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首页> 外文期刊>The FEBS journal >Selective targeting of the conserved active site cysteine of Mycobacterium tuberculosis methionine aminopeptidase with electrophilic reagents
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Selective targeting of the conserved active site cysteine of Mycobacterium tuberculosis methionine aminopeptidase with electrophilic reagents

机译：用亲电子试剂选择性靶向结核分枝杆菌蛋氨酸氨基肽酶的保守活性位点半胱氨酸

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摘要

Methionine aminopeptidases (MetAPs) cleave initiator methionine from similar to 70% of the newly synthesized proteins in every living cell, and specific inhibition or knockdown of this function is detrimental. MetAPs are metalloenzymes, and are broadly classified into two subtypes, type I and type II. Bacteria contain only type I MetAPs, and the active site of these enzymes contains a conserved cysteine. By contrast, in type II enzymes the analogous position is occupied by a conserved glycine. Here, we report the reactivity of the active site cysteine in a type I MetAP, MetAP1c, of Mycobacterium tuberculosis (MtMetAP1c) towards highly selective cysteine-specific reagents. The authenticity of selective modification of Cys105 of MtMetAP1c was established by using site-directed mutagenesis and crystal structure determination of covalent and noncovalent complexes. On the basis of these observations, we propose that metal ions in the active site assist in the covalent modification of Cys105 by orienting the reagents appropriately for a successful reaction. These studies establish, for the first time, that the conserved cysteine of type I MetAPs can be targeted for selective inhibition, and we believe that this chemistry can be exploited for further drug discovery efforts regarding microbial MetAPs.
机译：蛋氨酸氨基肽酶（MetAPs）从每个活细胞中类似于70％的新合成蛋白质中裂解启动子蛋氨酸，这种功能的特异性抑制或抑制是有害的。 MetAP是金属酶，大致分为两个亚型，I型和II型。细菌仅包含I型MetAP，并且这些酶的活性位点包含保守的半胱氨酸。相反，在II型酶中，类似的位置被保守的甘氨酸占据。在这里，我们报告了结核分枝杆菌（MtMetAP1c）对I型MetAP，MetAP1c的活性位点半胱氨酸对高选择性半胱氨酸特异性试剂的反应性。通过使用定点诱变和共价和非共价复合物的晶体结构测定，确定了MtMetAP1c的Cys105选择性修饰的真实性。基于这些观察，我们提出活性位点中的金属离子通过适当定向试剂以成功进行反应，协助Cys105的共价修饰。这些研究首次确定了保守的I型MetAPs的半胱氨酸可以作为选择性抑制的靶标，我们相信这种化学方法可以用于微生物MetAPs的进一步药物开发。

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