Cytochrome P450

From Wikipedia, the free encyclopedia - View original article

Cytochrome P450
CytP450Oxidase-1OG2.png
Cytochrome P450 Oxidase (CYP2C9)
Identifiers
Symbolp450
PfamPF00067
InterProIPR0011
PROSITEPDOC00081
SCOP2cpp
SUPERFAMILY2cpp
OPM superfamily41
OPM protein2bdm
 
Jump to: navigation, search
Cytochrome P450
CytP450Oxidase-1OG2.png
Cytochrome P450 Oxidase (CYP2C9)
Identifiers
Symbolp450
PfamPF00067
InterProIPR0011
PROSITEPDOC00081
SCOP2cpp
SUPERFAMILY2cpp
OPM superfamily41
OPM protein2bdm

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 21,000 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[edit]

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[edit]

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[edit]

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[edit]

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[edit]

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[edit]

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:

Other specific CYP functions[edit]

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[edit]

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]

FamilyFunctionMembersNames
CYP1drug and steroid (especially estrogen) metabolism, benzo(a)pyrene toxification3 subfamilies, 3 genes, 1 pseudogeneCYP1A1, CYP1A2, CYP1B1
CYP2drug and steroid metabolism13 subfamilies, 16 genes, 16 pseudogenesCYP2A6, CYP2A7, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2F1, CYP2J2, CYP2R1, CYP2S1, CYP2U1, CYP2W1
CYP3drug and steroid (including testosterone) metabolism1 subfamily, 4 genes, 2 pseudogenesCYP3A4, CYP3A5, CYP3A7, CYP3A43
CYP4arachidonic acid or fatty acid metabolism6 subfamilies, 12 genes, 10 pseudogenesCYP4A11, CYP4A22, CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4F22, CYP4V2, CYP4X1, CYP4Z1
CYP5thromboxane A2 synthase1 subfamily, 1 geneCYP5A1
CYP7bile acid biosynthesis 7-alpha hydroxylase of steroid nucleus2 subfamilies, 2 genesCYP7A1, CYP7B1
CYP8varied2 subfamilies, 2 genesCYP8A1 (prostacyclin synthase), CYP8B1 (bile acid biosynthesis)
CYP11steroid biosynthesis2 subfamilies, 3 genesCYP11A1, CYP11B1, CYP11B2
CYP17steroid biosynthesis, 17-alpha hydroxylase1 subfamily, 1 geneCYP17A1
CYP19steroid biosynthesis: aromatase synthesizes estrogen1 subfamily, 1 geneCYP19A1
CYP20unknown function1 subfamily, 1 geneCYP20A1
CYP21steroid biosynthesis2 subfamilies, 1 gene, 1 pseudogeneCYP21A2
CYP24vitamin D degradation1 subfamily, 1 geneCYP24A1
CYP26retinoic acid hydroxylase3 subfamilies, 3 genesCYP26A1, CYP26B1, CYP26C1
CYP27varied3 subfamilies, 3 genesCYP27A1 (bile acid biosynthesis), CYP27B1 (vitamin D3 1-alpha hydroxylase, activates vitamin D3), CYP27C1 (unknown function)
CYP397-alpha hydroxylation of 24-hydroxycholesterol1 subfamily, 1 geneCYP39A1
CYP46cholesterol 24-hydroxylase1 subfamily, 1 geneCYP46A1
CYP51cholesterol biosynthesis1 subfamily, 1 gene, 3 pseudogenesCYP51A1 (lanosterol 14-alpha demethylase)

P450s in other species[edit]

Animals[edit]

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[edit]

Microbial cytochromes P450 are often soluble enzymes and are involved in diverse metabolic processes. In bacteria the distribution of P450s is very variable with many bacteria having no identified P450s (e.g. E.coli). Some bacteria, predominantly actinomycetes, have numerous P450s (e.g.,[31][32]). Those so far identified are generally involved in either biotransformation of xenobiotic compounds (e.g. CYP105A1 from Streptomyces griseolus metabolizes sulfonylurea herbicides to less toxic derivatives,[33]) or are part of specialised metabolite biosynthetic pathways (e.g. CYP170B1 catalyses production of the sesquiterpenoid albaflavenone in Streptomyces albus,[34]). Although no P450 has yet been shown to be essential in a microbe, the CYP105 family is highly conserved with a representative in every streptomycete genome sequenced so far ([35]). Due to the solubility of bacterial P450 enzymes, they are generally regarded as easier to work with than the predominantly membrane bound eukaryotic P450s. This, combined with the remarkable chemistry they catalyse, has led to many studies using the heterologously expressed proteins in vitro. Few studies have investigated what P450s do in vivo, what the natural substrate(s) are and how P450s contribute to survival of the bacteria in the natural environment.Three examples that have contributed significantly to structural and mechanistic studies are listed here, but many different families exist.

Fungi[edit]

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.)[39]

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[edit]

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[edit]

The remarkable reactivity and substrate promiscuity of P450s have long attracted the attention of chemists.[40] 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,[41] (ii) exploring the compatibility of p450s with organic solvents,[42] and (iii) the use of small, non-chiral auxiliaries to predictably direct P450 oxidation.[citation needed]

InterPro subfamilies[edit]

InterPro subfamilies:

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[edit]

  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 2014-11-13. 
  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. ^ McLean (2006). "The preponderance of P450s in the Mycobacterium tuberculosis genome". Trends in Microbiology 14 (5): 220–228. doi:10.1016/j.tim.2006.03.002. 
  32. ^ Omura, Ikeda (2003). "Complete genome sequence and comparative analysis of the industrial microorganism Streptomyces avermitilis.". Nat Biotechnol 21 (5): 526 Extra |pages= or |at= (help). 
  33. ^ Leto, O'Keefe (1988). "Identification of constitutive and herbicide inducible cytochromes P-450 in Streptomyces griseolus". Arch Microbiol 149 (5): 406 Extra |pages= or |at= (help). 
  34. ^ Lamb, Moody (2012). "Investigating conservation of the albaflavenone biosynthetic pathway and CYP170 bifunctionality in streptomycetes". FEBS J 279 (9): 1640 Extra |pages= or |at= (help). 
  35. ^ Loveridge, Moody (2014). "CYP105 – diverse structures, functions and roles in an intriguing family of enzymes in Streptomyces". J Appl Microbiol. doi:10.1111/jam.12662. 
  36. ^ 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. 
  37. ^ 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. 
  38. ^ 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. 
  39. ^ 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. 
  40. ^ 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. 
  41. ^ 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. 
  42. ^ 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[edit]