Cytochrome P450

From Wikipedia, the free encyclopedia

Cytochrome P450
Structure of lanosterol 14α-demethylase (CYP51)

Cytochromes P450 (CYPs) are proteins of the superfamily containing heme as a cofactor and, therefore, are hemeproteins. CYPs use a variety of small and large molecules as substrates in enzymatic reactions. They are, in general, the terminal oxidase enzymes in electron transfer chains, broadly categorized as P450-containing systems. The term "P450" is derived from the spectrophotometric peak at the wavelength of the absorption maximum of the enzyme (450 nm) when it is in the reduced state and complexed with carbon monoxide.

CYP enzymes have been identified in all kingdoms of life: animals, plants, fungi, protists, bacteria, archaea, and even in viruses. However, they are not omnipresent; for example, they have not been found in Escherichia coli. More than 50,000 distinct CYP proteins are known.

Most CYPs require a protein partner to deliver one or more electrons to reduce the iron (and eventually molecular oxygen). Based on the nature of the electron transfer proteins, CYPs can be classified into several groups:

• Microsomal P450 systems, in which electrons are transferred from NADPH via cytochrome P450 reductase (variously CPR, POR, or CYPOR). Cytochrome b₅ (cyb₅) can also contribute reducing power to this system after being reduced by cytochrome b₅ reductase (CYB₅R).
• Mitochondrial P450 systems, which employ adrenodoxin reductase and adrenodoxin to transfer electrons from NADPH to P450.
• Bacterial P450 systems, which employ a ferredoxin reductase and a ferredoxin to transfer electrons to P450.
• CYB₅R/cyb₅/P450 systems, in which both electrons required by the CYP come from cytochrome b₅.
• FMN/Fd/P450 systems, originally found in Rhodococcus species, in which a FMN-domain-containing reductase is fused to the CYP.
• P450 only systems, which do not require external reducing power. Notable ones include thromboxane synthase (CYP5), prostacyclin synthase (CYP8), and CYP74A (allene oxide synthase).

The most common reaction catalyzed by cytochromes P450 is a monooxygenase reaction, e.g., insertion of one atom of oxygen into the aliphatic position of an organic substrate (RH) while the other oxygen atom is reduced to water:

RH + O₂ + NADPH + H⁺ → ROH + H₂O + NADP⁺

Many hydroxylation reactions (insertion of hydroxyl groups) use CYP enzymes.

Nomenclature

Genes encoding CYP enzymes, and the enzymes themselves, are designated with the root symbol CYP for the superfamily, followed by a number indicating the gene family, a capital letter indicating the subfamily, and another numeral for the individual gene. The convention is to italicise the name when referring to the gene. For example, CYP2E1 is the gene that encodes the enzyme CYP2E1—one of the enzymes involved in paracetamol (acetaminophen) metabolism. The CYP nomenclature is the official naming convention, although occasionally CYP450 or CYP₄₅₀ is used synonymously. However, some gene or enzyme names for CYPs may differ from this nomenclature, denoting the catalytic activity and the name of the compound used as substrate. Examples include CYP5A1, thromboxane A₂ synthase, abbreviated to TBXAS1 (ThromBoXane A₂ Synthase 1), and CYP51A1, lanosterol 14-α-demethylase, sometimes unofficially abbreviated to LDM according to its substrate (Lanosterol) and activity (DeMethylation).

The current nomenclature guidelines suggest that members of new CYP families share at least 40% amino acid identity, while members of subfamilies must share at least 55% amino acid identity. There are nomenclature committees that assign and track both base gene names (Cytochrome P450 Homepage) and allele names (CYP Allele Nomenclature Committee).

Mechanism

The "Fe(V) intermediate" at the bottom left is a simplification: it is an Fe(IV) with a radical heme ligand.

Structure

The active site of cytochrome P450 contains a heme-iron center. The iron is tethered to the protein via a cysteine thiolate ligand. This cysteine and several flanking residues are highly conserved in known CYPs and have the formal PROSITE signature consensus pattern [FW] - [SGNH] - x - [GD] - {F} - [RKHPT] - {P} - C - [LIVMFAP] - [GAD]. Because of the vast variety of reactions catalyzed by CYPs, the activities and properties of the many CYPs differ in many aspects. In general, the P450 catalytic cycle proceeds as follows:

Catalytic cycle

1. Substrate binds in proximity to the heme group, on the side opposite to the axial thiolate. Substrate binding induces a change in the conformation of the active site, often displacing a water molecule from the distal axial coordination position of the heme iron, and changing the state of the heme iron from low-spin to high-spin.
2. Substrate binding induces electron transfer from NAD(P)H via cytochrome P450 reductase or another associated reductase.
3. Molecular oxygen binds to the resulting ferrous heme center at the distal axial coordination position, initially giving a dioxygen adduct not unlike oxy-myoglobin.
4. A second electron is transferred, from either cytochrome P450 reductase, ferredoxins, or cytochrome b₅, reducing the Fe-O₂ adduct to give a short-lived peroxo state.
5. The peroxo group formed in step 4 is rapidly protonated twice, releasing one molecule of water and forming the highly reactive species referred to as P450 Compound 1 (or just Compound I). This highly reactive intermediate was isolated in 2010, P450 Compound 1 is an iron(IV) oxo (or ferryl) species with an additional oxidizing equivalent delocalized over the porphyrin and thiolate ligands. Evidence for the alternative perferryl iron(V)-oxo  is lacking.
6. Depending on the substrate and enzyme involved, P450 enzymes can catalyze any of a wide variety of reactions. A hypothetical hydroxylation is shown in this illustration. After the product has been released from the active site, the enzyme returns to its original state, with a water molecule returning to occupy the distal coordination position of the iron nucleus.

Oxygen rebound mechanism utilized by cytochrome P450 for conversion of hydrocarbons to alcohols via the action of "compound I", an iron(IV) oxide bound to a heme radical cation.

1. An alternative route for mono-oxygenation is via the "peroxide shunt" (path "S" in figure). This pathway entails oxidation of the ferric-substrate complex with oxygen-atom donors such as peroxides and hypochlorites. A hypothetical peroxide "XOOH" is shown in the diagram.

Spectroscopy

Binding of substrate is reflected in the spectral properties of the enzyme, with an increase in absorbance at 390 nm and a decrease at 420 nm. This can be measured by difference spectrometry and is referred to as the "type I" difference spectrum (see inset graph in figure). Some substrates cause an opposite change in spectral properties, a "reverse type I" spectrum, by processes that are as yet unclear. Inhibitors and certain substrates that bind directly to the heme iron give rise to the type II difference spectrum, with a maximum at 430 nm and a minimum at 390 nm (see inset graph in figure). If no reducing equivalents are available, this complex may remain stable, allowing the degree of binding to be determined from absorbance measurements in vitro C: If carbon monoxide (CO) binds to reduced P450, the catalytic cycle is interrupted. This reaction yields the classic CO difference spectrum with a maximum at 450 nm.

P450s in humans

Human CYPs are primarily membrane-associated proteins located either in the inner membrane of mitochondria or in the endoplasmic reticulum of cells. CYPs metabolize thousands of endogenous and exogenous chemicals. Some CYPs metabolize only one (or a very few) substrates, such as CYP19 (aromatase), while others may metabolize multiple substrates. Both of these characteristics account for their central importance in medicine. Cytochrome P450 enzymes are present in most tissues of the body, and play important roles in hormone synthesis and breakdown (including estrogen and testosterone synthesis and metabolism), cholesterol synthesis, and vitamin D metabolism. Cytochrome P450 enzymes also function to metabolize potentially toxic compounds, including drugs and products of endogenous metabolism such as bilirubin, principally in the liver.

The Human Genome Project has identified 57 human genes coding for the various cytochrome P450 enzymes.

Drug metabolism

Proportion of antifungal drugs metabolized by different families of CYPs.

CYPs are the major enzymes involved in drug metabolism, accounting for about 75% of the total metabolism. Most drugs undergo deactivation by CYPs, either directly or by facilitated excretion from the body. Also, many substances are bioactivated by CYPs to form their active compounds.

Drug interaction

Many drugs may increase or decrease the activity of various CYP isozymes either by inducing the biosynthesis of an isozyme (enzyme induction) or by directly inhibiting the activity of the CYP (enzyme inhibition). This is a major source of adverse drug interactions, since changes in CYP enzyme activity may affect the metabolism and clearance of various drugs. For example, if one drug inhibits the CYP-mediated metabolism of another drug, the second drug may accumulate within the body to toxic levels. Hence, these drug interactions may necessitate dosage adjustments or choosing drugs that do not interact with the CYP system. Such drug interactions are especially important to take into account when using drugs of vital importance to the patient, drugs with important side-effects and drugs with small therapeutic windows, but any drug may be subject to an altered plasma concentration due to altered drug metabolism.

A classical example includes anti-epileptic drugs. Phenytoin, for example, induces CYP1A2, CYP2C9, CYP2C19, and CYP3A4. Substrates for the latter may be drugs with critical dosage, like amiodarone or carbamazepine, whose blood plasma concentration may either increase because of enzyme inhibition in the former, or decrease because of enzyme induction in the latter.

Interaction of other substances

Naturally occurring compounds may also induce or inhibit CYP activity. For example, bioactive compounds found in grapefruit juice and some other fruit juices, including bergamottin, dihydroxybergamottin, and paradicin-A, have been found to inhibit CYP3A4-mediated metabolism of certain medications, leading to increased bioavailability and, thus, the strong possibility of overdosing. Because of this risk, avoiding grapefruit juice and fresh grapefruits entirely while on drugs is usually advised.

Other examples:

• Saint-John's wort, a common herbal remedy induces CYP3A4, but also inhibits CYP1A1, CYP1B1.
• Tobacco smoking induces CYP1A2 (example CYP1A2 substrates are clozapine, olanzapine, and fluvoxamine)
• At relatively high concentrations, starfruit juice has also been shown to inhibit CYP2A6 and other CYPs. Watercress is also a known inhibitor of the cytochrome P450 CYP2E1, which may result in altered drug metabolism for individuals on certain medications (e.g., chlorzoxazone).
• Tributyltin has been found to inhibit the function of cytochrome P450, leading to masculinization of mollusks.
• Goldenseal, with its two notable alkaloids berberine and hydrastine, has been shown to alter P450-marker enzymatic activities (involving CYP2C9, CYP2D6, and CYP3A4).

Other specific CYP functions

Steroid hormones

Steroidogenesis, showing many of the enzyme activities that are performed by cytochrome P450 enzymes. HSD: Hydroxysteroid dehydrogenase.

A subset of cytochrome P450 enzymes play important roles in the synthesis of steroid hormones (steroidogenesis) by the adrenals, gonads, and peripheral tissue:

• CYP11A1 (also known as P450scc or P450c11a1) in adrenal mitochondria affects "the activity formerly known as 20,22-desmolase" (steroid 20α-hydroxylase, steroid 22-hydroxylase, cholesterol side-chain scission).
• CYP11B1 (encoding the protein P450c11β) found in the inner mitochondrial membrane of adrenal cortex has steroid 11β-hydroxylase, steroid 18-hydroxylase, and steroid 18-methyloxidase activities.
• CYP11B2 (encoding the protein P450c11AS), found only in the mitochondria of the adrenal zona glomerulosa, has steroid 11β-hydroxylase, steroid 18-hydroxylase, and steroid 18-methyloxidase activities.
• CYP17A1, in endoplasmic reticulum of adrenal cortex has steroid 17α-hydroxylase and 17,20-lyase activities.
• CYP21A1 (P450c21) in adrenal cortex conducts 21-hydroxylase activity.
• CYP19A (P450arom, aromatase) in endoplasmic reticulum of gonads, brain, adipose tissue, and elsewhere catalyzes aromatization of androgens to estrogens.

Polyunsaturated fatty acids and eicosanoids

Certain cytochrome P450 enzymes are critical in metabolizing polyunsaturated fatty acids (PUFAs) to biologically active, intercellular cell signaling molecules (eicosanoids) and/or metabolize biologically active metabolites of the PUFA to less active or inactive products. These CYPs possess cytochrome P450 omega hydroxylase and/or epoxygenase enzyme activity.

• CYP1A1, CYP1A2, and CYP2E1 metabolize endogenous PUFAs to signaling molecules: they metabolize arachidonic acid (i.e. AA) to 19-hydroxyeicosatetraenoic acid (i.e. 19-HETE; see 20-hydroxyeicosatetraenoic acid); eicosapentaenoic acid (i.e. EPA) to epoxyeicosatetraenoic acids (i.e. EEQs); and docosahexaenoic acid (i.e. DHA) to epoxydocosapentaenoic acids (i.e. EDPs).
• CYP2C8, CYP2C9, CYP2C18, CYP2C19, and CYP2J2 metabolize endogenous PUFAs to signaling molecules: they metabolize AA to epoxyeicosatetraenoic acids (i.e. EETs); EPA to EEQs; and DHA to EDPs.
• CYP2S1 metabolizes PUFA to signaling molecules: it metabolizes AA to EETs ad EPA to EEQs.
• CYP3A4 metabolizes AA to EET signaling molecules.
• CYP4A11 metabolizes endogenous PUFAs to signaling molecules: it metabolizes AA to 20-HETE and EETs; it also hydroxylates DHA to 22-hydroxy-DHA (i.e. 12-HDHA).
• CYP4F2, CYP4F3A, and CYP4F3B (see CYP4F3 for latter two CYPs) metabolize PUFAs to signaling molecules: they metabolizes AA to 20-HETE. They also metabolize EPA to 19-hydroxyeicosapentaenoic acid (19-HEPE) and 20-hydroxyeicosapentaenoic acid (20-HEPE) as well as metabolize DHA to 22-HDA. They also inactivate or reduce the activity of signaling molecules: they metabolize leukotriene B4 (LTB4) to 20-hydroxy-LTB4, 5-hydroxyeicosatetraenoic acid (5-HETE) to 5,20-diHETE, 5-oxo-eicosatetraenoic acid (5-oxo-ETE) to 5-oxo,20-hydroxy-ETE, 12-hydroxyeicosatetraenoic acid (12-HETE) to 12,20-diHETE, EETs to 20-hydroxy-EETs, and lipoxins to 20-hydroxy products.
• CYP4F8 and CYP4F12 metabolize PUFAs to signaling molecules: they metabolizes EPA to EEQs and DHA to EDPs. They also metabolize AA to 18-hydroxyeicosatetraenoic acid (18-HETE) and 19-HETE.
• CYP4F11 inactivates or reduces the activity of signaling molecules: it metabolizes LTB4 to 20-hydroxy-LTB4, (5-HETE) to 5,20-diHETE, (5-oxo-ETE) to 5-oxo,20-hydroxy-ETE, (12-HETE) to 12,20-diHETE, EETs to 20-hydroxy-EETs, and lipoxins to 20-hydroxy products.
• CYP4F22 ω-hydroxylates extremely long "very long chain fatty acids", i.e. fatty acids that are 28 or more carbons long. The ω-hydroxylation of these special fatty acids is critical to creating and maintaining the skins water barrier function; autosomal recessive inactivating mutations of CYP4F22 are associated with the Lamellar ichthyosis subtype of Congenital ichthyosiform erythrodema in humans.

CYP families in humans

Humans have 57 genes and more than 59 pseudogenes divided among 18 families of cytochrome P450 genes and 43 subfamilies. This is a summary of the genes and of the proteins they encode.

Family	Function	Members	Names
CYP1	drug and steroid (especially estrogen) metabolism, benzo[a]pyrene toxification (forming (+)-benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide)	3 subfamilies, 3 genes, 1 pseudogene	CYP1A1, CYP1A2, CYP1B1
CYP2	drug and steroid metabolism	13 subfamilies, 16 genes, 16 pseudogenes	CYP2A6, CYP2A7, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2F1, CYP2J2, CYP2R1, CYP2S1, CYP2U1, CYP2W1
CYP3	drug and steroid (including testosterone) metabolism	1 subfamily, 4 genes, 2 pseudogenes	CYP3A4, CYP3A5, CYP3A7, CYP3A43
CYP4	arachidonic acid or fatty acid metabolism	6 subfamilies, 12 genes, 10 pseudogenes	CYP4A11, CYP4A22, CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4F22, CYP4V2, CYP4X1, CYP4Z1
CYP5	thromboxane A2 synthase	1 subfamily, 1 gene	CYP5A1
CYP7	bile acid biosynthesis 7-alpha hydroxylase of steroid nucleus	2 subfamilies, 2 genes	CYP7A1, CYP7B1
CYP8	varied	2 subfamilies, 2 genes	CYP8A1 (prostacyclin synthase), CYP8B1 (bile acid biosynthesis)
CYP11	steroid biosynthesis	2 subfamilies, 3 genes	CYP11A1, CYP11B1, CYP11B2
CYP17	steroid biosynthesis, 17-alpha hydroxylase	1 subfamily, 1 gene	CYP17A1
CYP19	steroid biosynthesis: aromatase synthesizes estrogen	1 subfamily, 1 gene	CYP19A1
CYP20	unknown function	1 subfamily, 1 gene	CYP20A1
CYP21	steroid biosynthesis	2 subfamilies, 1 gene, 1 pseudogene	CYP21A2
CYP24	vitamin D degradation	1 subfamily, 1 gene	CYP24A1
CYP26	retinoic acid hydroxylase	3 subfamilies, 3 genes	CYP26A1, CYP26B1, CYP26C1
CYP27	varied	3 subfamilies, 3 genes	CYP27A1 (bile acid biosynthesis), CYP27B1 (vitamin D3 1-alpha hydroxylase, activates vitamin D3), CYP27C1 (unknown function)
CYP39	7-alpha hydroxylation of 24-hydroxycholesterol	1 subfamily, 1 gene	CYP39A1
CYP46	cholesterol 24-hydroxylase	1 subfamily, 1 gene	CYP46A1
CYP51	cholesterol biosynthesis	1 subfamily, 1 gene, 3 pseudogenes	CYP51A1 (lanosterol 14-alpha demethylase)

P450s in other species

Animals

Many animals have as many or more CYP genes than humans do. Reported numbers range from 35 genes in the sponge Amphimedon queenslandica to 235 genes in the cephalochordate Branchiostoma floridae. Mice have genes for 101 CYPs, and sea urchins have even more (perhaps as many as 120 genes). Most CYP enzymes are presumed to have monooxygenase activity, as is the case for most mammalian CYPs that have been investigated (except for, e.g., CYP19 and CYP5). Gene and genome sequencing is far outpacing biochemical characterization of enzymatic function, though many genes with close homology to CYPs with known function have been found, giving clues to their functionality.

The classes of CYPs most often investigated in non-human animals are those either involved in development (e.g., retinoic acid or hormone metabolism) or involved in the metabolism of toxic compounds (such as heterocyclic amines or polyaromatic hydrocarbons). Often there are differences in gene regulation or enzyme function of CYPs in related animals that explain observed differences in susceptibility to toxic compounds (ex. canines inability to metabolize xanthines such as caffeine). Some drugs undergo metabolism in both species via different enzymes, resulting in different metabolites, while other drugs are metabolized in one species but excreted unchanged in another species. For this reason, one species's reaction to a substance is not a reliable indication of the substance's effects in humans.

CYPs have been extensively examined in mice, rats, dogs, and less so in zebrafish, in order to facilitate use of these model organisms in drug discovery and toxicology. Recently CYPs have also been discovered in avian species, in particular turkeys, that may turn out to be a useful model for cancer research in humans. CYP1A5 and CYP3A37 in turkeys were found to be very similar to the human CYP1A2 and CYP3A4 respectively, in terms of their kinetic properties as well as in the metabolism of aflatoxin B1.

CYPs have also been heavily studied in insects, often to understand pesticide resistance. For example, CYP6G1 is linked to insecticide resistance in DDT-resistant Drosophila melanogaster and CYP6Z1 in the mosquito malaria vector Anopheles gambiae is capable of directly metabolizing DDT.

Microbial

Microbial cytochromes P450 are often soluble enzymes and are involved in diverse metabolic processes. In bacteria the distribution of P450s is very variable with many bacteria having no identified P450s (e.g. E.coli). Some bacteria, predominantly actinomycetes, have numerous P450s (e.g.,). Those so far identified are generally involved in either biotransformation of xenobiotic compounds (e.g. CYP105A1 from Streptomyces griseolus metabolizes sulfonylurea herbicides to less toxic derivatives,) or are part of specialised metabolite biosynthetic pathways (e.g. CYP170B1 catalyses production of the sesquiterpenoid albaflavenone in Streptomyces albus,). Although no P450 has yet been shown to be essential in a microbe, the CYP105 family is highly conserved with a representative in every streptomycete genome sequenced so far. Due to the solubility of bacterial P450 enzymes, they are generally regarded as easier to work with than the predominantly membrane bound eukaryotic P450s. This, combined with the remarkable chemistry they catalyse, has led to many studies using the heterologously expressed proteins in vitro. Few studies have investigated what P450s do in vivo, what the natural substrate(s) are and how P450s contribute to survival of the bacteria in the natural environment.Three examples that have contributed significantly to structural and mechanistic studies are listed here, but many different families exist.

• Cytochrome P450cam (CYP101) originally from Pseudomonas putida has been used as a model for many cytochromes P450 and was the first cytochrome P450 three-dimensional protein structure solved by X-ray crystallography. This enzyme is part of a camphor-hydroxylating catalytic cycle consisting of two electron transfer steps from putidaredoxin, a 2Fe-2S cluster-containing protein cofactor.
• Cytochrome P450 eryF (CYP107A1) originally from the actinomycete bacterium Saccharopolyspora erythraea is responsible for the biosynthesis of the antibiotic erythromycin by C6-hydroxylation of the macrolide 6-deoxyerythronolide B.
• Cytochrome P450 BM3 (CYP102A1) from the soil bacterium Bacillus megaterium catalyzes the NADPH-dependent hydroxylation of several long-chain fatty acids at the ω–1 through ω–3 positions. Unlike almost every other known CYP (except CYP505A1, cytochrome P450 foxy), it constitutes a natural fusion protein between the CYP domain and an electron donating cofactor. Thus, BM3 is potentially very useful in biotechnological applications.
• Cytochrome P450 119 (CYP119) isolated from the thermophillic archea Sulfolobus acidocaldarius  has been used in a variety of mechanistic studies. Because thermophillic enzymes evolved to function at high temperatures, they tend to function more slowly at room temperature (if at all) and are therefore excellent mechanistic models.

Fungi

The commonly used azole class antifungal drugs work by inhibition of the fungal cytochrome P450 14α-demethylase. This interrupts the conversion of lanosterol to ergosterol, a component of the fungal cell membrane. (This is useful only because humans' P450 have a different sensitivity; this is how this class of antifungals work.)

Significant research is ongoing into fungal P450s, as a number of fungi are pathogenic to humans (such as Candida yeast and Aspergillus) and to plants.

Cunninghamella elegans is a candidate for use as a model for mammalian drug metabolism.

Plants

Plant cytochrome P450s are involved in a wide range of biosynthetic reactions and target a diverse range of biomolecules. These reactions lead to various fatty acid conjugates, plant hormones, secondary metabolites, lignins, and a variety of defensive compounds. Plant genome annotations suggest that cytochrome P450 genes make up as much as 1% of the plant genes. The number and diversity of P450 genes is responsible, in part, for the multitude of bioactive compounds.

P450s in biotechnology

The remarkable reactivity and substrate promiscuity of P450s have long attracted the attention of chemists. Recent progress towards realizing the potential of using P450s towards difficult oxidations have included: (i) eliminating the need for natural co-factors by replacing them with inexpensive peroxide containing molecules, (ii) exploring the compatibility of P450s with organic solvents, and (iii) the use of small, non-chiral auxiliaries to predictably direct P450 oxidation.

InterPro subfamilies

InterPro subfamilies:

• Cytochrome P450, B-class InterPro: IPR002397
• Cytochrome P450, mitochondrial InterPro: IPR002399
• Cytochrome P450, E-class, group I InterPro: IPR002401
• Cytochrome P450, E-class, group II InterPro: IPR002402
• Cytochrome P450, E-class, group IV InterPro: IPR002403
• Aromatase

Clozapine, imipramine, paracetamol, phenacetin Heterocyclic aryl amines Inducible and CYP1A2 5-10% deficient oxidize uroporphyrinogen to uroporphyrin (CYP1A2) in heme metabolism, but they may have additional undiscovered endogenous substrates. are inducible by some polycyclic hydrocarbons, some of which are found in cigarette smoke and charred food.

These enzymes are of interest, because in assays, they can activate compounds to carcinogens. High levels of CYP1A2 have been linked to an increased risk of colon cancer. Since the 1A2 enzyme can be induced by cigarette smoking, this links smoking with colon cancer.

Dextromethorphan

From Wikipedia, the free encyclopedia

Dextromethorphan

Clinical data
Trade names	Robitussin, Delsym, DM, DexAlone, Duract, others
AHFS/Drugs.com	Monograph
MedlinePlus	a682492
Pregnancy category	AU: A US: C (Risk not ruled out)
Dependence liability	Low
Routes of administration	By mouth
ATC code	R05DA09 (WHO)
Legal status
Legal status	AU: S2 (Pharmacy only) CA: OTC UK: P (Pharmacy medicines) US: OTC
Pharmacokinetic data
Bioavailability	11%
Metabolism	Hepatic (liver) enzymes: major CYP2D6, minor CYP3A4, and minor CYP3A5
Elimination half-life	2–4 hours (extensive metabolizers); 24 hours (poor metabolizers)
Excretion	Renal
Chemical and physical data
Formula	C18H25NO
Molar mass	271.40 g/mol
3D model (JSmol)	Interactive image
Melting point	111 °C (232 °F)

Dextromethorphan (DXM or DM) is a medication most often used as a cough suppressant in over-the-counter cold and cough medicines. It is sold in syrup, tablet, spray, and lozenge forms.

It is in the morphinan class of medications with sedative, dissociative, and stimulant properties (at lower doses). In its pure form, dextromethorphan occurs as a white powder.

DXM is also used recreationally. When exceeding approved dosages, dextromethorphan acts as a dissociative anesthetic. It has multiple mechanisms of action, including actions as a nonselective serotonin reuptake inhibitor and a sigma-1 receptor agonist. DXM and its major metabolite, dextrorphan, also act as an NMDA receptor antagonist at high doses, which produces effects similar to, yet distinct from, the dissociative states created by other dissociative anesthetics such as ketamine and phencyclidine.

The metabolic pathway continues from dextrorphan to 3-methoxymorphinan to 3-hydroxymorphinan. The 3-methoxymorphinan metabolite produces local anesthetic effects in rats, with potency between dextrorphan and DXM.

Medical uses

Generic dextromethorphan cough syrup.

Cough suppression

The primary use of dextromethorphan is as a cough suppressant, for the temporary relief of cough caused by minor throat and bronchial irritation (such as commonly accompanies the flu and common cold), as well as those resulting from inhaled particle irritants. However, controlled studies have found the symptomatic effectiveness of dextromethorphan similar to placebo.

Neuropsychiatric disorders

In 2010, the FDA approved the combination drug dextromethorphan/quinidine for the treatment of pseudobulbar affect (emotional instability). Dextromethorphan is the actual therapeutic agent in the combination; quinidine merely serves to inhibit the enzymatic degradation of dextromethorphan and thereby increase its circulating concentrations via inhibition of CYP2D6.

In 2016, the ASA released a promising study with the combination of dextromethorphan with pregabalin, acetaminophen, and naproxen which showed a decrease in postoperative pain intensity (preemptive analgesia).

Contraindications

Because dextromethorphan can trigger a histamine release (allergic reaction), atopic children, who are especially susceptible to allergic reactions, should be administered dextromethorphan only if absolutely necessary, and only under the strict supervision of a healthcare professional.

Adverse effects

Side effects of dextromethorphan at normal therapeutic doses can include:

• body rash/itching (see below)
• nausea
• vomiting
• drowsiness
• dizziness
• constipation
• diarrhea
• sedation
• confusion
• nervousness
• closed-eye hallucination

A rare side effect is respiratory depression.

Neurotoxicity

Dextromethorphan had been thought to cause Olney's lesions when administered intravenously; however, this was later proven inconclusive, due to lack of research on humans. Tests were performed on rats, giving them 50 mg and up every day up to a month. Neurotoxic changes, including vacuolation, have been observed in posterior cingulate and retrosplenial cortices of rats administered other NMDA receptor antagonists such as PCP, but not with dextromethorphan.

Dependence and withdrawal

In many documented cases, dextromethorphan has produced psychological dependence in people who used it recreationally. However, it does not produce physical addiction, according to the WHO Committee on Drug Dependence. It is considered less addictive than the other common weak opiate cough suppressant, codeine. Since dextromethorphan also acts as a serotonin reuptake inhibitor, users describe that regular recreational use over a long period of time can cause withdrawal symptoms similar to those of antidepressant discontinuation syndrome. Additionally, disturbances have been reported in sleep, senses, movement, mood, and thinking.

Overdose

Adverse effects of dextromethorphan in overdose at doses 3 to 10 times the recommended therapeutic dose:

• euphoria
• increased energy
• increased confidence
• mild nausea
• restlessness
• insomnia
• talking fast
• feelings of increased strength
• dilated pupils
• glassy eyes
• Dizziness

At doses 15 to 75 times the recommended therapeutic dose:

• hallucinations
• dissociation
• vomiting
• blurred vision
• double vision
• bloodshot eyes
• dilated pupils
• sweating
• fever
• bruxia
• hypotension
• hypertension
• tachycardia
• shallow respiration
• diarrhea
• urinary retention
• muscle spasms
• sedation
• euphoria
• paresthesia
• blackouts
• sight loss
• inability to focus eyes
• skin rash

Interactions

Dextromethorphan should not be taken with monoamine oxidase inhibitors (MAOIs)^[12] due to the potential for serotonin syndrome, which is a potentially life-threatening condition that can occur rapidly, due to a buildup of an excessive amount of serotonin in the body.

Caution should be exercised when taking dextromethorphan when drinking grapefruit juice or eating grapefruits, as compounds in grapefruit affect a number of drugs, including dextromethorphan, through the inhibition of the cytochrome p450 system in the liver, and can lead to excessive accumulation and prolonged effects. Grapefruit and grapefruit juices (especially white grapefruit juice, but also including other citrus fruits such as bergamot and lime, as well as a number of noncitrus fruits) generally are recommended to be avoided while using dextromethorphan and numerous other medications.

Pharmacology

Pharmacodynamics

Dextromethorphan (and metabolite)

Site	DXM	DXO	Species
NMDAR (MK-801)	2,120–8,945	486–906	Rat
σ1	142–652	118–481	Rat
σ2	11,060–22,864	11,325–15,582	Rat
MOR	1,280 ND	420 >1,000	Rat Human
DOR	11,500	34,700	Rat
KOR	7,000	5,950	Rat
SERT	23–40	401–484	Rat
NET	≥240	≥340	Rat
DAT	>1,000	>1,000	Rat
5-HT1A	>1,000	>1,000	Rat
5-HT1B/1D	61% at 1 μM	54% at 1 μM	Rat
5-HT2A	>1,000	>1,000	Rat
α1	>1,000	>1,000	Rat
α2	60% at 1 μM	>1,000	Rat
β	>1,000	35% at 1 μM	Rat
D2	>1,000	>1,000	Rat
H1	>1,000	95% at 1 μM	Rat
mAChRs	>1,000	100% at 1 μM	Rat
nAChRs	700–8,900 (IC50)	1,300–29,600 (IC50)	Rat
VDSCs	>50,000 (IC50)	ND	Rat
Values are Ki (nM), unless otherwise noted. The smaller the value, the more strongly the drug binds to the site.

Dextromethorphan has been found to possess the following actions:

• Uncompetitive antagonist of the NMDA receptor via the MK-801/PCP site
• Sigma σ₁ receptor agonist
• μ-Opioid receptor agonist
• SERT and NET blocker (i.e., serotonin–norepinephrine reuptake inhibitor)
• Negative allosteric modulator of nicotinic acetylcholine receptors
• Ligand of the serotonin 5-HT_1B/1D, histamine H₁, α₂-adrenergic, and muscarinic acetylcholine receptors

Rather than acting as a direct NMDA receptor antagonist itself, dextromethorphan acts as a prodrug of its much more potent metabolite dextrorphan, and this is the actual mediator of its dissociative effects. What role, if any, (+)-3-methoxymorphinan, dextromethorphan's other major metabolite, plays in its effects is not entirely clear.

Pharmacokinetics

Following oral administration, dextromethorphan is rapidly absorbed from the gastrointestinal tract, where it enters the bloodstream and crosses the blood–brain barrier.

At therapeutic doses, dextromethorphan acts centrally (meaning that it acts on the brain) as opposed to locally (on the respiratory tract). It elevates the threshold for coughing, without inhibiting ciliary activity. Dextromethorphan is rapidly absorbed from the gastrointestinal tract and converted into the active metabolite dextrorphan in the liver by the cytochrome P450 enzyme CYP2D6. The average dose necessary for effective antitussive therapy is between 10 and 45 mg, depending on the individual. The International Society for the Study of Cough recommends "an adequate first dose of medication is 60 mg in the adult and repeat dosing should be infrequent rather than the qds recommended."

DXM has an elimination half-life of approximately 4 hours in individuals with an extensive metabolizer phenotype; this is increased to approximately 13 hours when DXM is given in combination with quinidine. The duration of action after oral administration is about three to eight hours for dextromethorphan hydrobromide, and 10 to 12 hours for dextromethorphan polistirex. Around one in 10 of the Caucasian population has little or no CYP2D6 enzyme activity, leading to long-lived high drug levels.

Metabolism

Main metabolism pathways for DXM degeration catalyzed by cytochrome P450 monooxygenases (CYP3A4 and CYP2D6) and UDP-glucuronosyl-transferase (UGT).

The first pass through the hepatic portal vein results in some of the drug being metabolized by O-demethylation into an active metabolite of dextromethorphan called dextrorphan (DXO). DXO is the 3-hydroxy derivative of dextromethorphan. The therapeutic activity of dextromethorphan is believed to be caused by both the drug and this metabolite. Dextromethorphan also undergoes N-demethylation (to 3-methoxymorphinan or MEM), and partial conjugation with glucuronic acid and sulfate ions. Hours after dextromethorphan therapy, (in humans) the metabolites (+)-3-hydroxy-N-methylmorphinan, (+)-3-morphinan, and traces of the unchanged drug are detectable in the urine.

A major metabolic catalyst involved is the cytochrome P450 enzyme known as 2D6, or CYP2D6. A significant portion of the population has a functional deficiency in this enzyme and are known as poor CYP2D6 metabolizers. O-demethylation of DXM to DXO contributes to at least 80% of the DXO formed during DXM metabolism. As CYP2D6 is a major metabolic pathway in the inactivation of dextromethorphan, the duration of action and effects of dextromethorphan can be increased by as much as three times in such poor metabolizers. In one study on 252 Americans, 84.3% were found to be "fast" (extensive) metabolizers, 6.8% to be "intermediate" metabolizers, and 8.8% were "slow" metabolizers of DXM. A number of alleles for CYP2D6 are known, including several completely inactive variants. The distribution of alleles is uneven amongst ethnic groups.

A large number of medications are potent inhibitors of CYP2D6. Some types of medications known to inhibit CYP2D6 include certain SSRIs and tricyclic antidepressants, some antipsychotics, and the commonly available antihistamine diphenhydramine. Therefore, the potential of interactions exists between dextromethorphan and medications that inhibit this enzyme, particularly in slow metabolizers.

DXM is also metabolized by CYP3A4. N-demethylation is primarily accomplished by CYP3A4, contributing to at least 90% of the MEM formed as a primary metabolite of DXM.

A number of other CYP enzymes are implicated as minor pathways of DXM metabolism. CYP2B6 is actually more effective than CYP3A4 at N-demethylation of DXM, but, since the average individual has a much lower CYP2B6 content in his/her liver relative to CYP3A4, most N-demethylation of DXM is catalyzed by CYP3A4.

Chemistry

Dextromethorphan is the dextrorotatory enantiomer of levomethorphan, which is the methyl ether of levorphanol, both opioid analgesics. It is named according to IUPAC rules as (+)-3-methoxy-17-methyl-9α,13α,14α-morphinan. As its pure form, dextromethorphan occurs as an odorless, opalescent white powder. It is freely soluble in chloroform and insoluble in water; the hydrobromide salt is water-soluble up to 1.5 g/100 mL at 25 °C. Dextromethorphan is commonly available as the monohydrated hydrobromide salt, however some newer extended-release formulations contain dextromethorphan bound to an ion-exchange resin based on polystyrene sulfonic acid. Dextromethorphan's specific rotation in water is +27.6° (20 °C, Sodium D-line).

History

The racemic parent compound racemorphan was first described in a Swiss and US patent application from Hoffmann-La Roche in 1946 and 1947, respectively; a patent was granted in 1950. A resolution of the two isomers of racemorphan with tartaric acid was published in 1952, and DXM was successfully tested in 1954 as part of US Navy and CIA-funded research on nonaddictive substitutes for codeine. DXM was approved by the FDA in 1958 as an over-the-counter antitussive. As had been initially hoped, DXM was a solution for some of the problems associated with the use of codeine phosphate as a cough suppressant, such as sedation and opiate dependence, but like the dissociative anesthetics phencyclidine and ketamine, DXM later became associated with nonmedical use.

During the 1960s and 1970s, dextromethorphan became available in an over-the-counter tablet form by the brand name Romilar. In 1973, Romilar was taken off the shelves after a burst in sales because of frequent misuse, and was replaced by cough syrup in an attempt to cut down on abuse. The advent of widespread internet access in the 1990s allowed users to rapidly disseminate information about DXM, and online discussion groups formed around use and acquisition of the drug. As early as 1996, DXM HBr powder could be purchased in bulk from online retailers, allowing users to avoid consuming DXM in syrup preparations. As of January 1, 2012, dextromethorphan is prohibited for sale to minors in the state of California, except with a doctor's prescription.

In Indonesia, the National Agency of Drug and Food Control (BPOM-RI) prohibited single-component dextromethorphan drug sales with or without prescription. Indonesia is the only country in the world that makes single-component dextromethorphan illegal even by prescription and violators may be prosecuted by law. National Anti-Narcotics Agency (BNN RI) has even threatened to revoke pharmacies' and drug stores' licenses if they still stock dextromethorphan, and will notify the police for criminal prosecution. As a result of this regulation, 130 drugs have been withdrawn from the market, but drugs containing multicomponent dextromethorphan can be sold over the counter. In its official press release, BPOM-RI also stated that dextromethorphan is often used as a substitute for marijuana, amphetamine, and heroin by drug abusers, and its use as an antitussive is less beneficial nowadays.

Society and culture

Brand names

It may be used in generic labels and store brands, Benylin DM, Mucinex DM, Camydex-20 tablets, Robitussin, NyQuil, Dimetapp, Vicks, Coricidin, Delsym, TheraFlu, Cheracol D, Cinfatós and others.

Recreational use

Dextromethorphan gel capsules

Over-the-counter preparations containing dextromethorphan have been used in manners inconsistent with their labeling, often as a recreational drug. At doses much higher than medically recommended, DXM and its major metabolite, dextrorphan, acts as an NMDA receptor antagonist, which produces dissociative hallucinogenic states somewhat similar to ketamine and phencyclidine. Along with other drugs such as ketamine or phencyclidine, also known as PCP, there is a street name for dextromethorphan-infused substances which is also known as "Angel". It may produce distortions of the visual field – feelings of dissociation, distorted bodily perception, excitement, and a loss of sense of time. Some users report stimulant-like euphoria, particularly in response to music. Dextromethorphan usually provides its recreational effects in a non-linear fashion, so that they are experienced in significantly varied stages. These stages are commonly referred to as "plateaus". These plateaus are labeled between one and four, one being the lowest and so on. Each plateau is said to come with different related effects and experiences. Teens tend to have a higher likelihood to use dextromethorphan-related drugs as they are easier to access, and an easier way to cope with psychiatric disorders.

Research

Dextromethorphan/quinidine is also under investigation for the treatment of a variety of other neurological and neuropsychiatric conditions besides pseudobulbar affect, such as agitation associated with Alzheimer's disease and major depressive disorder.

Glutamic acid

From Wikipedia, the free encyclopedia

Glutamic acid

Names
Systematic IUPAC name 2-Aminopentanedioic acid
Other names 2-Aminoglutaric acid
Properties
Chemical formula	C5H9NO4
Molar mass	147.13 g·mol−1
Appearance	white crystalline powder
Density	1.4601 (20 °C)
Melting point	199 °C (390 °F; 472 K) decomposes
Solubility in water	7.5 g/L (20 °C)
Solubility	0.00035g/100g ethanol (25 °C)
Acidity (pKa)	2.10, 4.07, 9.47
Magnetic susceptibility (χ)	-78.5·10−6 cm3/mol

Glutamic acid (symbol Glu or E) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is non-essential in humans, meaning the body can synthesize it. It is also an excitatory neurotransmitter, in fact the most abundant one, in the vertebrate nervous system. It serves as the precursor for the synthesis of the inhibitory gamma-aminobutyric acid (GABA) in GABA-ergic neurons.

It has a formula C
₅H
₉O
₄N. Its molecular structure could be idealized as HOOC-CH(NH
₂)-(CH
₂)₂-COOH, with two carboxyl groups -COOH and one amino group -NH
₂. However, in the solid state and mildly acid water solutions, the molecule assumes an electrically neutral zwitterion structure ⁻OOC-CH(NH⁺
₃)-(CH
₂)₂-COOH. It is encoded by the codons GAA or GAG.

The acid can lose one proton from its second carboxyl group to form the conjugate base, the singly-negative anion glutamate ⁻OOC-CH(NH⁺
₃)-(CH
₂)₂-COO⁻. This form of the compound is prevalent in neutral solutions. The glutamate neurotransmitter plays the principal role in neural activation. This anion is also responsible for the savory flavor (umami) of certain foods, and used in glutamate flavorings such as MSG. In highly alkaline solutions the doubly negative anion ⁻OOC-CH(NH
₂)-(CH
₂)₂-COO⁻ prevails. The radical corresponding to glutamate is called glutamyl.

Chemistry

Ionization

The glutamate monoanion.

When glutamic acid is dissolved in water, the amino group (-NH
₂) may gain a proton (H⁺), and/or the carboxyl groups may lose protons, depending on the acidity of the medium.

In sufficiently acidic environments, the amino group gains a proton and the molecule becomes a cation with a single positive charge, HOOC-CH(NH⁺
₃)-(CH
₂)₂-COOH.

At pH values between about 2.5 and 4.1, the carboxylic acid closer to the amine generally loses a proton, and the acid becomes the neutral zwitterion ⁻OOC-CH(NH⁺
₃)-(CH
₂)₂-COOH. This is also the form of the compound in the crystalline solid state. The change in protonation state is gradual; the two forms are in equal concentrations at pH 2.10.

At even higher pH, the other carboxylic acid group loses its proton and the acid exists almost entirely as the glutamate anion ⁻OOC-CH(NH⁺
₃)-(CH
₂)₂-COO⁻, with a single negative charge overall. The change in protonation state occurs at pH 4.07. This form with both carboxylates lacking protons is dominant in the physiological pH range (7.35–7.45).

At even higher pH, the amino group loses the extra proton and the prevalent species is the doubly-negative anion ⁻OOC-CH(NH
₂)-(CH
₂)₂-COO⁻. The change in protonation state occurs at pH 9.47.

Optical isomerism

The carbon atom adjacent to the amino group is chiral (connected to four distinct groups), so glutamic acid can exist in two optical isomers, D(-) and L(+). The L form is the one most widely occurring in nature, but the D form occurs in some special contexts, such as the cell walls of the bacteria (which can manufacture it from the L form with the enzyme glutamate racemase) and the liver of mammals.

History

Although they occur naturally in many foods, the flavor contributions made by glutamic acid and other amino acids were only scientifically identified early in the twentieth century. The substance was discovered and identified in the year 1866, by the German chemist Karl Heinrich Ritthausen who treated wheat gluten (for which it was named) with sulfuric acid. In 1908 Japanese researcher Kikunae Ikeda of the Tokyo Imperial University identified brown crystals left behind after the evaporation of a large amount of kombu broth as glutamic acid. These crystals, when tasted, reproduced the ineffable but undeniable flavor he detected in many foods, most especially in seaweed. Professor Ikeda termed this flavor umami. He then patented a method of mass-producing a crystalline salt of glutamic acid, monosodium glutamate.

Synthesis

Biosynthesis

Reactants	Products	Enzymes
Glutamine + H2O	→ Glu + NH3	GLS, GLS2
NAcGlu + H2O	→ Glu + Acetate	N-acetyl-glutamate synthase
α-ketoglutarate + NADPH + NH4+	→ Glu + NADP+ + H2O	GLUD1, GLUD2
α-ketoglutarate + α-amino acid	→ Glu + α-keto acid	transaminase
1-Pyrroline-5-carboxylate + NAD+ + H2O	→ Glu + NADH	ALDH4A1
N-formimino-L-glutamate + FH4	→ Glu + 5-formimino-FH4	FTCD
NAAG	→ Glu + NAA	GCPII

 Industrial synthesis

Glutamic acid is produced on the largest scale of any amino acid, with an estimated annual production of about 1.5 million tons in 2006. Chemical synthesis was supplanted by the aerobic fermentation of sugars and ammonia in the 1950s, with the organism Corynebacterium glutamicum (also known as Brevibacterium flavum) being the most widely used for production. Isolation and purification can be achieved by concentration and crystallization; it is also widely available as its hydrochloride salt.

Function and uses

Metabolism

Glutamate is a key compound in cellular metabolism. In humans, dietary proteins are broken down by digestion into amino acids, which serve as metabolic fuel for other functional roles in the body. A key process in amino acid degradation is transamination, in which the amino group of an amino acid is transferred to an α-ketoacid, typically catalysed by a transaminase. The reaction can be generalised as such:

R₁-amino acid + R₂-α-ketoacid ⇌ R₁-α-ketoacid + R₂-amino acid

A very common α-keto acid is α-ketoglutarate, an intermediate in the citric acid cycle. Transamination of α-ketoglutarate gives glutamate. The resulting α-ketoacid product is often a useful one as well, which can contribute as fuel or as a substrate for further metabolism processes. Examples are as follows:

Alanine + α-ketoglutarate ⇌ pyruvate + glutamate

Aspartate + α-ketoglutarate ⇌ oxaloacetate + glutamate

Both pyruvate and oxaloacetate are key components of cellular metabolism, contributing as substrates or intermediates in fundamental processes such as glycolysis, gluconeogenesis, and the citric acid cycle.

Glutamate also plays an important role in the body's disposal of excess or waste nitrogen. Glutamate undergoes deamination, an oxidative reaction catalysed by glutamate dehydrogenase, as follows:

glutamate + H₂O + NADP⁺ → α-ketoglutarate + NADPH + NH₃ + H⁺

Ammonia (as ammonium) is then excreted predominantly as urea, synthesised in the liver. Transamination can thus be linked to deamination, effectively allowing nitrogen from the amine groups of amino acids to be removed, via glutamate as an intermediate, and finally excreted from the body in the form of urea.

Glutamate is also a neurotransmitter (see below), which makes it one of the most abundant molecules in the brain. Malignant brain tumors known as glioma or glioblastoma exploit this phenomenon by using glutamate as an energy source, especially when these tumors become more dependent on glutamate due to mutations in the gene IDH1.

Neurotransmitter

Glutamate is the most abundant excitatory neurotransmitter in the vertebrate nervous system. At chemical synapses, glutamate is stored in vesicles. Nerve impulses trigger release of glutamate from the presynaptic cell. Glutamate acts on ionotropic and metabotropic (G-protein coupled) receptors. In the opposing postsynaptic cell, glutamate receptors, such as the NMDA receptor or the AMPA receptor, bind glutamate and are activated. Because of its role in synaptic plasticity, glutamate is involved in cognitive functions such as learning and memory in the brain. The form of plasticity known as long-term potentiation takes place at glutamatergic synapses in the hippocampus, neocortex, and other parts of the brain. Glutamate works not only as a point-to-point transmitter, but also through spill-over synaptic crosstalk between synapses in which summation of glutamate released from a neighboring synapse creates extrasynaptic signaling/volume transmission. In addition, glutamate plays important roles in the regulation of growth cones and synaptogenesis during brain development as originally described by Mark Mattson.

Brain nonsynaptic glutamatergic signaling circuits

Extracellular glutamate in Drosophila brains has been found to regulate postsynaptic glutamate receptor clustering, via a process involving receptor desensitization. A gene expressed in glial cells actively transports glutamate into the extracellular space, while, in the nucleus accumbens-stimulating group II metabotropic glutamate receptors, this gene was found to reduce extracellular glutamate levels. This raises the possibility that this extracellular glutamate plays an "endocrine-like" role as part of a larger homeostatic system.

GABA precursor

Glutamate also serves as the precursor for the synthesis of the inhibitory gamma-aminobutyric acid (GABA) in GABA-ergic neurons. This reaction is catalyzed by glutamate decarboxylase (GAD), which is most abundant in the cerebellum and pancreas.

Stiff person syndrome is a neurologic disorder caused by anti-GAD antibodies, leading to a decrease in GABA synthesis and, therefore, impaired motor function such as muscle stiffness and spasm. Since the pancreas has abundant GAD, a direct immunological destruction occurs in the pancreas and the patients will have diabetes mellitus.

Flavor enhancer

Glutamic acid, being a constituent of protein, is present in foods that contain protein, but it can only be tasted when it is present in an unbound form. Significant amounts of free glutamic acid are present in a wide variety of foods, including cheese and soy sauce, and is responsible for umami, one of the five basic tastes of the human sense of taste. Glutamic acid is often used as a food additive and flavor enhancer in the form of its sodium salt, known as monosodium glutamate (MSG).

Nutrient

All meats, poultry, fish, eggs, dairy products, and kombu are excellent sources of glutamic acid. Some protein-rich plant foods also serve as sources. 30% to 35% of gluten (much of the protein in wheat) is glutamic acid. Ninety-five percent of the dietary glutamate is metabolized by intestinal cells in a first pass.

Plant growth

Auxigro is a plant growth preparation that contains 30% glutamic acid.

NMR spectroscopy

In recent years, there has been much research into the use of residual dipolar coupling (RDC) in nuclear magnetic resonance spectroscopy (NMR). A glutamic acid derivative, poly-γ-benzyl-L-glutamate (PBLG), is often used as an alignment medium to control the scale of the dipolar interactions observed.

Pharmacology

The drug phencyclidine (more commonly known as PCP) antagonizes glutamic acid non-competitively at the NMDA receptor. For the same reasons, dextromethorphan and ketamine also have strong dissociative and hallucinogenic effects. Acute infusion of the drug LY354740 (also known as eglumegad, an agonist of the metabotropic glutamate receptors 2 and 3) resulted in a marked diminution of yohimbine-induced stress response in bonnet macaques (Macaca radiata); chronic oral administration of LY354740 in those animals led to markedly reduced baseline cortisol levels (approximately 50 percent) in comparison to untreated control subjects. LY354740 has also been demonstrated to act on the metabotropic glutamate receptor 3 (GRM3) of human adrenocortical cells, downregulating aldosterone synthase, CYP11B1, and the production of adrenal steroids (i.e. aldosterone and cortisol). Glutamate does not easily pass the blood brain barrier, but, instead, is transported by a high-affinity transport system. It can also be converted into glutamine.