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首页> 外文期刊>Biochemistry >Hydrogen Peroxide-Mediated Isoniazid Activation Catalyzed by Mycobacterium tuberculosis Catalase-Peroxidase (KatG) and Its S315T Mutant
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Hydrogen Peroxide-Mediated Isoniazid Activation Catalyzed by Mycobacterium tuberculosis Catalase-Peroxidase (KatG) and Its S315T Mutant

机译：结核分枝杆菌过氧化氢酶-过氧化物酶（KatG）及其S315T突变体催化过氧化氢介导的异烟肼活化

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摘要

Inhibition of the enzyme Mycobacterium tuberculosis InhA (enoyl-acyl carrier protein reductase) due to formation of an isonicotinoyl-NAD adduct (IN-NAD) from isoniazid (INH) and nicotinamide adenine dinucleotide cofactor is considered central to the mode of action of INH,a first-line treatment for tuberculosis infection.INH action against mycobacteria requires catalase-peroxidase (KatG) function,and IN-NAD adduct formation is catalyzed in vitro by M.tuberculosis KatG under a variety of conditions,yet a physiologically relevant approach to the process has not emerged that allows scrutiny of the mechanism and the origins of INH resistance in the most prevalent drug-resistant strain bearing KatG[S315T].In this report,we describe how hydrogen peroxide,delivered at very low concentrations to ferric KatG,leads to efficient inhibition of InhA due to formation of the IN-NAD adduct.The rate of adduct formation mediated by wild-type KatG was about 20-fold greater than by the isoniazid-resistant KatG[S315T] mutant under optimal conditions (H_2O_2 supplied along with NAD~+ and INH).Slow adduct formation also occurs starting with NADH and INH,in the presence of KatG even in the absence of added peroxide,due to endogenous peroxide.The poor efficiency of the KatG[S315T] mutant can be enhanced merely by increasing the concentration of INH,consistent with this enzyme's reduced affinity for INH binding to the resting enzyme and the catalytically competent enzyme intermediate (Compound I).Origins of drug resistance in the KatG[S315T] mutant enzyme are analyzed at the structural level through examination of the three-dimensional X-ray crystal structure of the mutant enzyme.
机译：由于异烟肼（INH）和烟酰胺腺嘌呤二核苷酸辅因子形成了异烟酰基-NAD加合物（IN-NAD），因此抑制了结核分枝杆菌InhA（烯酰酰基载体蛋白还原酶）酶，这被认为是INH作用方式的关键，结核分枝杆菌的一线治疗。INH对分枝杆菌的作用需要过氧化氢酶-过氧化物酶（KatG）功能，并且结核分枝杆菌KatG在多种条件下都可以在体外催化IN-NAD加合物的形成，但是从生理学角度出发尚未出现能够仔细研究最普遍耐药的KatK菌株中INH耐药性的机制和起源的过程。在本报告中，我们描述了过氧化氢如何以极低的浓度输送至三价KatK铁。由于形成IN-NAD加合物而有效抑制InhA。野生型KatG介导的加合物形成速率比异烟肼耐药性高约20倍在最佳条件下（H_2O_2与NAD〜+和INH一起提供），KatG [S315T]突变体。即使在不存在添加过氧化物的情况下，由于内源性过氧化物，在KatK存在下，从NADH和INH开始，加合物形成也会缓慢发生。仅通过增加INH的浓度，就可以提高KatG [S315T]突变体的不良效率，这与该酶对INH与静止酶和催化活性酶中间体（化合物I）结合的亲和力降低有关。通过检查突变酶的三维X射线晶体结构，在结构水平上分析了KatG [S315T]突变酶。

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