Active and inhibited human catalase structures: Ligand and NADPH binding and catalytic mechanism
Active and inhibited human catalase structures: Ligand and NADPH binding and catalytic mechanism
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DOI：
10.1006/jmbi.1999.3458
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发表时间：
2000-02-11
影响因子：
5.6
通讯作者：
Tainer, JA
中科院分区：
文献类型：
--
作者：
Putnam, CD;Arvai, AS;Tainer, JA
人过氧化氢酶是一种含血红素的过氧化物酶体，可将过氧化氢分解为水和氧气;它与乙醇代谢、炎症、细胞凋亡、衰老和癌症有关。1.5埃分辨率的人酶结构（有和没有结合的NADPH）建立了哺乳动物过氧化氢酶折叠和组装的保守特征，暗示Tyr 370为酪氨酸自由基，表明同源mRNA通过过氧化氢酶NADPH结合位点的氧化还原敏感性结合的结构基础，并鉴定了出乎意料的大量水介导的结构域接触。基于在25埃长的通道中观察到的水位置的分子标尺机制解决了选择过氧化氢的问题。控制水介导的氢键由这把尺子选择更长的过氧化氢，并解释了突变的矛盾效应，增加活性位点的访问，但较低的催化速率。血红素活性位点通过Tyr-Arg-His-Asp电荷中继、精氨酸残基与血红素羧酸酯基团的氢键合和芳香族堆积而不损害过氧化物结合。非特异性氰化物和特异性3-氨基-1，2，4-三唑抑制剂复合物的结构鉴定了它们的抑制模式，有助于揭示过氧化氢酶的催化机制。总之，这些静息状态和抑制的人过氧化氢酶结构支持特定的，基于结构的过氧化氢酶底物识别，反应和抑制机制，并为理解乙醇中毒和人类多态性的可能影响提供了分子基础。(C)北京大学出版社.
Human catalase is an heme-containing peroxisomal enzyme that breaks down hydrogen peroxide to water and oxygen; it is implicated in ethanol metabolism, inflammation, apoptosis, aging and cancer. The 1.5 Angstrom resolution human enzyme structure, both with and without bound NADPH, establishes the conserved features of mammalian catalase fold and assembly, implicates Tyr370 as the tyrosine radical, suggests the structural basis for redox-sensitive binding of cognate mRNA via the catalase NADPH binding site, and identifies an unexpectedly substantial number of water-mediated domain contacts. A molecular ruler mechanism based on observed water positions in the 25 Angstrom-long channel resolves problems for selecting hydrogen peroxide. Control of water-mediated hydrogen bonds by this ruler selects for the longer hydrogen peroxide and explains the paradoxical effects of mutations that increase active site access but lower catalytic rate. The heme active site is tuned without compromising peroxide binding through a Tyr-Arg-His-Asp charge relay, arginine residue to heme carboxylate group hydrogen bonding, and aromatic stacking. Structures of the non-specific cyanide and specific 3-amino-1,2,4-triazole inhibitor complexes of human catalase identify their modes of inhibition and help reveal the catalytic mechanism of catalase. Taken together, these resting state and inhibited human catalase structures support specific, structure-based mechanisms for the catalase substrate recognition, reaction and inhibition and provide a molecular basis for understanding ethanol intoxication and the likely effects of human polymorphisms. (C) 2000 Academic Press.