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873  structures 2977  species 2  interactions 39592  sequences 282  architectures

Family: p450 (PF00067)

Summary: Cytochrome P450

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Cytochrome P450
CytP450Oxidase-1OG2.png
Cytochrome P450 Oxidase (CYP2C9)
Identifiers
Symbol p450
Pfam PF00067
InterPro IPR0011
PROSITE PDOC00081
SCOP 2cpp
SUPERFAMILY 2cpp
OPM superfamily 41
OPM protein 2bdm

Cytochromes P450 (CYPs) belong to the superfamily of proteins containing a heme cofactor and, therefore, are hemoproteins. 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 CO.

CYP enzymes have been identified in all domains of life - animals, plants, fungi, protists, bacteria, archaea, and even in viruses.[1] However, the enzymes have not been found in E. coli.[2][3] More than 18,000 distinct CYP proteins are known.[4]

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:[5]

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+

Nomenclature

Genes encoding CYP enzymes, and the enzymes themselves, are designated with the abbreviation CYP, 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 (and incorrectly) CYP450 or CYP450 is used. 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).[6]

The current nomenclature guidelines suggest that members of new CYP families share >40% amino acid identity, while members of subfamilies must share >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 P450 catalytic cycle

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 are highly conserved in known CYPs and have the formal PROSITE signature consensus pattern [FW] - [SGNH] - x - [GD] - {F} - [RKHPT] - {P} - C - [LIVMFAP] - [GAD].[7] 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:

  1. The substrate binds to the active site of the enzyme, in proximity to the heme group, on the side opposite the peptide chain. The bound substrate 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,[8] and sometimes changing the state of the heme iron from low-spin to high-spin.[9] This gives rise to a change 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[10]
  2. The change in the electronic state of the active site favors the transfer of an electron from NAD(P)H via cytochrome P450 reductase or another associated reductase[11] This takes place by way of the electron transfer chain, as described above, reducing the ferric heme iron to the ferrous state.
  3. Molecular oxygen binds covalently to the distal axial coordination position of the heme iron. The cysteine ligand is a better electron donor than histidine, which is normally found in heme-containing proteins. As a consequence, the oxygen is activated to a greater extent than in other heme proteins. However, this sometimes allows the iron-oxygen bond to dissociate, causing the so-called "uncoupling reaction", which releases a reactive superoxide radical and interrupts the catalytic cycle.[8]
  4. A second electron is transferred via the electron-transport system, from either cytochrome P450 reductase, ferredoxins, or cytochrome b5, reducing the dioxygen adduct to a negatively charged peroxo group. This is a short-lived intermediate state.
  5. The peroxo group formed in step 4 is rapidly protonated twice by local transfer from water or from surrounding amino-acid side-chains, releasing one water molecule, and forming a highly reactive species commonly referred to as P450 Compound 1 ( or Compound I). This highly reactive intermediate was not "seen in action" until 2010,[12] although it had been studied theoretically for many years.[8] P450 Compound 1 is most likely 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 [8] is lacking.[12]
  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.

S: An alternative route for mono-oxygenation is via the "peroxide shunt": Interaction with single-oxygen donors such as peroxides and hypochlorites can lead directly to the formation of the iron-oxo intermediate, allowing the catalytic cycle to be completed without going through steps 2, 3, 4, and 5.[10] A hypothetical peroxide "XOOH" is shown in the diagram.

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[13] 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.[14]

Drug metabolism

Proportion of antifungal drugs metabolized by different families of CYPs.[15]
Further information: Drug metabolism

CYPs are the major enzymes involved in drug metabolism, accounting for about 75% of the total metabolism.[16] 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.[citation needed]

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.[17] Because of this risk, avoiding grapefruit juice and fresh grapefruits entirely while on drugs is usually advised.[18]

Other examples:

  • At relatively high concentrations, starfruit juice has also been shown to inhibit CYP2A6 and other CYPs.[22] Watercress is also a known inhibitor of the Cytochrome P450 CYP2E1, which may result in altered drug metabolism for individuals on certain medications (ex., chlorzoxazone).[23]
  • Tributyltin has been found to inhibit the function of Cytochrome P450, leading to masculinization of mollusks.[24]

Other specific CYP functions

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:

CYP families in humans

Humans have 57 genes and more than 59 pseudogenes divided among 18 families of cytochrome P450 genes and 43 subfamilies.[25] 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.[14]

Family Function Members Names
CYP1 drug and steroid (especially estrogen) metabolism, benzo(a)pyrene toxification 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. For example, mice have genes for 101 CYPs, and sea urchins have even more (perhaps as many as 120 genes).[26] 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 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 reaction to a substance is not a reliable indication of the substances 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 great model for cancer research in humans.[27] 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.[28]

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[29] and CYP6Z1 in the mosquito malaria vector Anopheles gambiae is capable of directly metabolizing DDT.[30]

Microbial

Microbial 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 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 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.[31][32]
  • Cytochrome P450 119 (CYP119) isolated from the thermophillic archea Sulfolobus acidocaldarius [33] has been used in a variety of mechanistic studies.[12] 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.)[34]

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 cytochromes P450 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 biotechnology

The remarkable reactivity and substrate promiscuity of P450s have long attracted the attention of chemists.[35] 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,[36] (ii) exploring the compatibility of p450s with organic solvents,[37] and (iii) the use of small, non-chiral auxiliaries to predictably direct P450 oxidation.[citation needed]

InterPro subfamilies

InterPro subfamilies:

  • Cytochrome P450, B-class IPR002397
  • Cytochrome P450, mitochondrial IPR002399
  • Cytochrome P450, E-class, group I IPR002401
  • Cytochrome P450, E-class, group II IPR002402
  • Cytochrome P450, E-class, group IV IPR002403
  • Hydroxylate estrogen (CYP1A2 and 1B1)

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.[citation needed]

References

  1. ^ Lamb DC, Lei L, Warrilow AG, Lepesheva GI, Mullins JG, Waterman MR, Kelly SL (2009). "The first virally encoded cytochrome P450". Journal of Virology 83 (16): 8266-9. PMID 19515774
  2. ^ Roland Sigel; Sigel, Astrid; Sigel, Helmut (2007). The Ubiquitous Roles of Cytochrome P450 Proteins: Metal Ions in Life Sciences. New York: Wiley. ISBN 0-470-01672-8. 
  3. ^ Danielson PB (December 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. 
  4. ^ Nelson D. "Cytochrome P450 Homepage". University of Tennessee. Retrieved 2010-05-04. 
  5. ^ Hanukoglu, Israel (1996). "Electron Transfer Proteins of Cytochrome P450 Systems". Advances in Molecular and Cell Biology 14: 29–56. doi:10.1016/S1569-2558(08)60339-2. ISSN 1569-2558. 
  6. ^ "NCBI sequence viewer". Retrieved 2007-11-19. 
  7. ^ PROSITE consensus pattern for P450
  8. ^ a b c d Meunier B, de Visser SP, Shaik S (September 2004). "Mechanism of oxidation reactions catalyzed by cytochrome p450 enzymes". Chem. Rev. 104 (9): 3947–80. doi:10.1021/cr020443g. PMID 15352783. 
  9. ^ Poulos TL, Finzel BC, Howard AJ (June 1987). "High-resolution crystal structure of cytochrome P450cam". J. Mol. Biol. 195 (3): 687–700. doi:10.1016/0022-2836(87)90190-2. PMID 3656428. 
  10. ^ a b Ortiz de Montellano, Paul R.; Paul R. Ortiz de Montellano (2005). Cytochrome P450: structure, mechanism, and biochemistry (3rd ed.). New York: Kluwer Academic/Plenum Publishers. ISBN 0-306-48324-6. 
  11. ^ Sligar SG, Cinti DL, Gibson GG, Schenkman JB (October 1979). "Spin state control of the hepatic cytochrome P450 redox potential". Biochem. Biophys. Res. Commun. 90 (3): 925–32. doi:10.1016/0006-291X(79)91916-8. PMID 228675. 
  12. ^ a b c Rittle J, Green MT (November 2010). "Cytochrome P450 Compound I: Capture, Characterization, and C-H Bond Activation Kinetics". Science 330 (6006): 933–937. Bibcode:2010Sci...330..933R. doi:10.1126/science.1193478. PMID 21071661. 
  13. ^ Berka K1, Hendrychová T, Anzenbacher P, Otyepka M (2011). "Membrane position of ibuprofen agrees with suggested access path entrance to cytochrome P450 2C9 active site". Journal of Physical Chemistry A 115 (41): 11248–55. doi:10.1021/jp204488j. PMC 3257864. PMID 21744854. 
  14. ^ a b "P450 Table". 
  15. ^ doctorfungus > Antifungal Drug Interactions Content Director: Russell E. Lewis, Pharm.D. Retrieved on Jan 23, 2010
  16. ^ Guengerich FP (January 2008). "Cytochrome p450 and chemical toxicology". Chem. Res. Toxicol. 21 (1): 70–83. doi:10.1021/tx700079z. PMID 18052394.  (Metabolism in this context is the chemical modification or degradation of drugs.)
  17. ^ Bailey DG, Dresser GK (2004). "Interactions between grapefruit juice and cardiovascular drugs". Am J Cardiovasc Drugs 4 (5): 281–97. doi:10.2165/00129784-200404050-00002. PMID 15449971. 
  18. ^ Zeratsky K (2008-11-06). "Grapefruit juice: Can it cause drug interactions?". Ask a food & nutrition specialist. MayoClinic.com. Retrieved 2009-02-09. 
  19. ^ Chaudhary A, Willett KL (January 2006). "Inhibition of human cytochrome CYP 1 enzymes by flavonoids of St. John's wort". Toxicology 217 (2–3): 194–205. doi:10.1016/j.tox.2005.09.010. PMID 16271822. 
  20. ^ Strandell J, Neil A, Carlin G (February 2004). "An approach to the in vitro evaluation of potential for cytochrome P450 enzyme inhibition from herbals and other natural remedies". Phytomedicine 11 (2–3): 98–104. doi:10.1078/0944-7113-00379. PMID 15070158. 
  21. ^ Kroon LA (September 2007). "Drug interactions with smoking". Am J Health Syst Pharm 64 (18): 1917–21. doi:10.2146/ajhp060414. PMID 17823102. 
  22. ^ Zhang JW, Liu Y, Cheng J, Li W, Ma H, Liu HT, Sun J, Wang LM, He YQ, Wang Y, Wang ZT, Yang L (2007). "Inhibition of human liver cytochrome P450 by star fruit juice". J Pharm Pharm Sci 10 (4): 496–503. PMID 18261370. 
  23. ^ Leclercq I, Desager JP, Horsmans Y (August 1998). "Inhibition of chlorzoxazone metabolism, a clinical probe for CYP2E1, by a single ingestion of watercress". Clin Pharmacol Ther. 64 (2): 144–9. doi:10.1016/S0009-9236(98)90147-3. PMID 9728894. 
  24. ^ Walmsley, Simon. "Tributyltin pollution on a global scale. An overview of relevant and recent research: impacts and issues.". WWF UK. 
  25. ^ Nelson D (2003). Cytochromes P450 in humans. Retrieved May 9, 2005.
  26. ^ Goldstone JV, Hamdoun A, Cole BJ, Howard-Ashby M, Nebert DW, Scally M, Dean M, Epel D, Hahn ME, Stegeman JJ (December 2006). "The chemical defensome: Environmental sensing and response genes in the Strongylocentrotus purpuratus genome". Dev. Biol. 300 (1): 366–84. doi:10.1016/j.ydbio.2006.08.066. PMC 3166225. PMID 17097629. 
  27. ^ Rawal S, Kim JE, Coulombe, R Jr (December 2010). "Aflatoxin B1 in poultry: toxicology, metabolism and prevention". Res. Vet. Sci. 89 (3): 325–31. doi:10.1016/j.rvsc.2010.04.011. PMID 20462619. 
  28. ^ Rawal S, Coulombe, RA Jr (August 2011). "Metabolism of aflatoxin B1 in turkey liver microsomes: the relative roles of cytochromes P450 1A5 and 3A37". Toxicol. Appl. Pharmacol. 254 (3): 349–54. doi:10.1016/j.taap.2011.05.010. PMID 21616088. 
  29. ^ McCart C, Ffrench-Constant RH (June 2008). "Dissecting the insecticide-resistance- associated cytochrome P450 gene Cyp6g1". Pest Manag Sci 64 (6): 639–45. doi:10.1002/ps.1567. PMID 18338338. 
  30. ^ Chiu TL, Wen Z, Rupasinghe SG, Schuler MA (1 Jul 2008). "Comparative molecular modeling of Anopheles gambiae CYP6Z1, a mosquito P450 capable of metabolizing DDT". Proc Natl Acad Sci U S A 105 (26): 8855–60. Bibcode:2008PNAS..105.8855C. doi:10.1073/pnas.0709249105. PMC 2449330. PMID 18577597. 
  31. ^ Narhi L, Fulco A (5 June 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. 
  32. ^ 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. doi:10.1042/BST0341173. PMID 17073779. 
  33. ^ R. L. Wright, K. Harris, B. Solow, R. H. White, P. J. Kennelly (1996). "Cloning of a potential cytochrome P450 from the archaeon Sulfolobus solfataricus". FEBS Lett 384 (3): 235–9. doi:10.1016/0014-5793(96)00322-5. PMID 8617361. 
  34. ^ Vanden Bossche H, Marichal P, Gorrens J, Coene MC (September 1990). "Biochemical basis for the activity and selectivity of oral antifungal drugs". Br J Clin Pract Suppl 71: 41–6. PMID 2091733. 
  35. ^ Chefson A, Auclair K (2006). "Progress towards the easier use of P450 enzymes". Mol Biosyst. 10 (10): 462–9. doi:10.1039/b607001a. PMID 17216026. 
  36. ^ Chefson A, Zhao J, Auclair K (2006). "Replacement of natural cofactors by selected hydrogen peroxide donors or organic peroxides results in improved activity for CYP3A4 and CYP2D6". Chembiochem 6 (6): 916–9. doi:10.1002/cbic.200600006. PMID 16671126. 
  37. ^ Chefson A, Auclair K. (2007). "CYP3A4 activity in the presence of organic cosolvents, ionic liquids, or water-immiscible organic solvents". Chembiochem 10 (10): 1189–97. doi:10.1002/cbic.200700128. PMID 17526062. 

External links

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

Cytochrome P450 Provide feedback

Cytochrome P450s are haem-thiolate proteins [6] involved in the oxidative degradation of various compounds. They are particularly well known for their role in the degradation of environmental toxins and mutagens. They can be divided into 4 classes, according to the method by which electrons from NAD(P)H are delivered to the catalytic site. Sequence conservation is relatively low within the family - there are only 3 absolutely conserved residues - but their general topography and structural fold are highly conserved. The conserved core is composed of a coil termed the 'meander', a four-helix bundle, helices J and K, and two sets of beta-sheets. These constitute the haem-binding loop (with an absolutely conserved cysteine that serves as the 5th ligand for the haem iron), the proton-transfer groove and the absolutely conserved EXXR motif in helix K. While prokaryotic P450s are soluble proteins, most eukaryotic P450s are associated with microsomal membranes. their general enzymatic function is to catalyse regiospecific and stereospecific oxidation of non-activated hydrocarbons at physiological temperatures [6].

Literature references

  1. Graham-Lorence S, Amarneh B, White RE, Peterson JA, Simpson ER; , Protein Sci 1995;4:1065-1080.: A three-dimensional model of aromatase cytochrome P450. PUBMED:7549871 EPMC:7549871

  2. Degtyarenko KN, Archakov AI; , FEBS Lett 1993;332:1-8.: Molecular evolution of P450 superfamily and P450-containing monooxygenase systems. PUBMED:8405421 EPMC:8405421

  3. Nelson DR, Kamataki T, Waxman DJ, Guengerich FP, Estabrook RW, Feyereisen R, Gonzalez FJ, Coon MJ, Gunsalus IC, Gotoh O, et al; , DNA Cell Biol 1993;12:1-51.: The P450 superfamily: update on new sequences, gene mapping, accession numbers, early trivial names of enzymes, and nomenclature. PUBMED:7678494 EPMC:7678494

  4. Guengerich FP; , J Biol Chem 1991;266:10019-10022.: Reactions and significance of cytochrome P-450 enzymes. PUBMED:2037557 EPMC:2037557

  5. Nebert DW, Gonzalez FJ; , Annu Rev Biochem 1987;56:945-993.: P450 genes: structure, evolution, and regulation. PUBMED:3304150 EPMC:3304150

  6. Werck-Reichhart D, Feyereisen R; , Genome Biol 2000;1:REVIEWS3003.: Cytochromes P450: a success story. PUBMED:11178272 EPMC:11178272


External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR001128

Cytochrome P450 enzymes are a superfamily of haem-containing mono-oxygenases that are found in all kingdoms of life, and which show extraordinary diversity in their reaction chemistry. In mammals, these proteins are found primarily in microsomes of hepatocytes and other cell types, where they oxidise steroids, fatty acids and xenobiotics, and are important for the detoxification and clearance of various compounds, as well as for hormone synthesis and breakdown, cholesterol synthesis and vitamin D metabolism. In plants, these proteins are important for the biosynthesis of several compounds such as hormones, defensive compounds and fatty acids. In bacteria, they are important for several metabolic processes, such as the biosynthesis of antibiotic erythromycin in Saccharopolyspora erythraea (Streptomyces erythraeus).

Cytochrome P450 enzymes use haem to oxidise their substrates, using protons derived from NADH or NADPH to split the oxygen so a single atom can be added to a substrate. They also require electrons, which they receive from a variety of redox partners. In certain cases, cytochrome P450 can be fused to its redox partner to produce a bi-functional protein, such as with P450BM-3 from Bacillus megaterium [PUBMED:17023115], which has haem and flavin domains.

Organisms produce many different cytochrome P450 enzymes (at least 58 in humans), which together with alternative splicing can provide a wide array of enzymes with different substrate and tissue specificities. Individual cytochrome P450 proteins follow the nomenclature: CYP, followed by a number (family), then a letter (subfamily), and another number (protein); e.g. CYP3A4 is the fourth protein in family 3, subfamily A. In general, family members should share >40% identity, while subfamily members should share >55% identity.

Cytochrome P450 proteins can also be grouped by two different schemes. One scheme was based on a taxonomic split: class I (prokaryotic/mitochondrial) and class II (eukaryotic microsomes). The other scheme was based on the number of components in the system: class B (3-components) and class E (2-components). These classes merge to a certain degree. Most prokaryotes and mitochondria (and fungal CYP55) have 3-component systems (class I/class B) - a FAD-containing flavoprotein (NAD(P)H-dependent reductase), an iron-sulphur protein and P450. Most eukaryotic microsomes have 2-component systems (class II/class E) - NADPH:P450 reductase (FAD and FMN-containing flavoprotein) and P450. There are exceptions to this scheme, such as 1-component systems that resemble class E enzymes [PUBMED:16042601, PUBMED:15128046, PUBMED:8637843]. The class E enzymes can be further subdivided into five sequence clusters, groups I-V, each of which may contain more than one cytochrome P450 family (eg, CYP1 and CYP2 are both found in group I). The divergence of the cytochrome P450 superfamily into B- and E-classes, and further divergence into stable clusters within the E-class, appears to be very ancient, occurring before the appearance of eukaryotes.

More information about these proteins can be found at Protein of the Month: Cytochrome P450 [PUBMED:].

Gene Ontology

The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Alignments

We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the NCBI sequence database, and our metagenomics sequence database. More...

View options

We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.

  Seed
(50)
Full
(39592)
Representative proteomes NCBI
(39656)
Meta
(2722)
RP15
(5443)
RP35
(11134)
RP55
(16825)
RP75
(20665)
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PP/heatmap 1              
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1Cannot generate PP/Heatmap alignments for seeds; no PP data available

Key: ✓ available, x not generated, not available.

Format an alignment

  Seed
(50)
Full
(39592)
Representative proteomes NCBI
(39656)
Meta
(2722)
RP15
(5443)
RP35
(11134)
RP55
(16825)
RP75
(20665)
Alignment:
Format:
Order:
Sequence:
Gaps:
Download/view:

Download options

We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.

  Seed
(50)
Full
(39592)
Representative proteomes NCBI
(39656)
Meta
(2722)
RP15
(5443)
RP35
(11134)
RP55
(16825)
RP75
(20665)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download   Download  
Gzipped Download   Download   Download   Download   Download   Download   Download   Download  

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

External links

MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.

HMM logo

HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...

Trees

This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

Note: You can also download the data file for the tree.

Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: Overington and HMM_iterative_training
Previous IDs: none
Type: Domain
Author: Eddy SR
Number in seed: 50
Number in full: 39592
Average length of the domain: 330.60 aa
Average identity of full alignment: 17 %
Average coverage of the sequence by the domain: 79.49 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 21.0 21.0
Trusted cut-off 21.0 21.0
Noise cut-off 20.9 20.9
Model length: 463
Family (HMM) version: 17
Download: download the raw HMM for this family

Species distribution

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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. More...

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Interactions

There are 2 interactions for this family. More...

Flavodoxin_1 p450

Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the p450 domain has been found. There are 873 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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