cytochrome P450

Cytochrome P450 Oxidase (CYP2C9)

Cytochrome P450 (abbreviated CYP, P450, infrequently CYP450) is a very large and diverse superfamily of hemoproteins found in bacteria, archaea and eukaryotes.^[1] They are so named because of their properties i.e. bound to membranes within a cell (cyto) and contain a heme pigment (chrome and P) which absorbs light at a wavelength of 450 nm when exposed to carbon monoxide^[2]. Cytochromes P450 use a plethora of both exogenous and endogenous compounds as substrates in enzymatic reactions. Usually they form part of multicomponent electron transfer chains, called P450-containing systems. The most common reaction catalysed by cytochrome P450 is a monooxygenase reaction, i.e. insertion of one atom of oxygen into an organic substrate (RH) while the other oxygen atom is reduced to water:

CYP enzymes have been identified from all lineages of life, including mammals, birds, fish, insects, worms, sea squirts, sea urchins, plants, fungi, slime molds, bacteria and archaea. More than 7700 distinct CYP sequences are known (as of September 2007; see the web site of the P450 Nomenclature Committee for current counts).^[3]

• The name P450 refers to the "pigment at 450 nm", so named for the characteristic Soret peak formed by absorbance of light at wavelengths near 450 nm when the heme iron is reduced (with sodium dithionite) and complexed to carbon monoxide.

Nomenclature

Genes encoding CYP enzymes, and the enzymes themselves, are designated with the abbreviation "CYP", followed by an Arabic numeral 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 officially preferred naming convention. 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 CYP5, thromboxane A₂ synthase, abbreviated to TXAS (ThromboXane A₂ Synthase), and CYP51, lanosterol 14-α-demethylase, abbreviated to LDM according to its substrate (Lanosterol) and activity (DeMethylation). [1]

The current nomenclature guidelines suggest that members of new CYP families share >40% amino acid identity, while members of subfamiles must share >55% amino acid identity. There is a Nomenclature Committee that keeps track of and assigns new names.

Mechanism

Main article: P450-containing systems

The active site of cytochrome P450 contains a heme iron center. The iron is tethered to the P450 protein via a thiolate ligand derived from a cysteine residue. This cysteine and several flanking residues (RXCXG) are highly conserved in known CYPs^[4]. Because of the vast variety of reactions catalyzed by CYPs, the activities and properties of the many CYPs differ in many aspects. A general description of the P450 enzyme properties can be summarized as follows:

1. The resting state of the protein is as oxidized Fe³⁺.

2. Binding of a substrate initiates electron transport and oxygen binding.

3. Electrons are supplied to the CYP by another protein, either cytochrome P450 reductase, ferredoxins, or cytochrome b5 to reduce the heme iron.

4. Molecular oxygen is bound and split by the reduced heme iron.

5. An iron-bound oxidant, in some cases an iron(IV) oxo^{[citation needed]}, oxidizes the substrate to an alcohol or an epoxide, regenerating the resting state of the CYP.

Because most CYPs require a protein partner to deliver one or more electrons to reduce the iron (and eventually molecular oxygen), CYPs are properly speaking part of P450-containing systems of proteins. Five general schemes are known:

• CPR/cyb5/P450 systems employed by most eukaryotic microsomal (i.e., not mitochondrial) CYPs involve the reduction of cytochrome P450 reductase (variously CPR,POR, or CYPOR) by NADPH, and the transfer of reducing power as electrons to the CYP. Cytochrome b5 (cyb5) can also contribute reducing power to this system after being reduced by cytochrome b5 reductase (CYB5R).
• FR/Fd/P450 systems which are employed by mitochondrial and some bacterial CYPs.
• CYB5R/cyb5/P450 systems in which both electrons required by the CYP come from cytochrome b5.
• FMN/Fd/P450 systems originally found in Rhodococcus sp. in which a FMN-domain-containing reductase is fused to the CYP.
• P450 only systems, which do not require external reducing power. Notably these include CYP5 (thromboxane synthase), CYP8, prostacyclin synthase, and CYP74A (allene oxide synthase).

P450s in bacteria

Bacterial cytochromes P450 are often soluble enzymes and are involved in critical metabolic processes. 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 cytochrome P450s 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 comprised 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.^[5][6]

P450s in plants

Plant cytochrome P450s are involved in a wide range of biosynthetic reactions, leading to various fatty acid conjugates, plant hormones, defensive compounds, or medically important drugs. Terpenoids, which represent the largest class of characterized natural plant compounds, are often substrates for plant CYPs.

P450s in animals

Animal CYPs are primarily membrane-associated proteins, located either in the inner membrane of mitochondria or in the endoplasmic reticulum of cells. CYPs metabolise thousands of endogenous and exogenous compounds. Most CYPs can metabolize multiple substrates, and many can catalyze multiple reactions, which accounts for their central importance in metabolizing the extremely large number of endogenous and exogenous molecules. In the liver, these substrates include drugs and toxic compounds as well as metabolic products such as bilirubin (a breakdown product of hemoglobin). Cytochrome P450 enzymes are present in many other tissues of the body including the mucosa of the gastrointestinal tract, and play important roles in hormone synthesis and breakdown (including estrogen and testosterone synthesis and metabolism), cholesterol synthesis, and vitamin D metabolism. In most animals, including humans, hepatic cytochromes P450 are the most widely studied of the P450 enzymes.

The Human Genome Project has identified more than 63 human genes (57 full genes and 5 pseudogenes) coding for the various cytochrome P450 enzymes.^[7]

Drug metabolism

In drug metabolism, cytochrome P450 is probably the most important element of oxidative metabolism (a part of Phase I metabolism) in animals (metabolism in this context being the chemical modification or degradation of chemicals including drugs and endogenous compounds). Many drugs may increase or decrease the activity of various CYP isozymes in a phenomenon known as enzyme induction and 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, possibly causing an overdose. Hence, these drug interactions may necessitate dosage adjustments or choosing drugs which do not interact with the CYP system. In addition, naturally occurring compounds may cause a similar effect. For example, bioactive compounds found in grapefruit juice and some other fruit juices, including bergamottin, dihydroxybergamottin, and paradisin-A, have been found to inhibit CYP3A4-mediated metabolism of certain medications, leading to increased bioavailability and thus the strong possibility of overdosing.^[8] Because of this risk, avoiding grapefruit juice and fresh grapefruits entirely while on drugs is usually advised.

Other specific CYP functions in animals

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

• CYP11A1 (also known as P450scc or P450c11a1) in adrenal mitochondria effects “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.

CYP Families in humans

Humans have 57 genes and more than 59 pseudogenes divided among 18 families of cytochrome P450 genes and 43 subfamilies.^[9] This is a summary of the genes and of the proteins they encode. See the homepage of the Cytochrome P450 Nomenclature Committee for detailed information.^[7]

References

External links

• Human Cytochrome P450 (CYP) Allele Nomenclature Committee at Karolinska Institutet
• Cytochrome P450 Homepage – David Nelson's P450 database at University of Tennessee Health Science Center
• Cytochrome P450 drug interaction table – popular source for P450-mediated drug interaction information at Indiana University-Purdue University Indianapolis
• Kiril's Directory of P450 resources at International Centre for Genetic Engineering and Biotechnology
• The Insect P450 Site (run by Rene Feyereisen) at Institut National de la Recherche Agronomique
• UMich Orientation of Proteins in Membranes families/superfamily-41
• Estabrook R (2003). "A passion for P450s (rememberances of the early history of research on cytochrome P450)". Drug Metab Dispos 31 (12): 1461-73. PMID 14625342. 
• KEGG steroid metabolism pathway

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