Structures of Human Cytochrome P-450 2E1 INSIGHTS INTO THE BINDING OF INHIBITORS AND BOTH SMALL MOLECULAR WEIGHT AND FATTY ACID SUBSTRATES.

被引:190
作者
Porubsky, Patrick R. [1 ]
Meneely, Kathleen M. [1 ]
Scott, Emily E. [1 ]
机构
[1] Univ Kansas, Dept Med Chem, Lawrence, KS 66045 USA
基金
美国国家卫生研究院;
关键词
D O I
10.1074/jbc.M805999200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Human microsomal cytochrome P-450 2E1 (CYP2E1) monooxygenates > 70 low molecular weight xenobiotic compounds, as well as much larger endogenous fatty acid signaling molecules such as arachidonic acid. In the process, CYP2E1 can generate toxic or carcinogenic compounds, as occurs with acetaminophen overdose, nitrosamines in cigarette smoke, and reactive oxygen species from uncoupled catalysis. Thus, the diverse roles that CYP2E1 has in normal physiology, toxicity, and drug metabolism are related to its ability to metabolize diverse classes of ligands, but the structural basis for this was previously unknown. Structures of human CYP2E1 have been solved to 2.2 A for an indazole complex and 2.6 angstrom for a 4-methylpyrazole complex. Both inhibitors bind to the heme iron and hydrogen bond to Thr(303) within the active site. Complementing its small molecular weight substrates, the hydrophobic CYP2E1 active site is the smallest yet observed for a human cytochrome P-450. The CYP2E1 active site also has two adjacent voids: one enclosed above the I helix and the other forming a channel to the protein surface. Minor repositioning of the Phe(478) aromatic ring that separates the active site and access channel would allow the carboxylate of fatty acid substrates to interact with conserved (216)QXXNN(220) residues in the access channel while positioning the hydrocarbon terminus in the active site, consistent with experimentally observed omega-1 hydroxylation of saturated fatty acids. Thus, these structures provide insights into the ability of CYP2E1 to effectively bind and metabolize both small molecule substrates and fatty acids.
引用
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页码:33698 / 33707
页数:10
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