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MetaCyc Enzyme: cytochrome P450 2B6

Gene: CYP2B6 Accession Number: HS09587 (MetaCyc)

Synonyms: CYPIIB6, P450, IIB1, CPB6, CYP2B, P450 IIB1, cytochrome P450, family 2, subfamily B, polypeptide 6, cytochrome P450, subfamily IIB (phenobarbital-inducible), polypeptide 6, cytochrome P450 2B6

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 [Smith98].

CYP2B6 encodes a member of the cytochrome P450 superfamily that is localized in the endoplasmic reticulum and its expression is induced by phenobarbital [Sueyoshi99]. The enzyme is known to metabolize some xenobiotics, such as the anti-cancer drugs cyclophosphamide and ifosphamide. The substrate selectivity of CYP2B6 was assayed by site-directed mutagenesis and molecular modeling [Spatzenegger03].

In another assay, CYP2B6 cDNA was cloned and expressed in bacteria and in yeast, and the yeast-expressed protein was used to assess its role in the metabolism of ethoxyresorufin, pentoxyresorufin, benzyloxyresorufin, ethoxycoumarin, testosterone and cyclophosphamide [Gervot99].

The enzyme is expressed ubiquitously, and was detected in liver, brain, intestine and kidney, and at a lower level in the lung [Gervot99].

Transcript variants for this gene have been described [Yamano89, Miles90]; however, it has not been resolved whether these transcripts are in fact produced by this gene or by a closely related pseudogene, CYP2B7 [Miles89]. Both the gene and the pseudogene are located in the middle of a CYP2A pseudogene found in a large cluster of cytochrome P450 genes from the CYP2A, CYP2B and CYP2F subfamilies on chromosome 19q [Hoffman95].

A molecular model has been proposed [Lewis97].

Locations: endoplasmic reticulum membrane

Map Position: [41,888,928 -> 41,916,025]

Molecular Weight of Polypeptide: 56.278 kD (from nucleotide sequence)

Unification Links: ArrayExpress:P20813 , Ensembl:ENSG00000167594 , Entrez-gene:1555 , GeneCards:CYP2B6 , OMIM:605059 , PhosphoSite:P20813 , PhylomeDB:P20813 , Pride:P20813 , Protein Model Portal:P20813 , RefSeq:NM_000767 , RefSeq:NP_000758 , SMR:P20813 , String:9606.ENSP00000324648 , UCSC Human Genome:NM_000767 , UniGene:1360 , UniProt:P20813

Relationship Links: Entrez-Nucleotide:PART-OF:AC023172 , Entrez-Nucleotide:PART-OF:AF081569 , Entrez-Nucleotide:PART-OF:AF182277 , Entrez-Nucleotide:PART-OF:M29874 , Entrez-Nucleotide:PART-OF:X13494 , InterPro:IN-FAMILY:IPR001128 , InterPro:IN-FAMILY:IPR002401 , InterPro:IN-FAMILY:IPR008068 , InterPro:IN-FAMILY:IPR017972 , PDB:Structure:3IBD , PDB:Structure:3QOA , PDB:Structure:3QU8 , PDB:Structure:3UA5 , PDB:Structure:4I91 , Pfam:IN-FAMILY:PF00067 , Prints:IN-FAMILY:PR00385 , Prints:IN-FAMILY:PR00463 , Prints:IN-FAMILY:PR01685 , 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: unspecific monooxygenase (cytochrome P450 2B6)

Synonyms: cytochrome P450

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.


Enzymatic reaction of: bupropion hydroxylase (cytochrome P450 2B6)

EC Number: 1.14.14.1

bupropion + a reduced flavoprotein + oxygen <=> hydroxybupropion + 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: bupropion degradation

Summary:
A validated assay for bupropion hydroxylase activity has been described [Walsky04]. Pooled human liver microsomes gave a Km of 81.7 +/- 1.3 μM and a Vmax of 413 +/- 2 pmol/mg/min. Enzyme recombinantly expressed in an insect cell system had a Km of 66.8 +/- 1.4 μM and a Vmax of 12.9 +/- 0.1 pmol/mgmin.. The inhibitor 2.phenyl-2-(1-piperdinyl)propane, (PPP), had IC50 values of 7.74 +/- 0.47 μM for pooled human liver microsomes, and 2.02 +/- 0.19 μM for recombinantly expressed enzyme.

Individual variation in rates of bupropion hydroxylation in different human liver microsomal preparations has been observed at 500 μM bupropion. Expression of CYP2B6 protein significantly correlated with bupropion hydroxylase activity variation, as determined by immunoblotting [Faucette00]. In addition, CYP3A4 has been shown to have no significant role in bupropion hydroxylation in human liver at likely in vivo substrate concentrations [Faucette01].

Cofactors or Prosthetic Groups: NADPH [Walsky04]

Inhibitors (Unknown Mechanism): 2-phenyl-2-(1-piperdinyl)propane [Walsky04]

Kinetic Parameters:

Substrate
Km (μM)
Citations
bupropion
81.7
[Walsky04]

Exons/Introns:


References

Faucette00: Faucette SR, Hawke RL, Lecluyse EL, Shord SS, Yan B, Laethem RM, Lindley CM (2000). "Validation of bupropion hydroxylation as a selective marker of human cytochrome P450 2B6 catalytic activity." Drug Metab Dispos 28(10);1222-30. PMID: 10997944

Faucette01: Faucette SR, Hawke RL, Shord SS, Lecluyse EL, Lindley CM (2001). "Evaluation of the contribution of cytochrome P450 3A4 to human liver microsomal bupropion hydroxylation." Drug Metab Dispos 29(8);1123-9. PMID: 11454731

Gervot99: Gervot L, Rochat B, Gautier JC, Bohnenstengel F, Kroemer H, de Berardinis V, Martin H, Beaune P, de Waziers I (1999). "Human CYP2B6: expression, inducibility and catalytic activities." Pharmacogenetics 9(3);295-306. PMID: 10471061

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

Lewis97: Lewis DF, Lake BG (1997). "Molecular modelling of mammalian CYP2B isoforms and their interaction with substrates, inhibitors and redox partners." Xenobiotica 27(5);443-78. PMID: 9179987

Miles89: Miles JS, McLaren AW, Wolf CR (1989). "Alternative splicing in the human cytochrome P450IIB6 gene generates a high level of aberrant messages." Nucleic Acids Res 17(20);8241-55. PMID: 2813061

Miles90: Miles JS, McLaren AW, Gonzalez FJ, Wolf CR (1990). "Alternative splicing in the human cytochrome P450IIB6 gene: use of a cryptic exon within intron 3 and splice acceptor site within exon 4." Nucleic Acids Res 18(1);189. PMID: 2308828

Smith98: 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

Spatzenegger03: Spatzenegger M, Liu H, Wang Q, Debarber A, Koop DR, Halpert JR (2003). "Analysis of differential substrate selectivities of CYP2B6 and CYP2E1 by site-directed mutagenesis and molecular modeling." J Pharmacol Exp Ther 304(1);477-87. PMID: 12490624

Sueyoshi99: Sueyoshi T, Kawamoto T, Zelko I, Honkakoski P, Negishi M (1999). "The repressed nuclear receptor CAR responds to phenobarbital in activating the human CYP2B6 gene." J Biol Chem 274(10);6043-6. PMID: 10037683

Walsky04: Walsky RL, Obach RS (2004). "Validated assays for human cytochrome P450 activities." Drug Metab Dispos 32(6);647-60. PMID: 15155557

Yamano89: Yamano S, Nhamburo PT, Aoyama T, Meyer UA, Inaba T, Kalow W, Gelboin HV, McBride OW, Gonzalez FJ (1989). "cDNA cloning and sequence and cDNA-directed expression of human P450 IIB1: identification of a normal and two variant cDNAs derived from the CYP2B locus on chromosome 19 and differential expression of the IIB mRNAs in human liver." Biochemistry 28(18);7340-8. PMID: 2573390


Report Errors or Provide Feedback
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 Sat Nov 22, 2014, BIOCYC14A.