CYP2A6

Available structures

Human UniProt search: PDBe RCSB

List of PDB id codes
4RUI, 1Z10, 1Z11, 2FDU, 2FDV, 2FDW, 2FDY, 3EBS, 3T3Q, 3T3R, 4EJJ

Identifiers

Aliases

CYP2A6, CPA6, CYP2A, CYP2A3, CYPIIA6, P450C2A, P450PB, cytochrome P450 family 2 subfamily A member 6

External IDs

OMIM: 122720 HomoloGene: 85917 GeneCards: CYP2A6

Gene ontology
Molecular function	• iron ion binding • arachidonic acid epoxygenase activity • oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen • metal ion binding • monooxygenase activity • steroid hydroxylase activity • heme binding • oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen • enzyme binding • oxidoreductase activity • coumarin 7-hydroxylase activity
Cellular component	• organelle membrane • endoplasmic reticulum membrane • membrane • intracellular membrane-bounded organelle • endoplasmic reticulum • cytoplasmic microtubule
Biological process	• steroid metabolic process • exogenous drug catabolic process • epoxygenase P450 pathway • coumarin catabolic process • drug metabolic process • oxidation-reduction process • coumarin metabolic process
Sources:Amigo / QuickGO

Orthologs

Species

Human

Mouse

Entrez


1548


n/a

Ensembl


ENSG00000255974


n/a

UniProt


P11509


n/a

RefSeq (mRNA)


NM_000762


n/a

RefSeq (protein)


NP_000753.3


n/a

Location (UCSC)

Chr 19: 40.84 – 40.88 Mb

n/a

PubMed search

^[1]

n/a

Wikidata

View/Edit Human

Cytochrome P450 2A6 (abbreviated CYP2A6) is a member of the cytochrome P450 mixed-function oxidase system, which is involved in the metabolism of xenobiotics in the body. CYP2A6 is the primary enzyme responsible for the oxidation of nicotine and cotinine. It is also involved in the metabolism of several pharmaceuticals, carcinogens, and a number of coumarin-type alkaloids. CYP2A6 is the only enzyme in the human body that appreciably catalyzes the 7-hydroxylation of coumarin, such that the formation of the product of this reaction, 7-hydroxycoumarin, is used as a probe for CYP2A6 activity.

The CYP2A6 gene is part of a large cluster of cytochrome P450 genes from the CYP2A, CYP2B and CYP2F subfamilies on chromosome 19q. The gene was formerly referred to as CYP2A3; however, it has been renamed CYP2A6.^[2]

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles. ^{[§ 1]}

[[File:

[[<div style="display:block; width:58px; height:0px; overflow:hidden; position:relative; left:174.0px; top:75px; background:transparent; border-top:3px blue solid"></div>]]

[[<div style="display:block; width:53px; height:0px; overflow:hidden; position:relative; left:308.0px; top:87px; background:transparent; border-top:3px blue solid"></div>]]

[[<div style="display:block; width:53px; height:0px; overflow:hidden; position:relative; left:308.0px; top:67px; background:transparent; border-top:3px blue solid"></div>]]

[[<div style="display:block; width:51px; height:0px; overflow:hidden; position:relative; left:72.0px; top:120px; background:transparent; border-top:3px blue solid"></div>]]

[[<div style="display:block; width:59px; height:0px; overflow:hidden; position:relative; left:54.0px; top:178px; background:transparent; border-top:3px blue solid"></div>]]

[[<div style="display:block; width:80px; height:0px; overflow:hidden; position:relative; left:519.0px; top:112px; background:transparent; border-top:3px blue solid"></div>]]

[[<div style="display:block; width:44px; height:0px; overflow:hidden; position:relative; left:436.5px; top:97px; background:transparent; border-top:3px blue solid"></div>]]

[[<div style="display:block; width:44px; height:0px; overflow:hidden; position:relative; left:436.5px; top:117px; background:transparent; border-top:3px blue solid"></div>]]

[[<div style="display:block; width:34px; height:0px; overflow:hidden; position:relative; left:403.0px; top:155px; background:transparent; border-top:3px blue solid"></div>]]

[[<div style="display:block; width:46px; height:0px; overflow:hidden; position:relative; left:344.0px; top:130px; background:transparent; border-top:3px blue solid"></div>]]

[[<div style="display:block; width:46px; height:0px; overflow:hidden; position:relative; left:344.0px; top:150px; background:transparent; border-top:3px blue solid"></div>]]

[[<div style="display:block; width:46px; height:0px; overflow:hidden; position:relative; left:344.0px; top:170px; background:transparent; border-top:3px blue solid"></div>]]

[[<div style="display:block; width:39px; height:0px; overflow:hidden; position:relative; left:245.0px; top:352px; background:transparent; border-top:3px green solid"></div>]]

[[<div style="display:block; width:44px; height:0px; overflow:hidden; position:relative; left:350.0px; top:238px; background:transparent; border-top:3px blue solid"></div>]]

[[<div style="display:block; width:44px; height:0px; overflow:hidden; position:relative; left:440.0px; top:302px; background:transparent; border-top:3px blue solid"></div>]]

[[<div style="display:block; width:44px; height:0px; overflow:hidden; position:relative; left:544.0px; top:301px; background:transparent; border-top:3px blue solid"></div>]]

[[<div style="display:block; width:44px; height:0px; overflow:hidden; position:relative; left:321.0px; top:400px; background:transparent; border-top:3px blue solid"></div>]]

[[<div style="display:block; width:46px; height:0px; overflow:hidden; position:relative; left:311.0px; top:310px; background:transparent; border-top:3px blue solid"></div>]]

[[<div style="display:block; width:46px; height:0px; overflow:hidden; position:relative; left:311.0px; top:330px; background:transparent; border-top:3px blue solid"></div>]]

[[<div style="display:block; width:44px; height:0px; overflow:hidden; position:relative; left:321.0px; top:420px; background:transparent; border-top:3px blue solid"></div>]]

[[<div style="display:block; width:44px; height:0px; overflow:hidden; position:relative; left:188.0px; top:293px; background:transparent; border-top:3px blue solid"></div>]]

[[<div style="display:block; width:44px; height:0px; overflow:hidden; position:relative; left:188.0px; top:313px; background:transparent; border-top:3px blue solid"></div>]]

[[<div style="display:block; width:44px; height:0px; overflow:hidden; position:relative; left:53.0px; top:326px; background:transparent; border-top:3px blue solid"></div>]]

[[<div style="display:block; width:46px; height:0px; overflow:hidden; position:relative; left:75.0px; top:259px; background:transparent; border-top:3px blue solid"></div>]]

[[<div style="display:block; width:44px; height:0px; overflow:hidden; position:relative; left:197.0px; top:448px; background:transparent; border-top:3px blue solid"></div>]]

[[<div style="display:block; width:44px; height:0px; overflow:hidden; position:relative; left:197.0px; top:468px; background:transparent; border-top:3px blue solid"></div>]]

[[<div style="display:block; width:44px; height:0px; overflow:hidden; position:relative; left:208.5px; top:809px; background:transparent; border-top:3px blue solid"></div>]]

[[<div style="display:block; width:44px; height:0px; overflow:hidden; position:relative; left:326.5px; top:566px; background:transparent; border-top:3px blue solid"></div>]]

[[<div style="display:block; width:44px; height:0px; overflow:hidden; position:relative; left:326.5px; top:526px; background:transparent; border-top:3px blue solid"></div>]]

[[<div style="display:block; width:44px; height:0px; overflow:hidden; position:relative; left:326.5px; top:546px; background:transparent; border-top:3px blue solid"></div>]]

[[<div style="display:block; width:56px; height:0px; overflow:hidden; position:relative; left:491.0px; top:545px; background:transparent; border-top:3px blue solid"></div>]]

[[<div style="display:block; width:163px; height:0px; overflow:hidden; position:relative; left:79.0px; top:866px; background:transparent; border-top:3px blue solid"></div>]]

[[<div style="display:block; width:77px; height:0px; overflow:hidden; position:relative; left:164.0px; top:912px; background:transparent; border-top:3px blue solid"></div>]]

[[<div style="display:block; width:44px; height:0px; overflow:hidden; position:relative; left:288.0px; top:854px; background:transparent; border-top:3px blue solid"></div>]]

[[<div style="display:block; width:44px; height:0px; overflow:hidden; position:relative; left:308.0px; top:892px; background:transparent; border-top:3px blue solid"></div>]]

[[<div style="display:block; width:80px; height:0px; overflow:hidden; position:relative; left:437.0px; top:816px; background:transparent; border-top:3px blue solid"></div>]]

[[<div style="display:block; width:80px; height:0px; overflow:hidden; position:relative; left:389.0px; top:863px; background:transparent; border-top:3px green solid"></div>]]

[[<div style="display:block; width:44px; height:0px; overflow:hidden; position:relative; left:487.5px; top:842px; background:transparent; border-top:3px blue solid"></div>]]

[[<div style="display:block; width:44px; height:0px; overflow:hidden; position:relative; left:386.5px; top:890px; background:transparent; border-top:3px blue solid"></div>]]

[[<div style="display:block; width:44px; height:0px; overflow:hidden; position:relative; left:430.5px; top:890px; background:transparent; border-top:3px blue solid"></div>]]

[[<div style="display:block; width:44px; height:0px; overflow:hidden; position:relative; left:386.5px; top:910px; background:transparent; border-top:3px blue solid"></div>]]

[[<div style="display:block; width:44px; height:0px; overflow:hidden; position:relative; left:430.5px; top:910px; background:transparent; border-top:3px blue solid"></div>]]

[[<div style="display:block; width:44px; height:0px; overflow:hidden; position:relative; left:180.5px; top:966px; background:transparent; border-top:3px blue solid"></div>]]

[[<div style="display:block; width:44px; height:0px; overflow:hidden; position:relative; left:224.5px; top:966px; background:transparent; border-top:3px blue solid"></div>]]

[[<div style="display:block; width:44px; height:0px; overflow:hidden; position:relative; left:180.5px; top:946px; background:transparent; border-top:3px blue solid"></div>]]

[[<div style="display:block; width:44px; height:0px; overflow:hidden; position:relative; left:224.5px; top:946px; background:transparent; border-top:3px blue solid"></div>]]

[[

]]

|{{{bSize}}}px|alt=Fluorouracil (5-FU) Activity edit]]

Fluorouracil (5-FU) Activity edit

↑ The interactive pathway map can be edited at WikiPathways: "FluoropyrimidineActivity_WP1601".

Distribution

CYP2A6 localizes to the endoplasmic reticulum and is found predominantly in the liver.

Variability

Significant interindividual variability in CYP2A6 apoprotein and mRNA levels has been observed.

Induction

CYP2A6 is known to be inducible by phenobarbital and rifampicin, and it is suspected that other antiepileptic drugs may also have this effect.

CYP2A6 Ligands

**Selected inducers, inhibitors and substrates of CYP2A6**
Substrates	Inhibitors	Inducers
Many Carcinogens MNAN NNK NDEA MTBE Other toxins aflatoxin B₁ (mycotoxin) 1,3-butadiene (in synthetic rubber) coumarin (anticoagulant, found in cinnamon) DCBN (herbicide) 7-ethoxycoumarin (test substrate) skatole quinoline MOCA (in polyurethane production) halothane (anaesthetic) losigamone (anticonvulsant) methoxyflurane (anaesthetic) cotinine (metabolite of nicotine) nicotine (stimulant) SM-12502 (PAF antagonist valproic acid (anticonvulsant, mood-stabilizing) dexmedetomidine (sedative)^[3]	amiodarone (antiarrhythmic agent)^[3] amlodipine (calcium channel blocker)^[3] buprenorphine (semisynthetic opioid)^[3] clofibrate (fibrate)^[3] clotrimazole (antifungal)^[3] desipramine (tricyclic antidepressant)^[3] disulfiram (acetaldehyde dehydrogenase inhibitor)^[3] entacapone (COMT inhibitor, used in Parkinson's disease)^[3] fenofibrate (fibrate)^[3] gabapentin (anticonvulsant) grapefruit juice flavonoids isoniazid (antibacterial)^[3]^[4] ketoconazole (antifungal)^[3] letrozole (aromatase inhibitor, used in breast cancer)^[3] methimazole (antithyroid agent)^[3] methoxsalen (furanocoumarin, used in psoriasis)^[3] metyrapone (used to diagnose adrenal insufficiency)^[3] miconazole (antifungal)^[3] modafinil (wakefulness-promoting agent)^[3] nicotine (stimulant)^[3] orphenadrine (antihistamine)^[3] pilocarpine (muscarinic receptor agonist)^[3] pregabalin (anticonvulsant, a prodrug of gabapentin) selegiline (monoamine oxidase inhibitor)^[3]^[5] sulconazole (antifungal)^[3] tioconazole (antifungal)^[3] tranylcypromine (monoamine oxidase inhibitor)^[3]	Barbiturates amobarbital^[3] pentobarbital^[3] phenobarbital^[3] secobarbital^[3] rifampicin (antibacterial)^[3]

References

↑ "Human PubMed Reference:".
↑ "Entrez Gene: CYP2A6 cytochrome P450, family 2, subfamily A, polypeptide 6".
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 Lacy CF, Armstrong LL, Goldman MP, Lance LL (2007). Cytochrome P450 Enzymes: Substrates, Inhibitors, and Inducers. Hudson, OH: LexiComp Inc. pp. 1899–1912.
↑ Wen X, Wang JS, Neuvonen PJ, Backman JT (2002). "Isoniazid is a mechanism-based inhibitor of cytochrome P450 1A2, 2A6, 2C19 and 3A4 isoforms in human liver microsomes". Eur. J. Clin. Pharmacol. 57 (11): 799–804. doi:10.1007/s00228-001-0396-3. PMID 11868802.
↑ Siu EC, Tyndale RF (2008). "Selegiline is a mechanism-based inactivator of CYP2A6 inhibiting nicotine metabolism in humans and mice". J. Pharmacol. Exp. Ther. 324 (3): 992–9. doi:10.1124/jpet.107.133900. PMID 18065502.

Fernandez-Salguero P, Gonzalez FJ (1995). "The CYP2A gene subfamily: species differences, regulation, catalytic activities and role in chemical carcinogenesis". Pharmacogenetics. 5 (Special Issue): S123–8. doi:10.1097/00008571-199512001-00013. PMID 7581481.
Smith G, Stubbins MJ, Harries LW, Wolf CR (1999). "Molecular genetics of the human cytochrome P450 monooxygenase superfamily". Xenobiotica. 28 (12): 1129–65. doi:10.1080/004982598238868. PMID 9890157.
Pelkonen O, Rautio A, Raunio H, Pasanen M (2000). "CYP2A6: a human coumarin 7-hydroxylase". Toxicology. 144 (1–3): 139–47. doi:10.1016/S0300-483X(99)00200-0. PMID 10781881.
Tyndale RF, Sellers EM (2002). "Genetic variation in CYP2A6-mediated nicotine metabolism alters smoking behavior". Therapeutic drug monitoring. 24 (1): 163–71. doi:10.1097/00007691-200202000-00026. PMID 11805739.
Xu C, Goodz S, Sellers EM, Tyndale RF (2003). "CYP2A6 genetic variation and potential consequences". Adv. Drug Deliv. Rev. 54 (10): 1245–56. doi:10.1016/S0169-409X(02)00065-0. PMID 12406643.
Kamataki T, Fujieda M, Kiyotani K, et al. (2005). "Genetic polymorphism of CYP2A6 as one of the potential determinants of tobacco-related cancer risk". Biochem. Biophys. Res. Commun. 338 (1): 306–10. doi:10.1016/j.bbrc.2005.08.268. PMID 16176798.
Maurice M, Emiliani S, Dalet-Beluche I, et al. (1991). "Isolation and characterization of a cytochrome P450 of the IIA subfamily from human liver microsomes". Eur. J. Biochem. 200 (2): 511–7. doi:10.1111/j.1432-1033.1991.tb16212.x. PMID 1889415.
Yun CH, Shimada T, Guengerich FP (1991). "Purification and characterization of human liver microsomal cytochrome P-450 2A6". Mol. Pharmacol. 40 (5): 679–85. PMID 1944238.
Yamano S, Tatsuno J, Gonzalez FJ (1990). "The CYP2A3 gene product catalyzes coumarin 7-hydroxylation in human liver microsomes". Biochemistry. 29 (5): 1322–9. doi:10.1021/bi00457a031. PMID 2322567.
Miles JS, Bickmore W, Brook JD, et al. (1989). "Close linkage of the human cytochrome P450IIA and P450IIB gene subfamilies: implications for the assignment of substrate specificity". Nucleic Acids Res. 17 (8): 2907–17. doi:10.1093/nar/17.8.2907. PMC 317701. PMID 2726448.
Yamano S, Nagata K, Yamazoe Y, et al. (1989). "cDNA and deduced amino acid sequences of human P450 IIA3 (CYP2A3)". Nucleic Acids Res. 17 (12): 4888. doi:10.1093/nar/17.12.4888. PMC 318052. PMID 2748347.
Phillips IR, Shephard EA, Ashworth A, Rabin BR (1985). "Isolation and sequence of a human cytochrome P-450 cDNA clone". Proc. Natl. Acad. Sci. U.S.A. 82 (4): 983–7. doi:10.1073/pnas.82.4.983. PMC 397177. PMID 3856261.
Wainwright BJ, Watson EK, Shephard EA, Phillips IR (1985). "RFLP for a human cytochrome P-450 gene at 19q13.1-qter (HGM8 provisional designation CYPI)". Nucleic Acids Res. 13 (12): 4610. doi:10.1093/nar/13.12.4610. PMC 321810. PMID 4011450.
Fernandez-Salguero P, Hoffman SM, Cholerton S, et al. (1995). "A genetic polymorphism in coumarin 7-hydroxylation: sequence of the human CYP2A genes and identification of variant CYP2A6 alleles". Am. J. Hum. Genet. 57 (3): 651–60. PMC 1801261. PMID 7668294.
Ding S, Lake BG, Friedberg T, Wolf CR (1995). "Expression and alternative splicing of the cytochrome P-450 CYP2A7". Biochem. J. 306. ( Pt 1): 161–6. PMC 1136496. PMID 7864805.
Hoffman SM, Fernandez-Salguero P, Gonzalez FJ, Mohrenweiser HW (1996). "Organization and evolution of the cytochrome P450 CYP2A-2B-2F subfamily gene cluster on human chromosome 19". J. Mol. Evol. 41 (6): 894–900. doi:10.1007/bf00173169. PMID 8587134.
Hadidi H, Zahlsen K, Idle JR, Cholerton S (1998). "A single amino acid substitution (Leu160His) in cytochrome P450 CYP2A6 causes switching from 7-hydroxylation to 3-hydroxylation of coumarin". Food Chem. Toxicol. 35 (9): 903–7. doi:10.1016/S0278-6915(97)00066-5. PMID 9409631.
Oscarson M, Gullstén H, Rautio A, et al. (1998). "Genotyping of human cytochrome P450 2A6 (CYP2A6), a nicotine C-oxidase". FEBS Lett. 438 (3): 201–5. doi:10.1016/S0014-5793(98)01297-6. PMID 9827545.

PDB gallery

1z10: Crystal Structure of Human Microsomal P450 2A6 with Coumarin Bound

1z11: Crystal Structure of Human Microsomal P450 2A6 with Methoxsalen Bound

2fdu: Microsomal P450 2A6 with the inhibitor N,N-Dimethyl(5-(pyridin-3-yl)furan-2-yl)methanamine bound

2fdv: Microsomal P450 2A6 with the inhibitor N-Methyl(5-(pyridin-3-yl)furan-2-yl)methanamine bound

2fdw: Crystal Structure Of Human Microsomal P450 2A6 with the inhibitor (5-(Pyridin-3-yl)furan-2-yl)methanamine bound

2fdy: Microsomal P450 2A6 with the inhibitor Adrithiol bound

2p85: Structure of Human Lung Cytochrome P450 2A13 with indole bound in two alternate conformations

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 (CYP3A)	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)

Enzymes

Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Catalytically perfect enzyme Coenzyme Cofactor Enzyme catalysis Enzyme kinetics Lineweaver–Burk plot Michaelis–Menten kinetics

Regulation	Allosteric regulation Cooperativity Enzyme inhibitor

Classification	EC number Enzyme superfamily Enzyme family List of enzymes

Types	EC1 Oxidoreductases (list) EC2 Transferases (list) EC3 Hydrolases (list) EC4 Lyases (list) EC5 Isomerases (list) EC6 Ligases (list)

This article is issued from Wikipedia - version of the 6/8/2016. The text is available under the Creative Commons Attribution/Share Alike but additional terms may apply for the media files.