Structure of isocitrate lyase, a persistence factor of Mycobacterium tuberculosis
Structure of isocitrate lyase, a persistence factor of Mycobacterium tuberculosis
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DOI：
10.1038/77964
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发表时间：
2000-08-01
期刊：
影响因子：
--
通讯作者：
Sacchettini, JC
中科院分区：
文献类型：
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作者：
Sharma, V;Sharma, S;Sacchettini, JC
异柠檬酸裂解酶（ICL）通过维持炎性巨噬细胞的细胞内感染，在结核分枝杆菌在小鼠体内的持续存在中起关键作用。该酶通过将乙酰辅酶A从脂肪酸的β-氧化转移到乙醛酸分流途径来实现净碳增益。鉴于其作为抗持续性感染的药物靶标的潜力，我们在没有配体的情况下解决了其结构，并与两种抑制剂复合。共价修饰的活性位点残基，半胱氨酸191，由抑制剂3-溴丙酮酸陷阱的酶在催化构象的活性位点完全无法接近溶剂。具有抑制剂3-硝基丙酸的酶的C191 S突变体的结构提供了对反应机制的进一步了解。
Isocitrate lyase (ICL) plays a pivotal role in the persistence of Mycobacterium tuberculosis in mice by sustaining intracellular infection in inflammatory macrophages. The enzyme allows net carbon gain by diverting acetyl-CoA from beta-oxidation of fatty acids into the glyoxylate shunt pathway. Given its potential as a drug target against persistent infections, we solved its structure without ligand and in complex with two inhibitors. Covalent modification of an active site residue, Cys 191, by the inhibitor 3-bromopyruvate traps the enzyme in a catalytic conformation with the active site completely inaccessible to solvent. The structure of a C191S mutant of the enzyme with the inhibitor 3-nitropropionate provides further insight into the reaction mechanism.