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MetaCyc Enzyme: cytochrome P450 2A6

Gene: CYP2A6 Accession Number: HS10343 (MetaCyc)

Synonyms: CYP2A3, CPA6, CYPIIA6, coumarin 7-hydroxylase, IIA3, P450(I), cytochrome P450, family 2, subfamily A, polypeptide 6, xenobiotic monooxygenase, flavoprotein-linked monooxygenase, cytochrome P450, subfamily IIA (phenobarbital-inducible), polypeptide 3, cytochrome P450, subfamily IIA (phenobarbital-inducible), polypeptide 6

Species: Homo sapiens

Summary:
The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids [Smith98c].

CYP2A6 encodes a member of the cytochrome P450 superfamily that is localized in the endoplasmic reticulum and its expression is induced by phenobarbital. CYP2A6 represent up to 15% of human microsomes P450 proteins. The enzyme is known to hydroxylate coumarin [Pelkonen00, Lewis02], and also metabolizes nicotine [Nakajima96, Hukkanen05], aflatoxin B1, nitrosamines, and some pharmaceuticals, suc as tegafur [Ariyoshi02].

The cDNA has been isolated and sequenced [Phillips85, Yamano89, Yamano90]. The gene is part of a large cluster of cytochrome P450 genes from the CYP2A, CYP2B and CYP2F subfamilies on chromosome 19q [Hoffman95, FernandezSalgue95]. The gene was formerly referred to as CYP2A3; however, it has been renamed CYP2A6. Several alleles are known [FernandezSalgue95a].

Individuals with certain allelic variants are said to have a poor metaboliser phenotype, meaning they do not efficiently metabolize coumarin or nicotine [Tyndale02].

Since the enzyme catalyzes the metabolic activation of several procarcinogens including dietary and environmental nitrosamines, its activity has been linked to increased risk of several cancers [Topcu02, Nowell02, Godoy02].

Plant inhibitor: menthofurane, a hepatotoxin found in essential oils of Mentha species, is a potent, mechanism-based inactivator of CYP2A6. Its inactivation was characterized by a Ki of 2.5 μM and a kinact of 0.22 min-1 for human liver microsomes and a Ki of 0.84 μM and a kinact of 0.25 min-1 for purified expressed CYP2A6 [KhojastehBakht98].

Locations: endoplasmic reticulum membrane

Map Position: [41,741,168 <- 41,748,064]

Molecular Weight of Polypeptide: 56.517 kD (from nucleotide sequence), 49 kD (experimental) [Ding95 ]

Unification Links: ArrayExpress:P11509 , Ensembl:ENSG00000171563 , Entrez-gene:1548 , GeneCards:CYP2A6 , OMIM:122720 , OMIM:123960 , PhosphoSite:P11509 , PhylomeDB:P11509 , Pride:P11509 , Protein Model Portal:P11509 , RefSeq:NM_000762 , RefSeq:NP_000753 , SMR:P11509 , String:P11509 , UCSC Human Genome:NM_000762 , UniGene:334345 , UniProt:P11509

Relationship Links: Entrez-Nucleotide:PART-OF:AF182275 , Entrez-Nucleotide:PART-OF:M33318 , Entrez-Nucleotide:PART-OF:U22027 , Entrez-Nucleotide:PART-OF:X13897 , Entrez-Nucleotide:PART-OF:X13929 , InterPro:IN-FAMILY:IPR001128 , InterPro:IN-FAMILY:IPR002401 , InterPro:IN-FAMILY:IPR008067 , InterPro:IN-FAMILY:IPR017972 , PDB:Structure:1Z10 , PDB:Structure:1Z11 , PDB:Structure:2FDU , PDB:Structure:2FDV , PDB:Structure:2FDW , PDB:Structure:2FDY , PDB:Structure:3EBS , PDB:Structure:3T3Q , PDB:Structure:3T3R , PDB:Structure:4EJJ , Pfam:IN-FAMILY:PF00067 , Prints:IN-FAMILY:PR00385 , Prints:IN-FAMILY:PR00463 , Prints:IN-FAMILY:PR01684 , Prosite:IN-FAMILY:PS00086

Gene-Reaction Schematic: ?

GO Terms:

Cellular Component: GO:0005789 - endoplasmic reticulum membrane

Credits:
Revised 22-Jun-2009 by Caspi R , SRI International


Enzymatic reaction of: substrate,reduced-flavoprotein:oxygen oxidoreductase (RH-hydroxylating or -epoxidizing) (cytochrome P450 2A6)

EC Number: 1.14.14.1

RH + a reduced [NADPH-hemoprotein reductase] + oxygen <=> ROH + an oxidized [NADPH-hemoprotein reductase] + H2O

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the Enzyme Commission system.

The reaction is physiologically favored in the direction shown.

Inhibitors (Unknown Mechanism): (+)-menthofuran [KhojastehBakht98]


Enzymatic reaction of: nicotine,NADPH:oxygen oxidoreductase (cytochrome P450 2A6)

EC Number: 1.5.8.-

(S)-nicotine + an oxidized flavoprotein <=> nicotine-Δ1'5'-iminium ion + a reduced flavoprotein

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the direction in which it was curated.

The reaction is favored in the direction shown.

Alternative Substrates for (S)-nicotine: coumarin [Messina97 ]

In Pathways: nicotine degradation IV , nicotine degradation III

Summary:
Cytochrome P459 2A6 is the principal isoform involved in nicotine metabolism. Variation in activity in human liver microsomal preparations reflects genetic polymorphisms. Cotinine formation (via the nicotine iminium ion intermediate) is inhibited by the substrate coumarin. A mean Km for the nicotine to cotinine conversion in 31 human liver microsome preparations was 64.9 +/- 32.7 μM, with a range of 13-162 μM. The reaction was inhibited >80% by coumarin at 100 μM [Messina97].

Inhibitors (Unknown Mechanism): coumarin [Messina97]

Kinetic Parameters:

Substrate
Km (μM)
Citations
(S)-nicotine
64.9
[Messina97]


Enzymatic reaction of: nicotine hydroxylase (cytochrome P450 2A6)

EC Number: 1.14.14.1

(S)-nicotine + a reduced flavoprotein + oxygen <=> 2'-hydroxynicotine + an oxidized flavoprotein + H2O

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the Enzyme Commission system.

The reaction is physiologically favored in the direction shown.

In Pathways: nicotine degradation IV

Citations: [Hukkanen05]


Enzymatic reaction of: cotinine,NADPH:oxygen oxidoreductase (cytochrome P450 2A6)

EC Number: 1.14.14.1

cotinine + a reduced flavoprotein + oxygen <=> trans-3'-hydroxycotinine + an oxidized flavoprotein + H2O

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the Enzyme Commission system.

The reaction is physiologically favored in the direction shown.

Alternative Substrates for cotinine: coumarin [Nakajima96a ]

In Pathways: nicotine degradation III

Summary:
Cytochrome P450 2A6 was shown to catalyze the 3'-hydroxylation of cotinine in human liver microsomes. The reaction was inhibited by coumarin, a specific substrate of this enzyme (IC50 = 2.4μM.

Inhibitors (Unknown Mechanism): coumarin [Nakajima96a]


Enzymatic reaction of: 5'-hydroxycotinine synthetase (cytochrome P450 2A6)

EC Number: 1.14.14.1

cotinine + a reduced flavoprotein + oxygen <=> 5'-hydroxycotinine + an oxidized flavoprotein + H2O

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the Enzyme Commission system.

The reaction is physiologically favored in the direction shown.

In Pathways: nicotine degradation III

Citations: [Hukkanen05]


Enzymatic reaction of: cotinine hydroxylase (cytochrome P450 2A6)

EC Number: 1.14.14.1

cotinine + a reduced flavoprotein + oxygen <=> N'-hydroxymethyl-norcotinine + an oxidized flavoprotein + H2O

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the Enzyme Commission system.

The reaction is physiologically favored in the direction shown.

In Pathways: nicotine degradation III

Citations: [Hukkanen05]


References

Ariyoshi02: Ariyoshi N, Sekine H, Saito K, Kamataki T (2002). "Characterization of a genotype previously designated as CYP2A6 D-type: CYP2A6*4B, another entire gene deletion allele of the CYP2A6 gene in Japanese." Pharmacogenetics 12(6);501-4. PMID: 12172220

Ding95: 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. PMID: 7864805

FernandezSalgue95: Fernandez-Salguero P, Gonzalez FJ (1995). "The CYP2A gene subfamily: species differences, regulation, catalytic activities and role in chemical carcinogenesis." Pharmacogenetics 5 Spec No;S123-8. PMID: 7581481

FernandezSalgue95a: Fernandez-Salguero P, Hoffman SM, Cholerton S, Mohrenweiser H, Raunio H, Rautio A, Pelkonen O, Huang JD, Evans WE, Idle JR (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. PMID: 7668294

Godoy02: Godoy W, Albano RM, Moraes EG, Pinho PR, Nunes RA, Saito EH, Higa C, Filho IM, Kruel CD, Schirmer CC, Gurski R, Lang MA, Pinto LF (2002). "CYP2A6/2A7 and CYP2E1 expression in human oesophageal mucosa: regional and inter-individual variation in expression and relevance to nitrosamine metabolism." Carcinogenesis 23(4);611-6. PMID: 11960914

Hecht00: Hecht SS, Hochalter JB, Villalta PW, Murphy SE (2000). "2'-Hydroxylation of nicotine by cytochrome P450 2A6 and human liver microsomes: formation of a lung carcinogen precursor." Proc Natl Acad Sci U S A 97(23);12493-7. PMID: 11050152

Hoffman95: Hoffman SM, Fernandez-Salguero P, Gonzalez FJ, Mohrenweiser HW (1995). "Organization and evolution of the cytochrome P450 CYP2A-2B-2F subfamily gene cluster on human chromosome 19." J Mol Evol 41(6);894-900. PMID: 8587134

Hukkanen05: Hukkanen J, Jacob P, Benowitz NL (2005). "Metabolism and disposition kinetics of nicotine." Pharmacol Rev 57(1);79-115. PMID: 15734728

KhojastehBakht98: Khojasteh-Bakht SC, Koenigs LL, Peter RM, Trager WF, Nelson SD (1998). "(R)-(+)-Menthofuran is a potent, mechanism-based inactivator of human liver cytochrome P450 2A6." Drug Metab Dispos 26(7);701-4. PMID: 9660853

Lewis02: Lewis DF, Lake BG (2002). "Species differences in coumarin metabolism: a molecular modelling evaluation of CYP2A interactions." Xenobiotica 32(7);547-61. PMID: 12162851

Messina97: Messina ES, Tyndale RF, Sellers EM (1997). "A major role for CYP2A6 in nicotine C-oxidation by human liver microsomes." J Pharmacol Exp Ther 282(3);1608-14. PMID: 9316878

Murphy99: Murphy SE, Johnson LM, Pullo DA (1999). "Characterization of multiple products of cytochrome P450 2A6-catalyzed cotinine metabolism." Chem Res Toxicol 12(7);639-45. PMID: 10409404

Nakajima96: Nakajima M, Yamamoto T, Nunoya K, Yokoi T, Nagashima K, Inoue K, Funae Y, Shimada N, Kamataki T, Kuroiwa Y (1996). "Role of human cytochrome P4502A6 in C-oxidation of nicotine." Drug Metab Dispos 24(11);1212-7. PMID: 8937855

Nakajima96a: Nakajima M, Yamamoto T, Nunoya K, Yokoi T, Nagashima K, Inoue K, Funae Y, Shimada N, Kamataki T, Kuroiwa Y (1996). "Characterization of CYP2A6 involved in 3'-hydroxylation of cotinine in human liver microsomes." J Pharmacol Exp Ther 277(2);1010-5. PMID: 8627511

Nowell02: Nowell S, Sweeney C, Hammons G, Kadlubar FF, Lang NP (2002). "CYP2A6 activity determined by caffeine phenotyping: association with colorectal cancer risk." Cancer Epidemiol Biomarkers Prev 11(4);377-83. PMID: 11927498

Pelkonen00: Pelkonen O, Rautio A, Raunio H, Pasanen M (2000). "CYP2A6: a human coumarin 7-hydroxylase." Toxicology 144(1-3);139-47. PMID: 10781881

Phillips85: 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. PMID: 3856261

Smith98c: Smith G, Stubbins MJ, Harries LW, Wolf CR (1998). "Molecular genetics of the human cytochrome P450 monooxygenase superfamily." Xenobiotica 28(12);1129-65. PMID: 9890157

Topcu02: Topcu Z, Chiba I, Fujieda M, Shibata T, Ariyoshi N, Yamazaki H, Sevgican F, Muthumala M, Kobayashi H, Kamataki T (2002). "CYP2A6 gene deletion reduces oral cancer risk in betel quid chewers in Sri Lanka." Carcinogenesis 23(4);595-8. PMID: 11960911

Tyndale02: Tyndale RF, Sellers EM (2002). "Genetic variation in CYP2A6-mediated nicotine metabolism alters smoking behavior." Ther Drug Monit 24(1);163-71. PMID: 11805739

Yamano89: Yamano S, Nagata K, Yamazoe Y, Kato R, Gelboin HV, Gonzalez FJ (1989). "cDNA and deduced amino acid sequences of human P450 IIA3 (CYP2A3)." Nucleic Acids Res 17(12);4888. PMID: 2748347

Yamano90: Yamano S, Tatsuno J, Gonzalez FJ (1990). "The CYP2A3 gene product catalyzes coumarin 7-hydroxylation in human liver microsomes." Biochemistry 29(5);1322-9. PMID: 2322567


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Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
Page generated by SRI International Pathway Tools version 18.5 on Thu Nov 27, 2014, BIOCYC14B.