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首页> 外文期刊>Biochemistry >Mycobacterium tuberculosis KatG(S315T) Catalase-Peroxidase Retains All Active Site Properties for Proper Catalytic Function
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Mycobacterium tuberculosis KatG(S315T) Catalase-Peroxidase Retains All Active Site Properties for Proper Catalytic Function

机译：结核分枝杆菌KatG（S315T）过氧化氢酶过氧化物酶保留了所有活性位点的特性，可发挥适当的催化功能

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摘要

Mycobacterium tuberculosis (Mtb) KatG is a catalase-peroxidase that is thought to activate the antituberculosis drag isoniazid (INH).The local environment of Mtb KatG and its most prevalent INH-resistant mutant,KatG(S315T),is investigated with the exogenous ligands CO and NO in the absence and presence of INH by using resonance Raman,FTIR,and transient absorption spectroscopy.The Fe- His stretching vibration is detected at 244 cm~(-1) in the ferrous forms of both the wild-type enzyme and KatG(S315T).The ferrous-CO complex of both enzymes exhibits v(CO),v(Fe-CO),and d(Fe-C-O) vibrations at 1925,525,and 586 cm~(-1),respectively,indicating a positive electrostatic environment for the CO complex,which is probably weakly hydrogen-bonded to a distal residue.The CO geometry is nonlinear as indicated by the unusually high intensity of the Fe-C-O bending vibration.The v(Fe~(III)- NO) and sigma(Fe~(III)-N-O) vibrations are detected at 596 and 571 cm~(-1),respectively,in the ferric forms of wild-type and mutant enzyme and are indicative of a nonlinear binding geometry in support of the CO data.Although the presence of INH does not affect the vibrational frequencies of the CO- and NO-bound forms of either enzyme,it seems to perturb slightly their Raman intensities.Our results suggest a minimal,if any,perturbation of the distal heme pocket in the S31ST mutant.Instead,the S315T mutation seems to induce small changes in the KatG conformation/dynamics of the ligand access channel as indicated by CO rebinding kinetics in flash photolysis experiments.The implications of these findings for the catalytic mechanism and mechanism of INH resistance in KatG(S315T) are discussed.
机译：结核分枝杆菌（Mtb）KatG是一种过氧化氢酶过氧化物酶，被认为可以激活抗结核药物异烟肼（INH）.Mtb KatG及其最常见的对INH耐药的突变体KatG（S315T）的局部环境已通过外源配体进行了研究通过共振拉曼光谱，傅立叶变换红外光谱和瞬态吸收光谱研究在不存在和存在INH的情况下的CO和NO.Fe-His的拉伸振动在244 cm〜（-1）处以野生型酶和KatG（S315T）。两种酶的亚铁-一氧化碳配合物在1925、525和586 cm〜（-1）处分别表现出v（CO），v（Fe-CO）和d（Fe-CO）振动，表示CO络合物处于正静电环境，可能弱氢键结合到远端残基上.CO几何形状呈非线性，如Fe-CO弯曲振动异常高的强度所表明。v（Fe〜（III） -在铁和铁的野生形式中分别在596和571 cm〜（-1）处检测到sigma和（Fe〜（III）-NO）振动。突变型和突变型酶，并表明存在支持CO数据的非线性结合几何结构。尽管INH的存在不会影响任何一种酶的CO和NO结合形式的振动频率，但似乎会稍微扰乱其拉曼光谱我们的结果表明，S31ST突变体中远端血红素袋的扰动最小，如果有的话，相反，S315T突变似乎诱导了配体进入通道的KatG构象/动力学的细微变化，如CO的重新结合动力学所示。讨论了这些发现对KatG（S315T）的INH催化机理和抗INH机理的意义。

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