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Cytochrome P450

Cytochrome P450 Oxidase (CYP2C9)
Identifiers
Symbol p450
Pfam PF00067
InterPro IPR001128
PROSITE PDOC00081
SCOP 2cpp
OPM family 41
OPM protein 1w0f
Available PDB structures:

(More than 171 PDB structures deposited)

Cytochrome P450 (abbreviated CYP, P450, infrequently CYP450) is a very large and diverse superfamily of hemoproteins found in all domains of life.[1] 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, e.g. insertion of one atom of oxygen into an organic substrate (RH) while the other oxygen atom is reduced to water:

RH + O2 + 2H+ + 2e– → ROH + H2O

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).[2]

The name cytochrome P450 is derived from the fact that these are colored ('chrome') cellular ('cyto') proteins, with a "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 (often with sodium dithionite) and complexed to carbon monoxide.

Contents

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). [3]

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[2]. 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:

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 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. Hepatic cytochromes P450 are the most widely studied of the P450 enzymes. Cytochrome P450's are also present in the Blood Brain Barrier (BBB) in concentrations similar to those found in the liver. They strengthen the division between the blood and brain tissue by metabolising toxic compounds which may somehow cross the BBB. (E.g Bilirubin as metioned above in respect to the liver)

The Human Genome Project has identified more than 63 human genes (57 full genes and 5 pseudogenes) coding for the various cytochrome P450 enzymes.[4]

Drug metabolism

In drug metabolism, cytochrome P450 is probably the most important element of oxidative metabolism (a part of phase I metabolism) in humans (metabolism in this context being the chemical modification or degradation of chemicals including drugs and endogenous compounds).

Drug interaction

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. Such drug interactions are extra 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 decrease because of enzyme induction.

Interaction of other substances

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.[5] Because of this risk, avoiding grapefruit juice and fresh grapefruits entirely while on drugs is usually advised.

Other examples:

Other specific CYP functions

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

CYP Families

Humans have 57 genes and more than 59 pseudogenes divided among 18 families of cytochrome P450 genes and 43 subfamilies.[6] 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.[4]

Family Function Members Names
CYP1 drug and steroid (especially estrogen) metabolism 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, 11 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, 2 genes, 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 animals

Many animals have as many or more CYP genes than humans do. For example, 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). However, gene and genome sequencing is far outpacing biochemical characterization of enzymatic function, although many genes with close homology to CYPs with known function have been found.

The classes of CYPs most often investigated in non-human animals are those involved in either 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.

CYPs have been extensively examined in mice, rats, and dogs, and less so in zebrafish, in order to facilitate use of these model organisms in drug discovery and toxicology.

CYPs have also been heavily studied in insects, often to understand pesticide resistance.

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 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.[7][8]

P450s in fungi

The commonly used azole antifungal agents 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.

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.

InterPro subfamilies

InterPro subfamilies:

References

  1. ^ International Union of Pure and Applied Chemistry. "cytochrome P450". Compendium of Chemical Terminology Internet edition. Danielson P (2002). "The cytochrome P450 superfamily: biochemistry, evolution and drug metabolism in humans". Curr Drug Metab 3 (6): 561-97. doi:10.2174/1389200023337054. PMID 12369887. 
  2. ^ a b Dr. Nelson Lab Website. Retrieved on 2007-11-19.
  3. ^ NCBI sequence viewer. Retrieved on 2007-11-19.
  4. ^ a b "P450 Table".
  5. ^ Bailey DG, Dresser GK (2004). "Interactions between grapefruit juice and cardiovascular drugs". Am J Cardiovasc Drug 4 (5): 281-297. PMID 15449971. 
  6. ^ Nelson D (2003). Cytochrome P450s in humans. Retrieved May 9, 2005.
  7. ^ Narhi L, Fulco A (1986). "Characterization of a catalytically self-sufficient 119,000-dalton cytochrome P-450 monooxygenase induced by barbiturates in Bacillus megaterium". J Biol Chem 261 (16): 7160-9. PMID 3086309. 
  8. ^ Girvan H, Waltham T, Neeli R, Collins H, McLean K, Scrutton N, Leys D, Munro A (2006). "Flavocytochrome P450 BM3 and the origin of CYP102 fusion species". Biochem Soc Trans 34 (Pt 6): 1173-7. PMID 17073779. 

External links


v • d • e
Cytochromes, oxygenases: cytochrome P450 (EC 1.14)
CYP1
A1, A2, B1
CYP2
A6, A7, A13, B6, C8, C9, C18, C19, D6, E1, F1, J2, R1, S1, U1, W1
CYP3
A4, A5, A7, A43
CYP4
A11, A22, B1, F2, F3, F8, F11, F12, F22, V2, X1, Z1
CYP5-20
CYP5 (A1) - CYP7 (A1, B1) - CYP8 (A1, B1) - CYP11 (A1, B1, B2) - CYP17 (A1) - CYP19 (A1) - CYP20 (A1)
CYP21-51
CYP21 (A2) - CYP24 (A1) - CYP26 (A1, B1, C1) - CYP27 (A1, B1, C1) - CYP39 (A1) - CYP46 (A1) - CYP51 (A1)
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