Cytochrome P450 oxidase
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Cytochrome P450 oxidase (commonly abbreviated CYP) is a generic term for a large number of related, but distinct, oxidative enzymes (EC 1.14) important in vertebrate physiology. The cytochrome P450 mixed-function monooxygenase system is probably the most important element of Phase I metabolism in mammals. Cytochrome P450 sequences have been determined in mammals, birds, fish, insects, worms, sea squirts, plants, fungi, slime mold, and bacteria.
P450s are membrane-bound, either in the inner membrane of mitochondria or in the endoplasmic reticulum of liver cells where they metabolize thousands of endogenous and exogenous toxins, drugs, xenobiotics, and other unneeded and potentially harmful molecules. They are, however, present in other tissues of the body including the mucosa of the gastrointestinal tract. In most animals, including humans, hepatic cytochrome P450s are the most widely studied of the P450 enzymes.
The name stands for "pigment 450" or "pink 450", so named because they absorb light of wavelengths near 450 nm when bound to carbon monoxide, giving the complexes a pink colour.
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Molecular biology
Mammalian cytochrome P450 oxidases have about 500 amino acids and a heme group at the active site. Most can metabolize multiple substrates, and many can catalyze multiple reactions, which accounts for their central importance in metabolizing the potentially endless variety of foreign molecules. The cytochrome P450 monooxygenase system requires NADPH and molecular oxygen (O2) to function.
The Human Genome Project has identified 63 human genes coding for the various cytochrome P450 enzymes.
Nomenclature
Genes encoding for the P450 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 an Arabic numeral for the individual gene. The convention is to italicise when referring to the gene. For example, CYP2E1 is the gene which encodes for the enzyme CYP2E1 which is one of the enzymes involved in paracetamol metabolism.
CYPs involved in xenobiotic metabolism and other reactions
Humans have 18 families of cytochrome P450 genes and 43 subfamilies (Nelson, 2003):
- CYP1 drug metabolism (3 subfamilies, 3 genes, 1 pseudogene) – CYP1A2
- CYP2 drug and steroid metabolism (13 subfamilies, 16 genes, 16 pseudogenes) – CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1
- CYP3 drug metabolism (1 subfamily, 4 genes, 2 pseudogenes) – CYP3A4
- CYP4 arachidonic acid or fatty acid metabolism (5 subfamilies, 11 genes, 10 pseudogenes)
- CYP5 thromboxane A2 synthase (1 subfamily, 1 gene)
- CYP7A bile acid biosynthesis 7-alpha hydroxylase of steroid nucleus (1 subfamily member)
- CYP7B brain specific form of 7-alpha hydroxylase (1 subfamily member)
- CYP8A prostacyclin synthase (1 subfamily member)
- CYP8B bile acid biosynthesis (1 subfamily member)
- CYP11 steroid biosynthesis (2 subfamilies, 3 genes)
- CYP17 steroid biosynthesis (1 subfamily, 1 gene) 17-alpha hydroxylase
- CYP19 steroid biosynthesis (1 subfamily, 1 gene) aromatase forms estrogen
- CYP20 unknown function (1 subfamily, 1 gene)
- CYP21 steroid biosynthesis (1 subfamily, 1 gene, 1 pseudogene)
- CYP24 vitamin D degradation (1 subfamily, 1 gene)
- CYP26A retinoic acid hydroxylase important in development (1 subfamily member)
- CYP26B probable retinoic acid hydroxylase (1 subfamily member)
- CYP26C probabvle retinoic acid hydroxylase (1 subfamily member)
- CYP27A bile acid biosynthesis (1 subfamily member)
- CYP27B vitamin D3 1-alpha hydroxylase activates vitamin D3 (1 subfamily member)
- CYP27C unknown function (1 subfamily member)
- CYP39 7-alpha hydroxylation of 24-hydroxycholesterol (1 subfamily member)
- CYP46 cholesterol 24-hydroxylase (1 subfamily member)
- CYP51 cholesterol biosynthesis (1 subfamily, 1 gene, 3 pseudogenes) lanosterol 14-alpha demethylase
Other CYPs
A subset of cytochrome P450 enzymes play important roles in the synthesis of steroid hormones by the adrenals, gonads, and peripheral tissue:
- P450scc (also known as P450c11a1) in adrenal mitochondria effects “the activity formerly known as 20,22-desmolase” (20α-hydroxylase, 22-hydroxylase, cholesterol side chain scission).
- P450c11β in inner mitochondrial membrane of adrenal cortex conducts 11β-hydroxylase, 18-hydroxylase, 18-methyloxidase activities.
- P450c11AS, only in mitochondria of the adrenal zona glomerulosa conducts 11β-hydroxylase, 18-hydroxylase, 18-methyloxidase activities.
- P450c17, in endoplasmic reticulum of adrenal cortex conducts 17α-hydroxylase and 17,20-lyase activities.
- P450c21 in adrenal cortex conducts 21-hydroxylase activity.
- P450arom (aromatase) in endoplasmic reticulum of gonads, brain, adipose tissue, and elsewhere catalyzes aromatization of androgens to estrogens.
- P450BM3 (also known as CYP102) monooxygenation of C15 and C16 fatty acid chains.
References
- Nelson D (2003). Cytochrome P450s in humans. Retrieved May 9, 2005.
Further reading
- Cytochrome P450 Homepage
- Ortiz de Montellano PR (Ed.) (1995). Cytochrome P450: structure, mechanism, and biochemistry. (2nd ed.). New York: Plenum Press. ISBN 0306451417
- Narhi LO, Fulco AJ (1986). Characterization of a catalytically self-sufficient 119,000-dalton cytochrome P-450 monooxygenase induced by barbituates in Bacillus megaterium. J Biol Chem 261 (16), 7160-7169. PMID 3086309