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首页> 外文期刊>Life sciences >IDENTIFICATION OF A REGION IMPORTANT FOR HUMAN MONOAMINE OXIDASE B SUBSTRATE AND INHIBITOR SELECTIVITY
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IDENTIFICATION OF A REGION IMPORTANT FOR HUMAN MONOAMINE OXIDASE B SUBSTRATE AND INHIBITOR SELECTIVITY

机译：鉴定人单胺氧化酶B底物重要区域和抑制剂的选择性

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Monoamine oxidase (MAO) A and B are flavoenzymes that catalyze the oxidative deamination of biogenic and xenobiotic amines. To search for domains that confer substrate and inhibitor selectivities, two chimeric proteins were constructed and expressed in yeast. The kinetic constants and IC50 values were determined for these chimeric enzymes using MAO-A/B selective substrates and inhibitors. Replacement of MAO-A amino acids 161-375 with the corresponding region of MAO-B, termed AB(161-375) A, converted MAO-A catalytic properties to MAO-B like ones. The specificity constants (k(cat)/k(m)) for the oxidation of beta-phenylethylamine (PEA) (1.6 x 10(5) s(-1) M(-1)) and benzylamine (2.4 x 10(4) s(-1) M(-1) M(-1)) by AB(161-375) A were similar to wild-type MAO-B (PEA, 8 x 10(5) s(-1) M(-1); benzylamine, 4.9 x 10(4) S-1 M(-1)). Serotonin (5-HT), a preferred substrate for MAO-A, was not oxidized by AB(161-375) A or wild-type MAO-B. Furthermore, AB(161-375)A was more sensitive to the MAO-B specific inhibitor deprenyl (IC50 2.7 +/- 0.4 x 10(-8) M) than to the MAO-A specific inhibitor clorgyline (IC50 5.4 +/- 0.8 x 10(-7) M). However, the reciprocal chimera in which a MAO-B segment was replaced with the corresponding region of MAO-A, termed BA(152-366)B, lacked catalytic activity. The lack of catalytic activity was not due to aberrant expression but rather an inactive protein as demonstrated by Western blot analysis. These results demonstrate that MAO-B amino acids 152-366 contain a domain (s) that confers substrate and inhibitor selectivity. [References: 32]
机译：单胺氧化酶（MAO）A和B是黄酮酶，可催化生物胺和异种胺的氧化脱氨作用。为了寻找赋予底物和抑制剂选择性的结构域，构建了两种嵌合蛋白并在酵母中表达。使用MAO-A / B选择性底物和抑制剂测定这些嵌合酶的动力学常数和IC50值。用称为AB（161-375）A的相应MAO-B区域取代MAO-A氨基酸161-375，将MAO-A的催化性能转化为类似MAO-B的催化性能。 β-苯乙胺（PEA）（1.6 x 10（5）s（-1）M（-1））和苄胺（2.4 x 10（4）氧化的特异性常数（k（cat）/ k（m）） ）AB（161-375）A的s（-1）M（-1）M（-1））与野生型MAO-B（PEA，8 x 10（5）s（-1）M（ -1）;苄胺，4.9 x 10（4）S-1 M（-1））。 5-羟色胺（5-HT）是MAO-A的优选底物，未被AB（161-375）A或野生型MAO-B氧化。此外，AB（161-375）A对MAO-B特异抑制剂去异戊二烯（IC50 2.7 +/- 0.4 x 10（-8）M）的敏感性比对MAO-A特异抑制剂克洛可林（IC50 5.4 +/-）更敏感0.8 x 10（-7）M）。然而，其中MAO-B区段被MAO-A的相应区域（称为BA（152-366）B）代替的相互嵌合体缺乏催化活性。缺乏催化活性不是由于异常表达，而是由于蛋白质印迹分析所证实的无活性蛋白质。这些结果证明，MAO-B氨基酸152-366包含赋予底物和抑制剂选择性的结构域。 [参考：32]

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