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Cytochrome P450 oxidase

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Cytochrome P450 Oxidase (CYP2C9) Cytochrome P450 oxidase (abbreviated CYP or CYP450) is a generic term for a large number of evolutionary related oxidative enzymes (EC 1.14) important in animal, plant, and bacterial physiology. Most cytochromes P450 (CYPs) have about 525 amino acids and a heme (hæm) group at the active site. Most animal and plant CYPs have electron transfer protein cofactors, cytochrome P450 reductase and cytochrome b5, and use molecular oxygen (O2) to function, while bacterial CYPs use other protein cofactors to function. CYP homologs have been sequenced from all lineages of life, including mammals, birds, fish, insects, worms, sea squirts, sea urchins, plants, fungi, slime molds, bacteria and archaea. More than 6400 distinct CYP sequences are known and officially named (as of October 2006; see the web site of the P450 Nomenclature Committee for current counts).

  • 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.

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[edit] P450s in Bacteria

Bacterial cytochrome P450s are often soluble enzymes and are involved in critical metabolic processes of bacteria. 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 .

[edit] 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 potentially endless variety 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). Cytochromes P450 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 63 human genes (57 full genes and 5 pseudogenes) coding for the various cytochrome P450 enzymes [1].

[edit] Drug Metabolism

In drug metabolism, cytochrome P450 is probably the most important element of oxidative metabolism (also known as 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 also 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. Because of this risk, avoiding grapefruit juice and fresh grapefruits entirely while on drugs is usually advised.

[edit] 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 metabolic substrates for plant CYPs.

[edit] Nomenclature

Genes encoding for the 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 numerals for the individual gene. The convention is to italicise when referring to the gene. For example, CYP2E1 is the gene that encodes for the enzyme CYP2E1 – one of the enzymes involved in paracetamol (acetaminophen) metabolism.

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.

[edit] CYP Families in humans

Humans have 18 families of cytochrome P450 genes and 43 subfamilies (Nelson, 2003):

[edit] 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.

[edit] References

  • Nelson D (2003). Cytochrome P450s in humans. Retrieved May 9, 2005.
  • Bailey DG, Dresser GK "Interactions between grapefruit juice and cardiovascular drugs." Am J Cardiovasc Drug 2004 4(5):281-297 Abstract: [2]
  • Murray M, "Altered CYP expression and function in response to dietary factors: potential roles in disease pathogenesis" Curr Drug Metab 2006 7(1) 67-81. Abstract:[3]

[edit] External links

[edit] Further reading

ja:シトクロムP450 no:Cytokrom P450 pl:Cytochrom P450

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