Enzyme kinetics

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Dihydrofolate reductase from E. coli with its two substrates dihydrofolate (right) and NADPH (left), bound in the active site. The protein is shown as a ribbon diagram, with alpha helices in red, beta sheets in yellow and loops in blue. Generated from 7DFR.

Enzyme kinetics is the study of the chemical reactions that are catalysed by enzymes. In enzyme kinetics, the reaction rate is measured and the effects of varying the conditions of the reaction are investigated. Studying an enzyme's kinetics in this way can reveal the catalytic mechanism of this enzyme, its role in metabolism, how its activity is controlled, and how a drug or an agonist might inhibit the enzyme.

Enzymes are usually protein molecules that manipulate other molecules — the enzymes' substrates. These target molecules bind to an enzyme's active site and are transformed into products through a series of steps known as the enzymatic mechanism

E + S <——> ES <——> ES*< ——> EP <——> E + P

These mechanisms can be divided into single-substrate and multiple-substrate mechanisms. Kinetic studies on enzymes that only bind one substrate, such as triosephosphate isomerase, aim to measure the affinity with which the enzyme binds this substrate and the turnover rate. Some other examples of enzymes are phosphofructokinase and hexokinase, both of which are important for cellular respiration (glycolysis).

When enzymes bind multiple substrates, such as dihydrofolate reductase (shown right), enzyme kinetics can also show the sequence in which these substrates bind and the sequence in which products are released. An example of enzymes that bind a single substrate and release multiple products are proteases, which cleave one protein substrate into two polypeptide products. Others join two substrates together, such as DNA polymerase linking a nucleotide to DNA. Although these mechanisms are often a complex series of steps, there is typically one rate-determining step that determines the overall kinetics. This rate-determining step may be a chemical reaction or a conformational change of the enzyme or substrates, such as those involved in the release of product(s) from the enzyme.

Knowledge of the enzyme's structure is helpful in interpreting kinetic data. For example, the structure can suggest how substrates and products bind during catalysis; what changes occur during the reaction; and even the role of particular amino acid residues in the mechanism. Some enzymes change shape significantly during the mechanism; in such cases, it is helpful to determine the enzyme structure with and without bound substrate analogues that do not undergo the enzymatic reaction.

Not all biological catalysts are protein enzymes; RNA-based catalysts such as ribozymes and ribosomes are essential to many cellular functions, such as RNA splicing and translation. The main difference between ribozymes and enzymes is that RNA catalysts are composed of nucleotides, whereas enzymes are composed of amino acids. Ribozymes also perform a more limited set of reactions, although their reaction mechanisms and kinetics can be analysed and classified by the same methods.

General principles

As larger amounts of substrate are added to a reaction, the available enzyme binding sites become filled to the limit of $V_{\max }$. Beyond this limit the enzyme is saturated with substrate and the reaction rate ceases to increase.

The reaction catalysed by an enzyme uses exactly the same reactants and produces exactly the same products as the uncatalysed reaction. Like other catalysts, enzymes do not alter the position of equilibrium between substrates and products.^[1] However, unlike uncatalysed chemical reactions, enzyme-catalysed reactions display saturation kinetics. For a given enzyme concentration and for relatively low substrate concentrations, the reaction rate increases linearly with substrate concentration; the enzyme molecules are largely free to catalyse the reaction, and increasing substrate concentration means an increasing rate at which the enzyme and substrate molecules encounter one another. However, at relatively high substrate concentrations, the reaction rate asymptotically approaches the theoretical maximum; the enzyme active sites are almost all occupied and the reaction rate is determined by the intrinsic turnover rate of the enzyme. The substrate concentration midway between these two limiting cases is denoted by K_M.

The two most important kinetic properties of an enzyme are how quickly the enzyme becomes saturated with a particular substrate, and the maximum rate it can achieve. Knowing these properties suggests what an enzyme might do in the cell and can show how the enzyme will respond to changes in these conditions.

Enzyme assays

Progress curve for an enzyme reaction. The slope in the initial rate period is the initial rate of reaction v. The Michaelis–Menten equation describes how this slope varies with the concentration of substrate.

Enzyme assays are laboratory procedures that measure the rate of enzyme reactions. Because enzymes are not consumed by the reactions they catalyse, enzyme assays usually follow changes in the concentration of either substrates or products to measure the rate of reaction. There are many methods of measurement. Spectrophotometric assays observe change in the absorbance of light between products and reactants; radiometric assays involve the incorporation or release of radioactivity to measure the amount of product made over time. Spectrophotometric assays are most convenient since they allow the rate of the reaction to be measured continuously. Although radiometric assays require the removal and counting of samples (i.e., they are discontinuous assays) they are usually extremely sensitive and can measure very low levels of enzyme activity.^[2] An analogous approach is to use mass spectrometry to monitor the incorporation or release of stable isotopes as substrate is converted into product.

The most sensitive enzyme assays use lasers focused through a microscope to observe changes in single enzyme molecules as they catalyse their reactions. These measurements either use changes in the fluorescence of cofactors during an enzyme's reaction mechanism, or of fluorescent dyes added onto specific sites of the protein to report movements that occur during catalysis.^[3] These studies are providing a new view of the kinetics and dynamics of single enzymes, as opposed to traditional enzyme kinetics, which observes the average behaviour of populations of millions of enzyme molecules.^[4][5]

An example progress curve for an enzyme assay is shown above. The enzyme produces product at an initial rate that is approximately linear for a short period after the start of the reaction. As the reaction proceeds and substrate is consumed, the rate continuously slows (so long as substrate is not still at saturating levels). To measure the initial (and maximal) rate, enzyme assays are typically carried out while the reaction has progressed only a few percent towards total completion. The length of the initial rate period depends on the assay conditions and can range from milliseconds to hours. However, equipment for rapidly mixing liquids allows fast kinetic measurements on initial rates of less than one second.^[6] These very rapid assays are essential for measuring pre-steady-state kinetics, which are discussed below.

Most enzyme kinetics studies concentrate on this initial, approximately linear part of enzyme reactions. However, it is also possible to measure the complete reaction curve and fit this data to a non-linear rate equation. This way of measuring enzyme reactions is called progress-curve analysis.^[7] This approach is useful as an alternative to rapid kinetics when the initial rate is too fast to measure accurately.

Single-substrate reactions

Enzymes with single-substrate mechanisms include isomerases such as triosephosphateisomerase or bisphosphoglycerate mutase, intramolecular lyases such as adenylate cyclase and the hammerhead ribozyme, an RNA lyase.^[8] However, some enzymes that only have a single substrate do not fall into this category of mechanisms. Catalase is an example of this, as the enzyme reacts with a first molecule of hydrogen peroxide substrate, becomes oxidised and is then reduced by a second molecule of substrate. Although a single substrate is involved, the existence of a modified enzyme intermediate means that the mechanism of catalase is actually a ping–pong mechanism, a type of mechanism that is discussed in the Multi-substrate reactions section below.

Michaelis–Menten kinetics

Saturation curve for an enzyme showing the relation between the concentration of substrate and rate.

Single-substrate mechanism for an enzyme reaction. k₁, k₋₁ and k₂ are the rate constants for the individual steps.

As enzyme-catalysed reactions are saturable, their rate of catalysis does not show a linear response to increasing substrate. If the initial rate of the reaction is measured over a range of substrate concentrations (denoted as [S]), the reaction rate (v) increases as [S] increases, as shown on the right. However, as [S] gets higher, the enzyme becomes saturated with substrate and the rate reaches V_max, the enzyme's maximum rate.

The Michaelis–Menten kinetic model of a single-substrate reaction is shown on the right. There is an initial bimolecular reaction between the enzyme E and substrate S to form the enzyme–substrate complex ES but the rate of enzymatic reaction increase with the increase of the substrate concentration up to a certain level but then more increase in substrate concentration does not cause any increase in reaction rate as there no more E remain available for reacting with S and the rate of reaction become dependent on ES and the reaction become unimolecular reaction. Although the enzymatic mechanism for the unimolecular reaction $ES{\overset {k_{{cat}}}{\longrightarrow }}E+P$ can be quite complex, there is typically one rate-determining enzymatic step that allows this reaction to be modelled as a single catalytic step with an apparent unimolecular rate constant k_cat. If the reaction path proceeds over one or several intermediates, k_cat will be a function of several elementary rate constants, whereas in the simplest case of a single elementary reaction (e.g. no intermediates) it will be identical to the elementary unimolecular rate constant k₂. The apparent unimolecular rate constant k_cat is also called turnover number and denotes the maximum number of enzymatic reactions catalysed per second.

The Michaelis–Menten equation^[9] describes how the (initial) reaction rate v₀ depends on the position of the substrate-binding equilibrium and the rate constant k₂.

$v_{0}={\frac {V_{{\max }}[{\mbox{S}}]}{K_{M}+[{\mbox{S}}]}}$    (Michaelis–Menten equation)

with the constants

${\begin{aligned}K_{M}\ &{\stackrel {{\mathrm {def}}}{=}}\ {\frac {k_{{2}}+k_{{-1}}}{k_{{1}}}}\approx K_{D}\\V_{\max }\ &{\stackrel {{\mathrm {def}}}{=}}\ k_{{cat}}{[}E{]}_{{tot}}\end{aligned}}$

This Michaelis–Menten equation is the basis for most single-substrate enzyme kinetics. Two crucial assumptions underlie this equation (apart from the general assumption about the mechanism only involving no intermediate or product inhibition, and there is no allostericity or cooperativity). The first assumption is the so-called quasi-steady-state assumption (or pseudo-steady-state hypothesis), namely that the concentration of the substrate-bound enzyme (and hence also the unbound enzyme) changes much more slowly than those of the product and substrate and thus the change over time of the complex can be set to zero $d{[}ES{]}/{dt}\;{\overset {!}=}\;0$. The second assumption is that the total enzyme concentration does not change over time, thus ${[}E{]}_{{\text{tot}}}={[}E{]}+{[}ES{]}\;{\overset {!}=}\;{\text{const}}$. A complete derivation can be found here.

The Michaelis constant K_M is experimentally defined as the concentration at which the rate of the enzyme reaction is half V_max, which can be verified by substituting [S] = K_m into the Michaelis–Menten equation and can also be seen graphically. If the rate-determining enzymatic step is slow compared to substrate dissociation ($k_{2}\ll k_{{-1}}$), the Michaelis constant K_M is roughly the dissociation constant K_D of the ES complex.
If $[S]$ is small compared to $K_{M}$ then the term $[S]/(K_{M}+[S])\approx [S]/K_{M}$ and also very little ES complex is formed, thus $[E]_{0}\approx [E]$. Therefore, the rate of product formation is

$v_{0}\approx {\frac {k_{{cat}}}{K_{M}}}[E][S]\qquad \qquad {\text{if }}[S]\ll K_{M}$

Thus the product formation rate depends on the enzyme concentration as well as on the substrate concentration, the equation resembles a bimolecular reaction with a corresponding pseudo-second order rate constant $k_{2}/K_{M}$. This constant is a measure of catalytic efficiency. The most efficient enzymes reach a $k_{2}/K_{M}$ in the range of 10⁸ – 10¹⁰ M⁻¹ s⁻¹. These enzymes are so efficient they effectively catalyse a reaction each time they encounter a substrate molecule and have thus reached an upper theoretical limit for efficiency (diffusion limit); these enzymes have often been termed perfect enzymes.^[10]

Direct use of the Michaelis–Menten equation for time course kinetic analysis

The observed velocities predicted by the Michaelis–Menten equation can be used to directly model the time course disappearance of substrate and the production of product through incorporation of the Michaelis–Menten equation into the equation for first order chemical kinetics. This can only be achieved however if one recognises the problem associated with the use of Euler's number in the description of first order chemical kinetics. i.e. e^−k is a split constant that introduces a systematic error into calculations and can be rewritten as a single constant which represents the remaining substrate after each time period.^[11]

$[S]=[S]_{0}(1-k)^{{t}}\,$

$[S]=[S]_{0}(1-v/[S]_{0})^{{t}}\,$

$[S]=[S]_{0}(1-(V_{{\max }}[S]_{0}/(K_{M}+[S]_{0})/[S]_{0}))^{{t}}\,$

In 1983 Stuart Beal (and also independently Santiago Schnell and Claudio Mendoza in 1997) derived a closed form solution for the time course kinetics analysis of the Michaelis-Menten mechanism.^[12][13] The solution, known as the Schnell-Mendoza equation, has the form:

${\frac {[S]}{K_{M}}}=W\left[F(t)\right]\,$

where W[] is the Lambert-W function.^[14][15] and where F(t) is

$F(t)={\frac {[S]_{0}}{K_{M}}}\exp \!\left({\frac {[S]_{0}}{K_{M}}}-{\frac {V_{\max }}{K_{M}}}\,t\right)\,$

This equation is encompassed by the equation below, obtained by Berberan-Santos (MATCH Commun. Math. Comput. Chem. 63 (2010) 283), which is also valid when the initial substrate concentration is close to that of enzyme,

${\frac {[S]}{K_{M}}}=W\left[F(t)\right]-{\frac {V_{\max }}{k_{{cat}}K_{M}}}\ {\frac {W\left[F(t)\right]}{1+W\left[F(t)\right]}}\,$

where W[] is again the Lambert-W function.

Linear plots of the Michaelis–Menten equation

Lineweaver–Burk or double-reciprocal plot of kinetic data, showing the significance of the axis intercepts and gradient.

The plot of v versus [S] above is not linear; although initially linear at low [S], it bends over to saturate at high [S]. Before the modern era of nonlinear curve-fitting on computers, this nonlinearity could make it difficult to estimate K_M and V_max accurately. Therefore, several researchers developed linearisations of the Michaelis–Menten equation, such as the Lineweaver–Burk plot, the Eadie–Hofstee diagram and the Hanes–Woolf plot. All of these linear representations can be useful for visualising data, but none should be used to determine kinetic parameters, as computer software is readily available that allows for more accurate determination by nonlinear regression methods.^[16]

The Lineweaver–Burk plot or double reciprocal plot is a common way of illustrating kinetic data. This is produced by taking the reciprocal of both sides of the Michaelis–Menten equation. As shown on the right, this is a linear form of the Michaelis–Menten equation and produces a straight line with the equation y = mx + c with a y-intercept equivalent to 1/V_max and an x-intercept of the graph representing −1/K_M.

${\frac {1}{v}}={\frac {K_{{M}}}{V_{\max[}{\mbox{S}}]}}+{\frac {1}{V_{\max }}}$

Naturally, no experimental values can be taken at negative 1/[S]; the lower limiting value 1/[S] = 0 (the y-intercept) corresponds to an infinite substrate concentration, where 1/v=1/V_max as shown at the right; thus, the x-intercept is an extrapolation of the experimental data taken at positive concentrations. More generally, the Lineweaver–Burk plot skews the importance of measurements taken at low substrate concentrations and, thus, can yield inaccurate estimates of V_max and K_M.^[17] A more accurate linear plotting method is the Eadie-Hofstee plot. In this case, v is plotted against v/[S]. In the third common linear representation, the Hanes-Woolf plot, [S]/v is plotted against [S]. In general, data normalisation can help diminish the amount of experimental work and can increase the reliability of the output, and is suitable for both graphical and numerical analysis.^[18]

Practical significance of kinetic constants

The study of enzyme kinetics is important for two basic reasons. Firstly, it helps explain how enzymes work, and secondly, it helps predict how enzymes behave in living organisms. The kinetic constants defined above, K_M and V_max, are critical to attempts to understand how enzymes work together to control metabolism.

Making these predictions is not trivial, even for simple systems. For example, oxaloacetate is formed by malate dehydrogenase within the mitochondrion. Oxaloacetate can then be consumed by citrate synthase, phosphoenolpyruvate carboxykinase or aspartate aminotransferase, feeding into the citric acid cycle, gluconeogenesis or aspartic acid biosynthesis, respectively. Being able to predict how much oxaloacetate goes into which pathway requires knowledge of the concentration of oxaloacetate as well as the concentration and kinetics of each of these enzymes. This aim of predicting the behaviour of metabolic pathways reaches its most complex expression in the synthesis of huge amounts of kinetic and gene expression data into mathematical models of entire organisms. Alternatively, one useful simplification of the metabolic modelling problem is to ignore the underlying enzyme kinetics and only rely on information about the reaction network's stoichiometry, a technique called flux balance analysis.^[19][20]

Michaelis–Menten kinetics with intermediate

One could also consider the less simple case

${\begin{aligned}E+S{\underset {k_{{-1}}}{{\overset {k_{{1}}}{{\begin{smallmatrix}\displaystyle \longrightarrow \\\displaystyle \longleftarrow \end{smallmatrix}}}}}}ES{\overset {k_{2}}{\longrightarrow }}EI{\overset {k_{3}}{\longrightarrow }}E+P\end{aligned}}$

where a complex with the enzyme and an intermediate exists and the intermediate is converted into product in a second step. In this case we have a very similar equation^[21]

${\begin{aligned}v_{0}&=k_{{cat}}{\frac {{[}S{]}{[}E{]}_{0}}{K_{M}^{{\prime }}+{[}S{]}}}\end{aligned}}$

but the constants are different

${\begin{aligned}K_{M}^{{\prime }}\ &{\stackrel {{\mathrm {def}}}{=}}\ {\frac {k_{3}}{k_{2}+k_{3}}}K_{M}={\frac {k_{3}}{k_{2}+k_{3}}}\cdot {\frac {k_{{2}}+k_{{-1}}}{k_{{1}}}}\\k_{{cat}}\ &{\stackrel {{\mathrm {def}}}{=}}\ {\dfrac {k_{3}k_{2}}{k_{2}+k_{3}}}\end{aligned}}$

We see that for the limiting case $k_{3}\gg k_{2}$, thus when the last step from EI to E + P is much faster than the previous step, we get again the original equation. Mathematically we have then $K_{M}^{{\prime }}\approx K_{M}$ and $k_{{cat}}\approx k_{2}$.

Multi-substrate reactions

Multi-substrate reactions follow complex rate equations that describe how the substrates bind and in what sequence. The analysis of these reactions is much simpler if the concentration of substrate A is kept constant and substrate B varied. Under these conditions, the enzyme behaves just like a single-substrate enzyme and a plot of v by [S] gives apparent K_M and V_max constants for substrate B. If a set of these measurements is performed at different fixed concentrations of A, these data can be used to work out what the mechanism of the reaction is. For an enzyme that takes two substrates A and B and turns them into two products P and Q, there are two types of mechanism: ternary complex and ping–pong.

Ternary-complex mechanisms

Random-order ternary-complex mechanism for an enzyme reaction. The reaction path is shown as a line and enzyme intermediates containing substrates A and B or products P and Q are written below the line.

In these enzymes, both substrates bind to the enzyme at the same time to produce an EAB ternary complex. The order of binding can either be random (in a random mechanism) or substrates have to bind in a particular sequence (in an ordered mechanism). When a set of v by [S] curves (fixed A, varying B) from an enzyme with a ternary-complex mechanism are plotted in a Lineweaver–Burk plot, the set of lines produced will intersect.

Enzymes with ternary-complex mechanisms include glutathione S-transferase,^[22] dihydrofolate reductase^[23] and DNA polymerase.^[24] The following links show short animations of the ternary-complex mechanisms of the enzymes dihydrofolate reductase^[β] and DNA polymerase^[γ].

Ping–pong mechanisms

Ping–pong mechanism for an enzyme reaction. Intermediates contain substrates A and B or products P and Q.

As shown on the right, enzymes with a ping-pong mechanism can exist in two states, E and a chemically modified form of the enzyme E*; this modified enzyme is known as an intermediate. In such mechanisms, substrate A binds, changes the enzyme to E* by, for example, transferring a chemical group to the active site, and is then released. Only after the first substrate is released can substrate B bind and react with the modified enzyme, regenerating the unmodified E form. When a set of v by [S] curves (fixed A, varying B) from an enzyme with a ping–pong mechanism are plotted in a Lineweaver–Burk plot, a set of parallel lines will be produced. This is called a secondary plot.

Enzymes with ping–pong mechanisms include some oxidoreductases such as thioredoxin peroxidase,^[25] transferases such as acylneuraminate cytidylyltransferase^[26] and serine proteases such as trypsin and chymotrypsin.^[27] Serine proteases are a very common and diverse family of enzymes, including digestive enzymes (trypsin, chymotrypsin, and elastase), several enzymes of the blood clotting cascade and many others. In these serine proteases, the E* intermediate is an acyl-enzyme species formed by the attack of an active site serine residue on a peptide bond in a protein substrate. A short animation showing the mechanism of chymotrypsin is linked here.^[δ]

Non-Michaelis–Menten kinetics

Saturation curve for an enzyme reaction showing sigmoid kinetics.

Some enzymes produce a sigmoid v by [S] plot, which often indicates cooperative binding of substrate to the active site. This means that the binding of one substrate molecule affects the binding of subsequent substrate molecules. This behavior is most common in multimeric enzymes with several interacting active sites.^[28] Here, the mechanism of cooperation is similar to that of hemoglobin, with binding of substrate to one active site altering the affinity of the other active sites for substrate molecules. Positive cooperativity occurs when binding of the first substrate molecule increases the affinity of the other active sites for substrate. Negative cooperativity occurs when binding of the first substrate decreases the affinity of the enzyme for other substrate molecules.

Allosteric enzymes include mammalian tyrosyl tRNA-synthetase, which shows negative cooperativity,^[29] and bacterial aspartate transcarbamoylase^[30] and phosphofructokinase,^[31] which show positive cooperativity.

Cooperativity is surprisingly common and can help regulate the responses of enzymes to changes in the concentrations of their substrates. Positive cooperativity makes enzymes much more sensitive to [S] and their activities can show large changes over a narrow range of substrate concentration. Conversely, negative cooperativity makes enzymes insensitive to small changes in [S].

The Hill equation (biochemistry)^[32] is often used to describe the degree of cooperativity quantitatively in non-Michaelis–Menten kinetics. The derived Hill coefficient n measures how much the binding of substrate to one active site affects the binding of substrate to the other active sites. A Hill coefficient of <1 indicates negative cooperativity and a coefficient of >1 indicates positive cooperativity.

Pre-steady-state kinetics

Pre-steady state progress curve, showing the burst phase of an enzyme reaction.

In the first moment after an enzyme is mixed with substrate, no product has been formed and no intermediates exist. The study of the next few milliseconds of the reaction is called Pre-steady-state kinetics also referred to as Burst kinetics. Pre-steady-state kinetics is therefore concerned with the formation and consumption of enzyme–substrate intermediates (such as ES or E*) until their steady-state concentrations are reached.

This approach was first applied to the hydrolysis reaction catalysed by chymotrypsin.^[33] Often, the detection of an intermediate is a vital piece of evidence in investigations of what mechanism an enzyme follows. For example, in the ping–pong mechanisms that are shown above, rapid kinetic measurements can follow the release of product P and measure the formation of the modified enzyme intermediate E*.^[34] In the case of chymotrypsin, this intermediate is formed by an attack on the substrate by the nucleophilic serine in the active site and the formation of the acyl-enzyme intermediate.

In the figure to the right, the enzyme produces E* rapidly in the first few seconds of the reaction. The rate then slows as steady state is reached. This rapid burst phase of the reaction measures a single turnover of the enzyme. Consequently, the amount of product released in this burst, shown as the intercept on the y-axis of the graph, also gives the amount of functional enzyme which is present in the assay.^[35]

Chemical mechanism

An important goal of measuring enzyme kinetics is to determine the chemical mechanism of an enzyme reaction, i.e., the sequence of chemical steps that transform substrate into product. The kinetic approaches discussed above will show at what rates intermediates are formed and inter-converted, but they cannot identify exactly what these intermediates are.

Kinetic measurements taken under various solution conditions or on slightly modified enzymes or substrates often shed light on this chemical mechanism, as they reveal the rate-determining step or intermediates in the reaction. For example, the breaking of a covalent bond to a hydrogen atom is a common rate-determining step. Which of the possible hydrogen transfers is rate determining can be shown by measuring the kinetic effects of substituting each hydrogen by deuterium, its stable isotope. The rate will change when the critical hydrogen is replaced, due to a primary kinetic isotope effect, which occurs because bonds to deuterium are harder to break than bonds to hydrogen.^[36] It is also possible to measure similar effects with other isotope substitutions, such as ¹³C/¹²C and ¹⁸O/¹⁶O, but these effects are more subtle.^[37]

Isotopes can also be used to reveal the fate of various parts of the substrate molecules in the final products. For example, it is sometimes difficult to discern the origin of an oxygen atom in the final product; since it may have come from water or from part of the substrate. This may be determined by systematically substituting oxygen's stable isotope ¹⁸O into the various molecules that participate in the reaction and checking for the isotope in the product.^[38] The chemical mechanism can also be elucidated by examining the kinetics and isotope effects under different pH conditions,^[39] by altering the metal ions or other bound cofactors,^[40] by site-directed mutagenesis of conserved amino acid residues, or by studying the behaviour of the enzyme in the presence of analogues of the substrate(s).^[41]

Enzyme inhibition and activation

Kinetic scheme for reversible enzyme inhibitors.

Enzyme inhibitors are molecules that reduce or abolish enzyme activity, while enzyme activators are molecules that increase the catalytic rate of enzymes. These interactions can be either reversible (i.e., removal of the inhibitor restores enzyme activity) or irreversible (i.e., the inhibitor permanently inactivates the enzyme).

Reversible inhibitors

Traditionally reversible enzyme inhibitors have been classified as competitive, uncompetitive, or non-competitive, according to their effects on K_m and V_max. These different effects result from the inhibitor binding to the enzyme E, to the enzyme–substrate complex ES, or to both, respectively. The division of these classes arises from a problem in their derivation and results in the need to use two different binding constants for one binding event. The binding of an inhibitor and its effect on the enzymatic activity are two distinctly different things, another problem the traditional equations fail to acknowledge. In noncompetitive inhibition the binding of the inhibitor results in 100% inhibition of the enzyme only, and fails to consider the possibility of anything in between.^[42] The common form of the inhibitory term also obscures the relationship between the inhibitor binding to the enzyme and its relationship to any other binding term be it the Michaelis–Menten equation or a dose response curve associated with ligand receptor binding. To demonstrate the relationship the following rearrangement can be made:

${\cfrac {V_{\max }}{1+{\cfrac {[I]}{K_{i}}}}}$

${\cfrac {V_{\max }}{{\cfrac {[I]+K_{i}}{K_{i}}}}}$

Adding zero to the bottom ([I]-[I])

${\cfrac {V_{\max }}{{\cfrac {[I]+K_{i}}{[I]+K_{i}-[I]}}}}$

Dividing by [I]+K_i

${\cfrac {V_{\max }}{{\cfrac {1}{1-{\cfrac {[I]}{[I]+K_{i}}}}}}}$

$V_{\max }-V_{\max }{\cfrac {[I]}{[I]+K_{i}}}$

This notation demonstrates that similar to the Michaelis–Menten equation, where the rate of reaction depends on the percent of the enzyme population interacting with substrate^{[sentence fragment]}
fraction of the enzyme population bound by substrate

${\cfrac {[S]}{[S]+K_{m}}}$

fraction of the enzyme population bound by inhibitor

${\cfrac {[I]}{[I]+K_{i}}}$

the effect of the inhibitor is a result of the percent of the enzyme population interacting with inhibitor. The only problem with this equation in its present form is that it assumes absolute inhibition of the enzyme with inhibitor binding, when in fact there can be a wide range of effects anywhere from 100% inhibition of substrate turn over to just >0%. To account for this the equation can be easily modified to allow for different degrees of inhibition by including a delta V_max term.

$V_{\max }-\Delta V_{\max }{\cfrac {[I]}{[I]+K_{i}}}$

or

$V_{\max }1-(V_{\max }1-V_{\max }2){\cfrac {[I]}{[I]+K_{i}}}$

This term can then define the residual enzymatic activity present when the inhibitor is interacting with individual enzymes in the population. However the inclusion of this term has the added value of allowing for the possibility of activation if the secondary V_max term turns out to be higher than the initial term. To account for the possibly of activation as well the notation can then be rewritten replacing the inhibitor "I" with a modifier term denoted here as "X".

$V_{\max }1-(V_{\max }1-V_{\max }2){\cfrac {[X]}{[X]+K_{x}}}$

While this terminology results in a simplified way of dealing with kinetic effects relating to the maximum velocity of the Michaelis–Menten equation, it highlights potential problems with the term used to describe effects relating to the K_m. The K_m relating to the affinity of the enzyme for the substrate should in most cases relate to potential changes in the binding site of the enzyme which would directly result from enzyme inhibitor interactions. As such a term similar to the one proposed above to modulate V_max should be appropriate in most situations:^[43][44]

$K_{m}1-(K_{m}1-K_{m}2){\cfrac {[X]}{[X]+K_{x}}}$

Irreversible inhibitors

Enzyme inhibitors can also irreversibly inactivate enzymes, usually by covalently modifying active site residues. These reactions, which may be called suicide substrates, follow exponential decay functions and are usually saturable. Below saturation, they follow first order kinetics with respect to inhibitor.

Mechanisms of catalysis

The energy variation as a function of reaction coordinate shows the stabilisation of the transition state by an enzyme.

The favoured model for the enzyme–substrate interaction is the induced fit model.^[45] This model proposes that the initial interaction between enzyme and substrate is relatively weak, but that these weak interactions rapidly induce conformational changes in the enzyme that strengthen binding. These conformational changes also bring catalytic residues in the active site close to the chemical bonds in the substrate that will be altered in the reaction.^[46] Conformational changes can be measured using circular dichroism or dual polarisation interferometry. After binding takes place, one or more mechanisms of catalysis lower the energy of the reaction's transition state by providing an alternative chemical pathway for the reaction. Mechanisms of catalysis include catalysis by bond strain; by proximity and orientation; by active-site proton donors or acceptors; covalent catalysis and quantum tunnelling.^[34][47]

Enzyme kinetics cannot prove which modes of catalysis are used by an enzyme. However, some kinetic data can suggest possibilities to be examined by other techniques. For example, a ping–pong mechanism with burst-phase pre-steady-state kinetics would suggest covalent catalysis might be important in this enzyme's mechanism. Alternatively, the observation of a strong pH effect on V_max but not K_m might indicate that a residue in the active site needs to be in a particular ionisation state for catalysis to occur.

History

In 1902 Victor Henri proposed a quantitative theory of enzyme kinetics,^[48] but at the time the experimental significance of the hydrogen ion concentration was not yet recognized. After Peter Lauritz Sørensen had defined the logarithmic pH-scale and introduced the concept of buffering in 1909^[49] the German chemist Leonor Michaelis and his Canadian postdoc Maud Leonora Menten repeated Henri's experiments and confirmed his equation, which is now generally referred to as Michaelis-Menten kinetics (sometimes also Henri-Michaelis-Menten kinetics).^[50] Their work was further developed by G. E. Briggs and J. B. S. Haldane, who derived kinetic equations that are still widely considered today a starting point in modeling enzymatic activity.^[51]

The major contribution of the Henri-Michaelis-Menten approach 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 complex. The enzyme then catalyzes the chemical step in the reaction and releases the product. The kinetics of many enzymes is adequately described by the simple Michaelis-Menten model, but all enzymes have internal motions that are not accounted for in the model and can have significant contributions to the overall reaction kinetics. This can be modeled by introducing several Michaelis-Menten pathways that are connected with fluctuating rates,^[52][53][54] which is a mathematical extension of the basic Michaelis Menten mechanism.^[55]

Software

ENZO

ENZO (Enzyme Kinetics) is a graphical interface tool for building kinetic models of enzyme catalyzed reactions. ENZO automatically generates the corresponding differential equations from a stipulated enzyme reaction scheme. These differential equations are processed by a numerical solver and a regression algorithm which fits the coefficients of differential equations to experimentally observed time course curves. ENZO allows rapid evaluation of rival reaction schemes and can be used for routine tests in enzyme kinetics.^[56]

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Traded as	NYSE: T Dow Jones Industrial Average Component S&P 500 Component
Industry	Telecommunications
Predecessor	American Telephone and Telegraph Company
Founded	October 5, 1983 (1983-10-05)[1]
Headquarters	Dallas, Texas, United States
Key people	Randall Stephenson (Chairman & CEO)[2]
Products	Fixed line mobile telephony broadband fixed-line internet services digital television
Revenue	US$ 132.447 billion (2014)[3]
Operating income	US$ 13.866 billion (2014)[3]
Net income	US$ 6.224 billion (2014)[3]
Total assets	US$ 292.829 billion (2014)[3]
Total equity	US$ 86.924 billion (2014)[3]
Number of employees	243,620 (2015)[3]
Subsidiaries	AT&T Corporation AT&T Mobility BellSouth Southwestern Bell AT&T Teleholdings Cricket Wireless Iusacell
Website	att.com
Footnotes / references for DJIA listing, http://www.marketwatch.com/investing/index/djia

AT&T Inc. is an American multinational telecommunications corporation, headquartered at Whitacre Tower in downtown Dallas, Texas.^[4] AT&T is the second largest provider of mobile telephone and the largest provider of fixed telephone^[5] in the United States, and also provides broadband subscription television services. AT&T is the third-largest company in Texas (the largest non-oil company, behind only ExxonMobil and ConocoPhillips, and also the largest Dallas company).^[6] As of May 2014^[update], AT&T is the 23rd-largest company in the world as measured by a composite of revenues, profits, assets and market value,^[7] and the 16th-largest non-oil company.^[8] As of 2014^[update], it is also the 20th-largest mobile telecom operator in the world, with over 120.6 million mobile customers.^[9]

The current iteration of AT&T Inc. began its existence as Southwestern Bell Corporation, one of seven Regional Bell Operating Companies (RBOC's) created in 1983 in the divestiture of parent company American Telephone and Telegraph Company (founded 1885, later AT&T Corp.) due to the 1982 United States v. AT&T antitrust lawsuit. Southwestern Bell changed its name to SBC Communications Inc. in 1995. In 2005, SBC purchased former parent AT&T Corp. and took on its branding, with the merged entity naming itself AT&T Inc. and using the iconic AT&T Corp. logo and stock-trading symbol.

The current AT&T reconstitutes much of the former Bell System and includes ten of the original 22 Bell Operating Companies, along with the original long distance division.^[10]

History

Prior to 2005 purchase by SBC

AT&T can indirectly trace its origin back to the original Bell Telephone Company founded by Alexander Graham Bell after his invention of the telephone. One of that company's subsidiaries was American Telephone and Telegraph Company (AT&T), established in 1885, which acquired the Bell Company on December 31, 1899 for legal reasons, leaving AT&T as the main company. AT&T established a network of subsidiaries in the United States that held a government-authorized phone service monopoly, formalized with the Kingsbury Commitment, throughout most of the twentieth century. This monopoly was known as the Bell System, and during this period, AT&T was also known by the nickname Ma Bell. For periods of time, the former AT&T was the world's largest phone company.

In 1982, US regulators broke up the AT&T monopoly, requiring AT&T to divest its regional subsidiaries and turning them each into individual companies. These new companies were known as Regional Bell Operating Companies, or more informally, Baby Bells. AT&T continued to operate long distance services, but thanks to the breakup, faced competition from new competitors such as MCI and Sprint.

Southwestern Bell was one of the companies created by the breakup of AT&T. It wasn't long before the company started a series of acquisitions. This includes the 1987 acquisition of Metromedia mobile business, and the acquisition of several cable companies in the early 1990s. In the later half of the 1990s, the company acquired several other telecommunications companies, including some baby bells, while selling its cable business. During this time, the company changed its name to SBC Communications. By 1998, the company was in the top 15 of the Fortune 500, and by 1999 the company was part of the Dow Jones Industrial Average.

Since 2005

In 2005, SBC purchased AT&T for $16 billion. After this purchase, SBC adopted the AT&T name and brand. The original 1885 AT&T still exists as the long-distance phone subsidiary of this company.

In September 2013, AT&T announced it would expand into Latin America through a collaboration with Carlos Slim’s America Movil.^[11] On December 17, 2013, AT&T announced plans to sell its Connecticut wireline operations to Stamford-based Frontier Communications. Roughly 2,700 wireline employees supporting AT&T’s operations in Connecticut will transfer with the business to Frontier, as well as 900,000 voice connections, 415,000 broadband connections, and 180,000 U-verse video subscribers.^[12]

On May 18, 2014, AT&T announced it had agreed to purchase DirecTV. In the deal, which has been approved by boards of both companies, DirecTV stockholders will receive $95 a share in cash and stock, valuing the deal at $48.5 billion. Including assumed debt, the total purchase price is about $67.1 billion. The deal was aimed at increasing AT&T's market share in the pay-TV sector; its existing U-Verse brand has modest market share (5.7 million users compared to DirecTV's 20 million US customers as of 2014) and operates in only 22 states. It will also give AT&T access to fast-growing Latin American markets, where DirecTV has 18 million subscribers. Additionally, the purchase will allow the AT&T to offer TV through both fiber-optic lines and satellites by maintaining the DirecTV brand as a separate subsidiary, and give the company greater flexibility in creating TV/phone/Internet bundles.^[13] The deal will face regulatory approval by the FCC, the U.S. Department of Justice, and some Latin American governments. It is expected to take about 12 months to complete.^[14]

It was announced on November 7, 2014, that Mexican carrier Iusacell is being acquired by AT&T, in order to create a wider North American network.^[15]

In January 2015, AT&T announced it would be acquiring the bankrupt Mexican wireless business of NII Holdings for around $1.875 billion.^[16]

Political contributions and lobbying

According to the Center for Responsive Politics, AT&T is the second-largest donor to United States political campaigns,^[17] and the top American corporate donor,^[18] having contributed more than US$47.7 million since 1990, 56% and 44% of which went to Republican and Democratic recipients, respectively.^[19] Also, during the period of 1998 to 2010, the company expended US$130 million on lobbying in the United States.^[18] A key political issue for AT&T has been the question of which businesses win the right to profit by providing broadband internet access in the United States.^[20]
In 2005, AT&T was among 53 entities that contributed the maximum of $250,000 to the second inauguration of President George W. Bush.^[21][22][23]

American Legislative Exchange Council

Bill Leahy, representing AT&T, sits on the Private Enterprise Board of the American Legislative Exchange Council (ALEC).^[24]

Legislation

AT&T supported the Federal Communications Commission Process Reform Act of 2013 (H.R. 3675; 113th Congress), a bill that would make a number of changes to procedures that the Federal Communications Commission (FCC) follows in its rulemaking processes.^[25] The FCC would have to act in a more transparent way as a result of this bill, forced to accept public input about regulations.^[26] Executive Vice President - Federal Relations Tim McKone said that the bill's "much needed institutional reforms will help arm the agency with the tools to keep pace with the Internet speed of today's marketplace. It will also ensure that outmoded regulatory practices for today's competitive marketplace are properly placed in the dustbin of history."^[27]

Landline operating companies

Of the twenty-four companies that were part of the Bell System, ten are a part of the current AT&T:^[28]

• BellSouth Telecommunications (formerly known as Southern Bell; includes former South Central Bell)
• Illinois Bell
• Indiana Bell
• Michigan Bell
• Ohio Bell
• Pacific Bell (formerly Pacific Telephone & Telegraph)
  • Nevada Bell (formerly known as Bell Telephone Company of Nevada)
• Southwestern Bell
• Wisconsin Bell (formerly Wisconsin Telephone)

Former operating companies

The following companies have gone to defunct status or sold under SBC/AT&T ownership:

• Southwestern Bell Texas – a separate operating company created by SBC, absorbed operations of original SWBT on December 30, 2001 and became Southwestern Bell Telephone, L.P.; eventually merged into SWBT Inc. in 2007 which became the current Southwestern Bell
• Southern New England Telephone - sold to Frontier Communications in 2014
  • Woodbury Telephone – merged into Southern New England Telephone on June 1, 2007.

Future of rural landlines

AT&T stated that it would declare its intentions for its rural landlines on November 7, 2012.^[29] AT&T had previously announced that it was considering a sale of its rural landlines, which are not wired for AT&T's U-verse service; however, it has also stated that it may keep the business after all.
AT&T would not be the first Baby Bell to sell off rural landlines. Ameritech sold some of its Wisconsin lines to CenturyTel in 1998; BellSouth sold some of its lines to MebTel in the 2000s; U S WEST sold many historically Bell landlines to Lynch Communications and Pacific Telecom in the 1990s; Verizon sold many of its New England lines to FairPoint in 2008 and its West Virginia operations to Frontier Communications in 2010.

It was announced on October 24, 2014 that Frontier Communications would officially take over control of the AT&T landline network in Connecticut at 12:1 October 25, 2014 after being approved by state utility regulators in early October 2014. The deal worth about $2 billion included Frontier inheriting about 2,500 of AT&T's employees and many of AT&T buildings.^[30]

Corporate structure

AT&T office in San Antonio, Texas with new logo and orange highlight from the former Cingular

AT&T Inc. has retained the holding companies it has acquired over the years resulting in the following corporate structure:

• AT&T Inc., publicly traded holding company
  • Southwestern Bell Telephone Company d/b/a AT&T Arkansas, AT&T Kansas, AT&T Missouri, AT&T Oklahoma, AT&T Southwest, AT&T Texas
  • AT&T Teleholdings, Inc. d/b/a AT&T East, AT&T Midwest, AT&T West; formerly Ameritech, acquired in 1999; absorbed Pacific Telesis and SNET Corp. under AT&T ownership
    • Illinois Bell Telephone Company d/b/a AT&T Illinois
    • Indiana Bell Telephone Company d/b/a AT&T Indiana
    • Michigan Bell Telephone Company d/b/a AT&T Michigan
    • The Ohio Bell Telephone Company d/b/a AT&T Ohio
    • Pacific Bell Telephone Company d/b/a AT&T California
      • Nevada Bell Telephone Company d/b/a AT&T Nevada
    • Wisconsin Bell, Inc. d/b/a AT&T Wisconsin
  • AT&T Corp., acquired 2005
    • Alascom, Inc. d/b/a AT&T Alaska
  • BellSouth Corporation d/b/a AT&T South, acquired 2006
  • BellSouth Telecommunications, LLC d/b/a AT&T Alabama, AT&T Florida, AT&T Georgia, AT&T Louisiana, AT&T Kentucky, AT&T Mississippi, AT&T North Carolina, AT&T South Carolina, AT&T Southeast, AT&T Tennessee
  • AT&T Mobility
  • Cricket Wireless
  • Iusacell

Corporate governance

Stephenson at the 2008 World Economic Forum

AT&T's current board of directors:^[31]

• Randall L. Stephenson – Chairman and Chief Executive Officer
• James H. Blanchard
• Gilbert F. Amelio
• Reuben V. Anderson
• Jaime Chico Pardo
• James P. Kelly
• Jon C. Madonna
• Lynn M. Martin
• John B. McCoy
• Joyce M. Roché
• Matthew K. Rose
• Laura D'Andrea Tyson

Criticism and controversies

Hemisphere database

The company maintains a database of call detail records of all telephone calls that have passed through its network since 1987. AT&T employees work at High Intensity Drug Trafficking Area offices (operated by the Office of National Drug Control Policy) in Los Angeles, Atlanta, and Houston so data can be quickly turned over to law enforcement agencies. Records are requested via administrative subpoena, without the involvement of a court or grand jury.

Censorship

In September 2007, AT&T changed their legal policy to state that "AT&T may immediately terminate or suspend all or a portion of your Service,^[32] any Member ID, electronic mail address, IP address, Universal Resource Locator or domain name used by you, without notice for conduct that AT&T believes"..."(c) tends to damage the name or reputation of AT&T or its parents, affiliates and subsidiaries."^[33] By October 10, 2007 AT&T had altered the terms and conditions for its Internet service to explicitly support freedom of expression by its subscribers, after an outcry claiming the company had given itself the right to censor its subscribers' transmissions.^[34] Section 5.1 of AT&T's new terms of service now reads "AT&T respects freedom of expression and believes it is a foundation of our free society to express differing points of view. AT&T will not terminate, disconnect or suspend service because of the views you or we express on public policy matters, political issues or political campaigns."^[35]

Privacy controversy

Diagram of how alleged wiretapping worked. From EFF court filings^[36]

 

In 2006, the Electronic Frontier Foundation lodged a class action lawsuit, Hepting v. AT&T, which alleged that AT&T had allowed agents of the National Security Agency (NSA) to monitor phone and Internet communications of AT&T customers without warrants. If true, this would violate the Foreign Intelligence Surveillance Act of 1978 and the First and Fourth Amendments of the U.S. Constitution. AT&T has yet to confirm or deny that monitoring by the NSA is occurring. In April 2006, a retired former AT&T technician, Mark Klein, lodged an affidavit supporting this allegation.^[37][38] The Department of Justice has stated they will intervene in this lawsuit by means of State Secrets Privilege.^[39] In July 2006, the United States District Court for the Northern District of California – in which the suit was filed – rejected a federal government motion to dismiss the case. The motion to dismiss, which invoked the State Secrets Privilege, had argued that any court review of the alleged partnership between the federal government and AT&T would harm national security. The case was immediately appealed to the Ninth Circuit. It was dismissed on June 3, 2009, citing retroactive legislation in the Foreign Intelligence Surveillance Act.^{[citation needed]} In May 2006, USA Today reported that all international and domestic calling records had been handed over to the National Security Agency by AT&T, Verizon, SBC, and BellSouth for the purpose of creating a massive calling database.^[40] The portions of the new AT&T that had been part of SBC Communications before November 18, 2005 were not mentioned.
On June 21, 2006, the San Francisco Chronicle reported that AT&T had rewritten rules on their privacy policy. The policy, which took effect June 23, 2006, says that "AT&T – not customers – owns customers' confidential info and can use it 'to protect its legitimate business interests, safeguard others, or respond to legal process.' "^[41]

On August 22, 2007, National Intelligence Director Mike McConnell confirmed that AT&T was one of the telecommunications companies that assisted with the government's warrantless wire-tapping program on calls between foreign and domestic sources.^[42]

On November 8, 2007, Mark Klein, a former AT&T technician, told Keith Olbermann of MSNBC that all Internet traffic passing over AT&T lines was copied into a locked room at the company's San Francisco office – to which only employees with National Security Agency clearance had access.^[43]
AT&T keeps for five to seven years a record of who text messages whom and the date and time, but not the content of the messages.^[44]

Intellectual property filtering

In January 2008, the company reported plans to begin filtering all Internet traffic which passes through its network for intellectual property violations.^[45] Commentators in the media have speculated that if this plan is implemented, it would lead to a mass exodus of subscribers leaving AT&T,^[46] although this is misleading as Internet traffic may go through the company's network anyway.^[45] Internet freedom proponents used these developments as justification for government-mandated network neutrality.

Discrimination against local Public-access television channels

AT&T is accused by community media groups of discriminating against local Public, educational, and government access (PEG) cable TV channels:, by "impictions that will severely restrict the audience".^[47]

According to Barbara Popovic, Executive Director of the Chicago public-access service CAN-TV, the new AT&T U-verse system forces all Public-access television into a special menu system, denying normal functionality such as channel numbers, access to the standard program guide, and DVR recording.^[47] The Ratepayer Advocates division of the California Public Utilities Commission reported: "Instead of putting the stations on individual channels, AT&T has bundled community stations into a generic channel that can only be navigated through a complex and lengthy process."^[47]

Sue Buske (president of telecommunications consulting firm the Buske Group and a former head of the National Federation of Local Cable Programmers/Alliance for Community Media) argue that this is "an overall attack [...] on public access across the [United States], the place in the dial around cities and communities where people can make their own media in their own communities".^[47]

Information security

In June 2010, a hacker group known as Goatse Security discovered a vulnerability within the AT&T that could allow anyone to uncover email addresses belonging to customers of AT&T 3G service for the Apple iPad.^[48] These email addresses could be accessed without a protective password.^[49] Using a script, Goatse Security collected thousands of email addresses from AT&T.^[48] Goatse Security informed AT&T about the security flaw through a third party.^[50] Goatse Security then disclosed around 114,000 of these emails to Gawker Media, which published an article about the security flaw and disclosure in Valleywag.^[48][50] Praetorian Security Group criticized the web application that Goatse Security exploited as "poorly designed".^[48]

Accusations of enabling fraud

In March 2012, the United States federal government announced a lawsuit against AT&T. The specific accusations state that AT&T "violated the False Claims Act by facilitating and seeking federal payment for IP Relay calls by international callers who were ineligible for the service and sought to use it for fraudulent purposes. The complaint alleges that, out of fears that fraudulent call volume would drop after the registration deadline, AT&T knowingly adopted a non-compliant registration system that did not verify whether the user was located within the United States. The complaint further contends that AT&T continued to employ this system even with the knowledge that it facilitated use of IP Relay by fraudulent foreign callers, which accounted for up to 95 percent of AT&T's call volume. The government's complaint alleges that AT&T improperly billed the TRS Fund for reimbursement of these calls and received millions of dollars in federal payments as a result."^[51]

Naming rights and sponsorships

Buildings

AT&T Midtown Center in Atlanta, Georgia

• AT&T 220 Building – building in Indianapolis, Indiana
• AT&T Building – building in Detroit, Michigan
• AT&T Building – building in Indianapolis, Indiana
• AT&T Building – building in Kingman, Arizona
• AT&T Building – (aka "The Batman Building") in Nashville, Tennessee
• AT&T Building – building in Omaha, Nebraska
• AT&T Building Addition – building in Detroit, Michigan
• AT&T Center – building in Los Angeles
• AT&T Center – building in St. Louis, Missouri
• AT&T Center – building in Charlotte, NC
• AT&T City Center – building in Birmingham, Alabama
• AT&T Corporate Center – building in Chicago, Illinois
• AT&T Huron Road Building – building in Cleveland, Ohio
• AT&T Lenox Park Campus – AT&T Mobility Headquarters in DeKalb County just outside Atlanta, Georgia
• AT&T Midtown Center – building in Atlanta, Georgia
• AT&T Switching Center – building in Los Angeles
• AT&T Switching Center – building in Oakland, California
• AT&T Switching Center – building in San Francisco
• AT&T Building – building in San Diego
• Whitacre Tower (One AT&T Plaza) – Corporate Headquarters, Dallas, Texas

Venues

AT&T Center in San Antonio, Texas

• AT&T Center – San Antonio, Texas (formerly SBC Center)
• AT&T Field – Chattanooga, Tennessee (formerly BellSouth Park)
• AT&T Park – San Francisco (formerly Pacific Bell Park, SBC Park)
• AT&T Plaza – Chicago, Illinois (public space that hosts the Cloud Gate sculpture in Millennium Park)
• AT&T Plaza – Dallas, Texas (plaza in front of the American Airlines Center at Victory Park)
• AT&T Performing Arts Center – Dallas, Texas
• AT&T Stadium – Arlington, Texas (formerly Cowboys Stadium)
• Jones AT&T Stadium – Lubbock, Texas (formerly Clifford B. and Audrey Jones Stadium, Jones SBC Stadium)
• TPC San Antonio – San Antonio, Texas (AT&T Oaks Course & AT&T Canyons Course)
• War Memorial Stadium, AT&T Field - Little Rock, Arkansas

Sponsorships

• AT&T Champions Classic – Valencia, California
• AT&T Championship - San Antonio, Texas
• AT&T Classic – Atlanta, Georgia (formerly BellSouth Classic)
• AT&T Cotton Bowl Classic (formerly Mobil Cotton Bowl Classic, Southwestern Bell Cotton Bowl Classic, SBC Cotton Bowl Classic) – played in Arlington, Texas, at AT&T Stadium.
• AT&T National – Washington, D.C.
• AT&T Pebble Beach National Pro-Am
• AT&T Red River Rivalry – Dallas, Texas (formerly Red River Shootout, SBC Red River Rivalry)
• Major League Soccer and the United States Soccer Federation, including the U.S. men's and U.S. women's national teams and the Major League Soccer All-Star Game from 2009
• United States Olympic team^[52]
• National Collegiate Athletic Association (Corporate Champion)^[53]
• AT&T American Cup, Artistic gymnastics competition. Sponsored by AT&T since 2011.

Miscellaneous

• AT&T (SEPTA station) – Public Transportation Station in Philadelphia, PA

Global presence

AT&T offers services in many locations throughout the Asia Pacific; its regional headquarters is located in Hong Kong.^[54]

It was announced on November 7, 2014, that Mexican carrier Iusacell is being acquired by AT&T.^[15]