "zymase". In 1907, he received the Nobel Prize in Chemistry for "his discovery of cell-free fermentation". Following Buchner's example, enzymes are usually named according to the reaction they carry out: the suffix -ase is combined with the name of the substrate (e.g., lactase is the enzyme that cleaves lactose) or to the type of reaction (e.g., DNA polymerase forms DNA polymers).

The biochemical identity of enzymes was still unknown in the early 1900s. Many scientists observed that enzymatic activity was associated with proteins, but others (such as Nobel laureate Richard Willstätter) argued that proteins were merely carriers for the true enzymes and that proteins per se were incapable of catalysis. In 1926, James B. Sumner showed that the enzyme urease was a pure protein and crystallized it; he did likewise for the enzyme catalase in 1937. The conclusion that pure proteins can be enzymes was definitively demonstrated by John Howard Northrop and Wendell Meredith Stanley, who worked on the digestive enzymes pepsin (1930), trypsin and chymotrypsin. These three scientists were awarded the 1946 Nobel Prize in Chemistry.

The discovery that enzymes could be crystallized eventually allowed their structures to be solved by x-ray crystallography. This was first done for lysozyme, an enzyme found in tears, saliva and egg whites that digests the coating of some bacteria; the structure was solved by a group led by David Chilton Phillips and published in 1965. This high-resolution structure of lysozyme marked the beginning of the field of structural biology and the effort to understand how enzymes work at an atomic level of detail.

Classification and nomenclature

Enzymes can be classified by two main criteria: either amino acid sequence similarity (and thus evolutionary relationship) or enzymatic activity.

Enzyme activity. An enzyme's name is often derived from its substrate or the chemical reaction it catalyzes, with the word ending in -ase. Examples are lactase, alcohol dehydrogenase and DNA polymerase. Different enzymes that catalyze the same chemical reaction are called isozymes.

The International Union of Biochemistry and Molecular Biology have developed a nomenclature for enzymes, the EC numbers (for "Enzyme Commission"). Each enzyme is described by "EC" followed by a sequence of four numbers which represent the hierarchy of enzymatic activity (from very general to very specific). That is, the first number broadly classifies the enzyme based on its mechanism while the other digits add more and more specificity.

The top-level classification is:

These sections are subdivided by other features such as the substrate, products, and chemical mechanism. An enzyme is fully specified by four numerical designations. For example, hexokinase (EC 2.7.1.1) is a transferase (EC 2) that adds a phosphate group (EC 2.7) to a hexose sugar, a molecule containing an alcohol group (EC 2.7.1).[22]

Sequence similarity. EC categories do not reflect sequence similarity. For instance, two ligases of the same EC number that catalyze exactly the same reaction can have completely different sequences. Independent of their function, enzymes, like any other proteins, have been classified by their sequence similarity into numerous families. These families have been documented in dozens of different protein and protein family databases such as Pfam.

Non-homologous isofunctional enzymes. Unrelated enzymes that have the same enzymatic activity have been called non-homologous isofunctional enzymesHorizontal gene transfer may spread these genes to unrelated species, especially bacteria where they can replace endogenous genes of the same function, leading to hon-homologous gene displacement.

Structure

A graph showing that reaction rate increases exponentially with temperature until denaturation causes it to decrease again.
Enzyme activity initially increases with temperature (Q10 coefficient) until the enzyme's structure unfolds (denaturation), leading to an optimal rate of reaction at an intermediate temperature.

Enzymes are generally globular proteins, acting alone or in larger complexes. The sequence of the amino acids specifies the structure which in turn determines the catalytic activity of the enzyme. Although structure determines function, a novel enzymatic activity cannot yet be predicted from structure alone. Enzyme structures unfold (denature) when heated or exposed to chemical denaturants and this disruption to the structure typically causes a loss of activity. Enzyme denaturation is normally linked to temperatures above a species' normal level; as a result, enzymes from bacteria living in volcanic environments such as hot springs are prized by industrial users for their ability to function at high temperatures, allowing enzyme-catalysed reactions to be operated at a very high rate.

Enzymes are usually much larger than their substrates. Sizes range from just 62 amino acid residues, for the monomer of 4-oxalocrotonate tautomerase, to over 2,500 residues in the animal fatty acid synthase. Only a small portion of their structure (around 2–4 amino acids) is directly involved in catalysis: the catalytic site. This catalytic site is located next to one or more binding sites where residues orient the substrates. The catalytic site and binding site together compose the enzyme's active site. The remaining majority of the enzyme structure serves to maintain the precise orientation and dynamics of the active site.

In some enzymes, no amino acids are directly involved in catalysis; instead, the enzyme contains sites to bind and orient catalytic cofactors.[31] Enzyme structures may also contain allosteric sites where the binding of a small molecule causes a conformational change that increases or decreases activity.

A small number of RNA-based biological catalysts called ribozymes exist, which again can act alone or in complex with proteins. The most common of these is the ribosome which is a complex of protein and catalytic RNA components.

Mechanism

Lysozyme displayed as an opaque globular surface with a pronounced cleft which the substrate depicted as a stick diagram snuggly fits into.
Organisation of enzyme structure and lysozyme example. Binding sites in blue, catalytic site in red and peptidoglycan substrate in black. (PDB: 9LYZ​)

Substrate binding

Enzymes must bind their substrates before they can catalyse any chemical reaction. Enzymes are usually very specific as to what substrates they bind and then the chemical reaction catalysed. Specificity is achieved by binding pockets with complementary shape, charge and hydrophilic/hydrophobic characteristics to the substrates. Enzymes can therefore distinguish between very similar substrate molecules to be chemoselective, regioselective and stereospecific.

Some of the enzymes showing the highest specificity and accuracy are involved in the copying and expression of the genome. Some of these enzymes have "proof-reading" mechanisms. Here, an enzyme such as DNA polymerase catalyzes a reaction in a first step and then checks that the product is correct in a second step. This two-step process results in average error rates of less than 1 error in 100 million reactions in high-fidelity mammalian polymerases. Similar proofreading mechanisms are also found in RNA polymeraseaminoacyl tRNA synthetases and ribosomes.

Conversely, some enzymes display enzyme promiscuity, having broad specificity and acting on a range of different physiologically relevant substrates. Many enzymes possess small side activities which arose fortuitously (i.e. neutrally), which may be the starting point for the evolutionary selection of a new function.

Hexokinase displayed as an opaque surface with a pronounced open binding cleft next to unbound substrate (top) and the same enzyme with more closed cleft that surrounds the bound substrate (bottom)
Enzyme changes shape by induced fit upon substrate binding to form enzyme-substrate complex. Hexokinase has a large induced fit motion that closes over the substrates adenosine triphosphate and xylose. Binding sites in blue, substrates in black and Mg2+ cofactor in yellow. (PDB: 2E2N​, 2E2Q​)

"Lock and key" model

To explain the observed specificity of enzymes, in 1894 Emil Fischer proposed that both the enzyme and the substrate possess specific complementary geometric shapes that fit exactly into one another. This is often referred to as "the lock and key" model. This early model explains enzyme specificity, but fails to explain the stabilization of the transition state that enzymes achieve.

Induced fit model

In 1958, Daniel Koshland suggested a modification to the lock and key model: since enzymes are rather flexible structures, the active site is continuously reshaped by interactions with the substrate as the substrate interacts with the enzyme. As a result, the substrate does not simply bind to a rigid active site; the amino acid side-chains that make up the active site are molded into the precise positions that enable the enzyme to perform its catalytic function. In some cases, such as glycosidases, the substrate molecule also changes shape slightly as it enters the active site. The active site continues to change until the substrate is completely bound, at which point the final shape and charge distribution is determined. Induced fit may enhance the fidelity of molecular recognition in the presence of competition and noise via the conformational proofreading mechanism.

Catalysis

Enzymes can accelerate reactions in several ways, all of which lower the activation energy (ΔG, Gibbs free energy)

  1. By stabilizing the transition state:
    • Creating an environment with a charge distribution complementary to that of the transition state to lower its energy
  2. By providing an alternative reaction pathway:
    • Temporarily reacting with the substrate, forming a covalent intermediate to provide a lower energy transition state
  3. By destabilizing the substrate ground state:
    • Distorting bound substrate(s) into their transition state form to reduce the energy required to reach the transition state
    • By orienting the substrates into a productive arrangement to reduce the reaction entropy change (the contribution of this mechanism to catalysis is relatively small)

Enzymes may use several of these mechanisms simultaneously. For example, proteases such as trypsin perform covalent catalysis using a catalytic triad, stabilize charge build-up on the transition states using an oxyanion hole, complete hydrolysis using an oriented water substrate.

Dynamics

Enzymes are not rigid, static structures; instead they have complex internal dynamic motions – that is, movements of parts of the enzyme's structure such as individual amino acid residues, groups of residues forming a protein loop or unit of secondary structure, or even an entire protein domain. These motions give rise to a conformational ensemble of slightly different structures that interconvert with one another at equilibrium. Different states within this ensemble may be associated with different aspects of an enzyme's function. For example, different conformations of the enzyme dihydrofolate reductase are associated with the substrate binding, catalysis, cofactor release, and product release steps of the catalytic cycle, consistent with catalytic resonance theory. The transitions between the different conformations during the catalytic cycle involve internal viscoelastic motion that is facilitated by high-strain regions where amino acids are rearranged.

Substrate presentation

Substrate presentation is a process where the enzyme is sequestered away from its substrate. Enzymes can be sequestered to the plasma membrane away from a substrate in the nucleus or cytosol.[55] Or within the membrane, an enzyme can be sequestered into lipid rafts away from its substrate in the disordered region. When the enzyme is released it mixes with its substrate. Alternatively, the enzyme can be sequestered near its substrate to activate the enzyme. For example, the enzyme can be soluble and upon activation bind to a lipid in the plasma membrane and then act upon molecules in the plasma membrane.

Allosteric modulation

Allosteric sites are pockets on the enzyme, distinct from the active site, that bind to molecules in the cellular environment. These molecules then cause a change in the conformation or dynamics of the enzyme that is transduced to the active site and thus affects the reaction rate of the enzyme. In this way, allosteric interactions can either inhibit or activate enzymes. Allosteric interactions with metabolites upstream or downstream in an enzyme's metabolic pathway cause feedback regulation, altering the activity of the enzyme according to the flux through the rest of the pathway.

Cofactors

Thiamine pyrophosphate displayed as an opaque globular surface with an open binding cleft where the substrate and cofactor both depicted as stick diagrams fit into.
Chemical structure for thiamine pyrophosphate and protein structure of transketolase. Thiamine pyrophosphate cofactor in yellow and xylulose 5-phosphate substrate in black. (PDB: 4KXV​)

Some enzymes do not need additional components to show full activity. Others require non-protein molecules called cofactors to be bound for activity. Cofactors can be either inorganic (e.g., metal ions and iron–sulfur clusters) or organic compounds (e.g., flavin and heme). These cofactors serve many purposes; for instance, metal ions can help in stabilizing nucleophilic species within the active site. Organic cofactors can be either coenzymes, which are released from the enzyme's active site during the reaction, or prosthetic groups, which are tightly bound to an enzyme. Organic prosthetic groups can be covalently bound (e.g., biotin in enzymes such as pyruvate carboxylase).

An example of an enzyme that contains a cofactor is carbonic anhydrase, which uses a zinc cofactor bound as part of its active site. These tightly bound ions or molecules are usually found in the active site and are involved in catalysis. For example, flavin and heme cofactors are often involved in redox reactions.

Enzymes that require a cofactor but do not have one bound are called apoenzymes or apoproteins. An enzyme together with the cofactor(s) required for activity is called a holoenzyme (or haloenzyme). The term holoenzyme can also be applied to enzymes that contain multiple protein subunits, such as the DNA polymerases; here the holoenzyme is the complete complex containing all the subunits needed for activity.

Coenzymes

Coenzymes are small organic molecules that can be loosely or tightly bound to an enzyme. Coenzymes transport chemical groups from one enzyme to another. Examples include NADH, NADPH and adenosine triphosphate (ATP). Some coenzymes, such as flavin mononucleotide (FMN), flavin adenine dinucleotide (FAD), thiamine pyrophosphate (TPP), and tetrahydrofolate (THF), are derived from vitamins. These coenzymes cannot be synthesized by the body de novo and closely related compounds (vitamins) must be acquired from the diet. The chemical groups carried include:

Since coenzymes are chemically changed as a consequence of enzyme action, it is useful to consider coenzymes to be a special class of substrates, or second substrates, which are common to many different enzymes. For example, about 1000 enzymes are known to use the coenzyme NADH.

Coenzymes are usually continuously regenerated and their concentrations maintained at a steady level inside the cell. For example, NADPH is regenerated through the pentose phosphate pathway and S-adenosylmethionine by methionine adenosyltransferase. This continuous regeneration means that small amounts of coenzymes can be used very intensively. For example, the human body turns over its own weight in ATP each day.

Thermodynamics

A two dimensional plot of reaction coordinate (x-axis) vs. energy (y-axis) for catalyzed and uncatalyzed reactions. The energy of the system steadily increases from reactants (x = 0) until a maximum is reached at the transition state (x = 0.5), and steadily decreases to the products (x = 1). However, in an enzyme catalysed reaction, binding generates an enzyme-substrate complex (with slightly reduced energy) then increases up to a transition state with a smaller maximum than the uncatalysed reaction.
The energies of the stages of a chemical reaction. Uncatalysed (dashed line), substrates need a lot of activation energy to reach a transition state, which then decays into lower-energy products. When enzyme catalysed (solid line), the enzyme binds the substrates (ES), then stabilizes the transition state (ES) to reduce the activation energy required to produce products (EP) which are finally released.

As with all catalysts, enzymes do not alter the position of the chemical equilibrium of the reaction. In the presence of an enzyme, the reaction runs in the same direction as it would without the enzyme, just more quickly. For example, carbonic anhydrase catalyzes its reaction in either direction depending on the concentration of its reactants:

The rate of a reaction is dependent on the activation energy needed to form the transition state which then decays into products. Enzymes increase reaction rates by lowering the energy of the transition state. First, binding forms a low energy enzyme-substrate complex (ES). Second, the enzyme stabilises the transition state such that it requires less energy to achieve compared to the uncatalyzed reaction (ES). Finally the enzyme-product complex (EP) dissociates to release the products.

Enzymes can couple two or more reactions, so that a thermodynamically favorable reaction can be used to "drive" a thermodynamically unfavourable one so that the combined energy of the products is lower than the substrates. For example, the hydrolysis of ATP is often used to drive other chemical reactions.

Kinetics

Schematic reaction diagrams for uncatalzyed (Substrate to Product) and catalyzed (Enzyme + Substrate to Enzyme/Substrate complex to Enzyme + Product)
A chemical reaction mechanism with or without enzyme catalysis. The enzyme (E) binds substrate (S) to produce product (P).
 
A two dimensional plot of substrate concentration (x axis) vs. reaction rate (y axis). The shape of the curve is hyperbolic. The rate of the reaction is zero at zero concentration of substrate and the rate asymptotically reaches a maximum at high substrate concentration.
Saturation curve for an enzyme reaction showing the relation between the substrate concentration and reaction rate.
 

Enzyme kinetics is the investigation of how enzymes bind substrates and turn them into products. The rate data used in kinetic analyses are commonly obtained from enzyme assays. In 1913 Leonor Michaelis and Maud Leonora Menten proposed a quantitative theory of enzyme kinetics, which is referred to as Michaelis–Menten kinetics. The major contribution of Michaelis and Menten was to think of enzyme reactions in two stages. In the first, the substrate binds reversibly to the enzyme, forming the enzyme-substrate complex. This is sometimes called the Michaelis–Menten complex in their honor. The enzyme then catalyzes the chemical step in the reaction and releases the product. This work was further developed by G. E. Briggs and J. B. S. Haldane, who derived kinetic equations that are still widely used today.

Enzyme rates depend on solution conditions and substrate concentration. To find the maximum speed of an enzymatic reaction, the substrate concentration is increased until a constant rate of product formation is seen. This is shown in the saturation curve on the right. Saturation happens because, as substrate concentration increases, more and more of the free enzyme is converted into the substrate-bound ES complex. At the maximum reaction rate (Vmax) of the enzyme, all the enzyme active sites are bound to substrate, and the amount of ES complex is the same as the total amount of enzyme.

Vmax is only one of several important kinetic parameters. The amount of substrate needed to achieve a given rate of reaction is also important. This is given by the Michaelis–Menten constant (Km), which is the substrate concentration required for an enzyme to reach one-half its maximum reaction rate; generally, each enzyme has a characteristic KM for a given substrate. Another useful constant is kcat, also called the turnover number, which is the number of substrate molecules handled by one active site per second.

The efficiency of an enzyme can be expressed in terms of kcat/Km. This is also called the specificity constant and incorporates the rate constants for all steps in the reaction up to and including the first irreversible step. Because the specificity constant reflects both affinity and catalytic ability, it is useful for comparing different enzymes against each other, or the same enzyme with different substrates. The theoretical maximum for the specificity constant is called the diffusion limit and is about 108 to 109 (M−1 s−1). At this point every collision of the enzyme with its substrate will result in catalysis, and the rate of product formation is not limited by the reaction rate but by the diffusion rate. Enzymes with this property are called catalytically perfect or kinetically perfect. Example of such enzymes are triose-phosphate isomerase, carbonic anhydrase, acetylcholinesterase, catalase, fumarase, β-lactamase, and superoxide dismutase. The turnover of such enzymes can reach several million reactions per second. But most enzymes are far from perfect: the average values of and are about and , respectively.

Michaelis–Menten kinetics relies on the law of mass action, which is derived from the assumptions of free diffusion and thermodynamically driven random collision. Many biochemical or cellular processes deviate significantly from these conditions, because of macromolecular crowding and constrained molecular movement. More recent, complex extensions of the model attempt to correct for these effects.

Inhibition

Two dimensional representations of the chemical structure of folic acid and methotrexate highlighting the differences between these two substances (amidation of pyrimidone and methylation of secondary amine).
The coenzyme folic acid (left) and the anti-cancer drug methotrexate (right) are very similar in structure (differences show in green). As a result, methotrexate is a competitive inhibitor of many enzymes that use folates.

Enzyme reaction rates can be decreased by various types of enzyme inhibitors.

Types of inhibition

Competitive

A competitive inhibitor and substrate cannot bind to the enzyme at the same time. Often competitive inhibitors strongly resemble the real substrate of the enzyme. For example, the drug methotrexate is a competitive inhibitor of the enzyme dihydrofolate reductase, which catalyzes the reduction of dihydrofolate to tetrahydrofolate. The similarity between the structures of dihydrofolate and this drug are shown in the accompanying figure. This type of inhibition can be overcome with high substrate concentration. In some cases, the inhibitor can bind to a site other than the binding-site of the usual substrate and exert an allosteric effect to change the shape of the usual binding-site.

Non-competitive

A non-competitive inhibitor binds to a site other than where the substrate binds. The substrate still binds with its usual affinity and hence Km remains the same. However the inhibitor reduces the catalytic efficiency of the enzyme so that Vmax is reduced. In contrast to competitive inhibition, non-competitive inhibition cannot be overcome with high substrate concentration.

Uncompetitive

An uncompetitive inhibitor cannot bind to the free enzyme, only to the enzyme-substrate complex; hence, these types of inhibitors are most effective at high substrate concentration. In the presence of the inhibitor, the enzyme-substrate complex is inactive. This type of inhibition is rare.

Mixed

A mixed inhibitor binds to an allosteric site and the binding of the substrate and the inhibitor affect each other. The enzyme's function is reduced but not eliminated when bound to the inhibitor. This type of inhibitor does not follow the Michaelis–Menten equation.

Irreversible

An irreversible inhibitor permanently inactivates the enzyme, usually by forming a covalent bond to the protein. Penicillin and aspirin are common drugs that act in this manner.

Functions of inhibitors

In many organisms, inhibitors may act as part of a feedback mechanism. If an enzyme produces too much of one substance in the organism, that substance may act as an inhibitor for the enzyme at the beginning of the pathway that produces it, causing production of the substance to slow down or stop when there is sufficient amount. This is a form of negative feedback. Major metabolic pathways such as the citric acid cycle make use of this mechanism.

Since inhibitors modulate the function of enzymes they are often used as drugs. Many such drugs are reversible competitive inhibitors that resemble the enzyme's native substrate, similar to methotrexate above; other well-known examples include statins used to treat high cholesterol, and protease inhibitors used to treat retroviral infections such as HIV. A common example of an irreversible inhibitor that is used as a drug is aspirin, which inhibits the COX-1 and COX-2 enzymes that produce the inflammation messenger prostaglandin. Other enzyme inhibitors are poisons. For example, the poison cyanide is an irreversible enzyme inhibitor that combines with the copper and iron in the active site of the enzyme cytochrome c oxidase and blocks cellular respiration.

Factors affecting enzyme activity

As enzymes are made up of proteins, their actions are sensitive to change in many physio chemical factors such as pH, temperature, substrate concentration, etc.

The following table shows pH optima for various enzymes.


Enzyme Optimum pH pH description
Pepsin 1.5–1.6 Highly acidic
Invertase 4.5 Acidic
Lipase (stomach) 4.0–5.0 Acidic
Lipase (castor oil) 4.7 Acidic
Lipase (pancreas) 8.0 Alkaline
Amylase (malt) 4.6–5.2 Acidic
Amylase (pancreas) 6.7–7.0 Acidic-neutral
Cellobiase 5.0 Acidic
Maltase 6.1–6.8 Acidic
Sucrase 6.2 Acidic
Catalase 7.0 Neutral
Urease 7.0 Neutral
Cholinesterase 7.0 Neutral
Ribonuclease 7.0–7.5 Neutral
Fumarase 7.8 Alkaline
Trypsin 7.8–8.7 Alkaline
Adenosine triphosphate 9.0 Alkaline
Arginase 10.0 Highly alkaline

Biological function

Enzymes serve a wide variety of functions inside living organisms. They are indispensable for signal transduction and cell regulation, often via kinases and phosphatases. They also generate movement, with myosin hydrolyzing adenosine triphosphate (ATP) to generate muscle contraction, and also transport cargo around the cell as part of the cytoskeleton. Other ATPases in the cell membrane are ion pumps involved in active transport. Enzymes are also involved in more exotic functions, such as luciferase generating light in firefliesViruses can also contain enzymes for infecting cells, such as the HIV integrase and reverse transcriptase, or for viral release from cells, like the influenza virus neuraminidase.

An important function of enzymes is in the digestive systems of animals. Enzymes such as amylases and proteases break down large molecules (starch or proteins, respectively) into smaller ones, so they can be absorbed by the intestines. Starch molecules, for example, are too large to be absorbed from the intestine, but enzymes hydrolyze the starch chains into smaller molecules such as maltose and eventually glucose, which can then be absorbed. Different enzymes digest different food substances. In ruminants, which have herbivorous diets, microorganisms in the gut produce another enzyme, cellulase, to break down the cellulose cell walls of plant fiber.

Metabolism

Schematic diagram of the glycolytic metabolic pathway starting with glucose and ending with pyruvate via several intermediate chemicals. Each step in the pathway is catalyzed by a unique enzyme.
The metabolic pathway of glycolysis releases energy by converting glucose to pyruvate via a series of intermediate metabolites. Each chemical modification (red box) is performed by a different enzyme.

Several enzymes can work together in a specific order, creating metabolic pathways. In a metabolic pathway, one enzyme takes the product of another enzyme as a substrate. After the catalytic reaction, the product is then passed on to another enzyme. Sometimes more than one enzyme can catalyze the same reaction in parallel; this can allow more complex regulation: with, for example, a low constant activity provided by one enzyme but an inducible high activity from a second enzyme.

Enzymes determine what steps occur in these pathways. Without enzymes, metabolism would neither progress through the same steps and could not be regulated to serve the needs of the cell. Most central metabolic pathways are regulated at a few steps, typically through enzymes whose activity involves the phosphorylation by ATP. Because this reaction releases so much energy, other reactions that are thermodynamically unfavorable can be coupled to ATP hydrolysis, driving the overall series of linked metabolic reactions.

Control of activity

There are five main ways that enzyme activity is controlled in the cell.

Regulation

Enzymes can be either activated or inhibited by other molecules. For example, the end product(s) of a metabolic pathway are often inhibitors for one of the first enzymes of the pathway (usually the first irreversible step, called committed step), thus regulating the amount of end product made by the pathways. Such a regulatory mechanism is called a negative feedback mechanism, because the amount of the end product produced is regulated by its own concentration. Negative feedback mechanism can effectively adjust the rate of synthesis of intermediate metabolites according to the demands of the cells. This helps with effective allocations of materials and energy economy, and it prevents the excess manufacture of end products. Like other homeostatic devices, the control of enzymatic action helps to maintain a stable internal environment in living organisms.

Post-translational modification

Examples of post-translational modification include phosphorylation, myristoylation and glycosylation. For example, in the response to insulin, the phosphorylation of multiple enzymes, including glycogen synthase, helps control the synthesis or degradation of glycogen and allows the cell to respond to changes in blood sugar. Another example of post-translational modification is the cleavage of the polypeptide chain. Chymotrypsin, a digestive protease, is produced in inactive form as chymotrypsinogen in the pancreas and transported in this form to the stomach where it is activated. This stops the enzyme from digesting the pancreas or other tissues before it enters the gut. This type of inactive precursor to an enzyme is known as a zymogen or proenzyme.

Quantity

Enzyme production (transcription and translation of enzyme genes) can be enhanced or diminished by a cell in response to changes in the cell's environment. This form of gene regulation is called enzyme induction. For example, bacteria may become resistant to antibiotics such as penicillin because enzymes called beta-lactamases are induced that hydrolyse the crucial beta-lactam ring within the penicillin molecule. Another example comes from enzymes in the liver called cytochrome P450 oxidases, which are important in drug metabolism. Induction or inhibition of these enzymes can cause drug interactions. Enzyme levels can also be regulated by changing the rate of enzyme degradation. The opposite of enzyme induction is enzyme repression.

Subcellular distribution

Enzymes can be compartmentalized, with different metabolic pathways occurring in different cellular compartments. For example, fatty acids are synthesized by one set of enzymes in the cytosol, endoplasmic reticulum and Golgi and used by a different set of enzymes as a source of energy in the mitochondrion, through β-oxidation. In addition, trafficking of the enzyme to different compartments may change the degree of protonation (e.g., the neutral cytoplasm and the acidic lysosome) or oxidative state (e.g., oxidizing periplasm or reducing cytoplasm) which in turn affects enzyme activity. In contrast to partitioning into membrane bound organelles, enzyme subcellular localisation may also be altered through polymerisation of enzymes into macromolecular cytoplasmic filaments.

Organ specialization

In multicellular eukaryotes, cells in different organs and tissues have different patterns of gene expression and therefore have different sets of enzymes (known as isozymes) available for metabolic reactions. This provides a mechanism for regulating the overall metabolism of the organism. For example, hexokinase, the first enzyme in the glycolysis pathway, has a specialized form called glucokinase expressed in the liver and pancreas that has a lower affinity for glucose yet is more sensitive to glucose concentration. This enzyme is involved in sensing blood sugar and regulating insulin production.

Involvement in disease

Ribbon diagram of phenylalanine hydroxylase with bound cofactor, coenzyme and substrate
In phenylalanine hydroxylase over 300 different mutations throughout the structure cause phenylketonuria. Phenylalanine substrate and tetrahydrobiopterin coenzyme in black, and Fe2+ cofactor in yellow. (PDB: 1KW0​)
Hereditary defects in enzymes are generally inherited in an autosomal fashion because there are more non-X chromosomes than X-chromosomes, and a recessive fashion because the enzymes from the unaffected genes are generally sufficient to prevent symptoms in carriers.

Since the tight control of enzyme activity is essential for homeostasis, any malfunction (mutation, overproduction, underproduction or deletion) of a single critical enzyme can lead to a genetic disease. The malfunction of just one type of enzyme out of the thousands of types present in the human body can be fatal. An example of a fatal genetic disease due to enzyme insufficiency is Tay–Sachs disease, in which patients lack the enzyme hexosaminidase.

One example of enzyme deficiency is the most common type of phenylketonuria. Many different single amino acid mutations in the enzyme phenylalanine hydroxylase, which catalyzes the first step in the degradation of phenylalanine, result in build-up of phenylalanine and related products. Some mutations are in the active site, directly disrupting binding and catalysis, but many are far from the active site and reduce activity by destabilising the protein structure, or affecting correct oligomerisation. This can lead to intellectual disability if the disease is untreated. Another example is pseudocholinesterase deficiency, in which the body's ability to break down choline ester drugs is impaired. Oral administration of enzymes can be used to treat some functional enzyme deficiencies, such as pancreatic insufficiency and lactose intolerance.

Another way enzyme malfunctions can cause disease comes from germline mutations in genes coding for DNA repair enzymes. Defects in these enzymes cause cancer because cells are less able to repair mutations in their genomes. This causes a slow accumulation of mutations and results in the development of cancers. An example of such a hereditary cancer syndrome is xeroderma pigmentosum, which causes the development of skin cancers in response to even minimal exposure to ultraviolet light.

Evolution

Similar to any other protein, enzymes change over time through mutations and sequence divergence. Given their central role in metabolism, enzyme evolution plays a critical role in adaptation. A key question is therefore whether and how enzymes can change their enzymatic activities alongside. It is generally accepted that many new enzyme activities have evolved through gene duplication and mutation of the duplicate copies although evolution can also happen without duplication. One example of an enzyme that has changed its activity is the ancestor of methionyl aminopeptidase (MAP) and creatine amidinohydrolase (creatinase) which are clearly homologous but catalyze very different reactions (MAP removes the amino-terminal methionine in new proteins while creatinase hydrolyses creatine to sarcosine and urea). In addition, MAP is metal-ion dependent while creatinase is not, hence this property was also lost over time. Small changes of enzymatic activity are extremely common among enzymes. In particular, substrate binding specificity (see above) can easily and quickly change with single amino acid changes in their substrate binding pockets. This is frequently seen in the main enzyme classes such as kinases.

Artificial (in vitro) evolution is now commonly used to modify enzyme activity or specificity for industrial applications (see below).

Industrial applications

Enzymes are used in the chemical industry and other industrial applications when extremely specific catalysts are required. Enzymes in general are limited in the number of reactions they have evolved to catalyze and also by their lack of stability in organic solvents and at high temperatures. As a consequence, protein engineering is an active area of research and involves attempts to create new enzymes with novel properties, either through rational design or in vitro evolution. These efforts have begun to be successful, and a few enzymes have now been designed "from scratch" to catalyze reactions that do not occur in nature.

Application Enzymes used Uses
Biofuel industry Cellulases Break down cellulose into sugars that can be fermented to produce cellulosic ethanol.
Ligninases Pretreatment of biomass for biofuel production.
Biological detergent Proteases, amylases, lipases Remove protein, starch, and fat or oil stains from laundry and dishware.
Mannanases Remove food stains from the common food additive guar gum.
Brewing industry Amylase, glucanases, proteases Split polysaccharides and proteins in the malt.
Betaglucanases Improve the wort and beer filtration characteristics.
Amyloglucosidase and pullulanases Make low-calorie beer and adjust fermentability.
Acetolactate decarboxylase (ALDC) Increase fermentation efficiency by reducing diacetyl formation.
Culinary uses Papain Tenderize meat for cooking.
Dairy industry Rennin Hydrolyze protein in the manufacture of cheese.
Lipases Produce Camembert cheese and blue cheeses such as Roquefort.
Food processing Amylases Produce sugars from starch, such as in making high-fructose corn syrup.
Proteases Lower the protein level of flour, as in biscuit-making.
Trypsin Manufacture hypoallergenic baby foods.
Cellulases, pectinases Clarify fruit juices.
Molecular biology Nucleases, DNA ligase and polymerases Use restriction digestion and the polymerase chain reaction to create recombinant DNA.
Paper industry Xylanases, hemicellulases and lignin peroxidases Remove lignin from kraft pulp.
Personal care Proteases Remove proteins on contact lenses to prevent infections.
Starch industry Amylases Convert starch into glucose and various syrups.

 

g factor (psychometrics)

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