2FDU

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

Summary for 2FDU

• Entry DOI: 10.2210/pdb2fdu/pdb
• Related: 1Z10 1Z11 2FDV 2FDW 2FDY
• Descriptor: Cytochrome P450 2A6, SULFATE ION, PROTOPORPHYRIN IX CONTAINING FE, ... (5 entities in total)
• Functional Keywords: cyp2a6, p450 2a6, p450, monooxygenase, drug metabolizing enzyme, coumarin 7-hydroxylase, nicotine oxidase, oxidoreductase
• Biological source: Homo sapiens (human)
• Cellular location: Endoplasmic reticulum membrane; Peripheral membrane protein: P11509
• Total number of polymer chains: 4
• Total formula weight: 222153.63

Authors

Yano, J.K.,Stout, C.D.,Johnson, E.F. (deposition date: 2005-12-14, release date: 2006-11-28, Last modification date: 2023-08-30)

Primary citation

Yano, J.K.,Denton, T.T.,Cerny, M.A.,Zhang, X.,Johnson, E.F.,Cashman, J.R.
Synthetic Inhibitors of Cytochrome P-450 2A6: Inhibitory Activity, Difference Spectra, Mechanism of Inhibition, and Protein Cocrystallization.
J.Med.Chem., 49:6987-7001, 2006

PubMed Abstract: A series of 3-heteroaromatic analogues of nicotine were synthesized to delineate structural and mechanistic requirements for selectively inhibiting human cytochrome P450 (CYP) 2A6. Thiophene, substituted thiophene, furan, substituted furan, acetylene, imidazole, substituted imidazole, thiazole, pyrazole, substituted pyrazole, and aliphatic and isoxazol moieties were used to replace the N-methylpyrrolidine ring of nicotine. A number of potent inhibitors were identified, and several exhibited high selectivity for CYP2A6 relative to CYP2E1, -3A4, -2B6, -2C9, -2C19, and -2D6. The majority of these inhibitors elicited type II difference spectra indicating the formation of a coordinate covalent bond to the heme iron. The majority of inhibitors were reversible inhibitors although several mechanism-based inactivators were identified. Most of the inhibitors were also relatively metabolically stable. X-ray crystal structures of CYP2A6 cocrystallized with three furan analogues bearing methanamino side chains indicated that the amine side chain coordinated to the heme iron. The pyridyl moiety was positioned to accept a hydrogen bond from Asn297, and all three inhibitors exhibited orthogonal aromatic-aromatic interactions with protein side chains. For comparison, the cocrystal structure of 4,4'-dipyridyl disulfide was also obtained and showed that the pyridine moiety could assume a different orientation than that observed for the 3-heteroaromatic pyridines examined. For the 3-heteroromatic pyridines, N-methyl and N,N-dimethyl amino groups increased the apparent Ki and distorted helix I of the protein. Substitution of a phenyl ring for the pyridyl ring also increased the apparent Ki, which is likely to reflect the loss of the hydrogen bonding interaction with Asn297. In contrast, inhibitory potency for other P450s was increased, and the selectivity of the phenyl analogues for CYP2A6 was decreased relative to the pyridyl compounds. The results suggest that inhibitors that compliment the active site features of CYP2A6 can exhibit significant selectivity for CYP2A6 relative to other human liver drug-metabolizing P450s.

PubMed: 17125252
DOI: 10.1021/jm060519r

Experimental method

X-RAY DIFFRACTION (1.85 Å)