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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >LEUKOTRIENE A(4) HYDROLASE - MAPPING OF A HENICOSAPEPTIDE INVOLVED IN MECHANISM-BASED INACTIVATION
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LEUKOTRIENE A(4) HYDROLASE - MAPPING OF A HENICOSAPEPTIDE INVOLVED IN MECHANISM-BASED INACTIVATION

机译：白三烯A（4）水解酶-参与基于机理的活化的缩肤的映射

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摘要

Leukotriene A(4) (LTA(4)) hydrolase [(7E,9E,11Z, 14Z)-(5S,6S)-5,6-epoxyicosa-7,9,11,14-tetraenoate hydrolase; EC 3.3.2.6] is a bifunctional zinc metalloenzyme which converts LTA(4) into the chemotactic agent leukotriene B-4 (LTB(4)). Suicide inactivation, a typical feature of LTA(4) hydrolase/aminopeptidase, occurs via an irreversible, apparently mechanism-based, covalent binding of LTA(4) to the protein in a 1:1 stoichiometry. Differential lysine-specific peptide mapping of unmodified and suicide-inactivated LTA(4) hydrolase has been used to identify a henicosapeptide, encompassing the amino acid residues 365-385 of human LTA(4) hydrolase, which is involved in the binding of LTA4, LTA(4) methyl ester, and LTA(4) ethyl ester to the native enzyme, A modified form of this peptide, generated by lysine-specific digestion of LTA(4) hydrolase inactivated by LTA(4) ethyl ester, could be isolated for complete Edman degradation, The sequence analysis revealed a gap at position 14, which shows that binding of the leukotriene epoxide had occurred via Tyr-378 in LTA(4) hydrolase, Inactivation of the epoxide hydrolase acid the aminopeptidase activity was accompanied by a proportionate modification of the peptide. Furthermore, both enzyme inactivation and peptide modification could be prevented by preincubation of LTA(4) hydrolase with the competitive inhibitor bestatin, which demonstrates that the henicosapeptide contains functional elements of the active site(s), It may now be possible to clarify the molecular mechanisms underlying suicide inactivation and epoxide hydrolysis by site-directed mutagenesis combined with structural analysis of the lipid molecule, covalently bound to the peptide. [References: 24]
机译：白三烯A（4）（LTA（4））水解酶[（7E，9E，11Z，14Z）-（5S，6S）-5,6-epoxyicosa-7,9,11,14-丁烯酸水解酶; EC 3.3.2.6]是一种双功能锌金属酶，可将LTA（4）转化为趋化剂白三烯B-4（LTB（4））。自杀失活，LTA（4）水解酶/氨基肽酶的典型特征，是通过不可逆的，显然基于机理的LTA（4）与蛋白质以1：1的化学计量共价结合而发生的。未修饰的和自杀灭活的LTA（4）水解酶的赖氨酸特异性多肽图谱已被用于鉴定半胱氨酸肽，其包含人LTA（4）水解酶的氨基酸残基365-385，参与了LTA4的结合， LTA（4）甲酯和LTA（4）乙酯对天然酶的分离，可以分离出经LTA（4）乙酯灭活的LTA（4）水解酶的赖氨酸特异性消化而产生的该肽的修饰形式对于完全的Edman降解，序列分析显示在14位有一个缺口，表明在LTA（4）水解酶中通过Tyr-378发生了白三烯环氧化物的结合，环氧化物水解酶的失活，氨基肽酶的活性与之成比例。肽的修饰。此外，可以通过将LTA（4）水解酶与竞争性抑制剂Bestatin一起预孵育来防止酶失活和肽修饰，这表明半肽含有活性位点的功能元件，现在有可能阐明分子通过定点诱变结合脂质分子的结构分析，实现自杀灭活和环氧化物水解的基本机理。 [参考：24]

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