de Oliveira Maycon Vinicius Damasceno, Furtado Renan Machado, da Costa Kauê S, Vakal Serhii, Lima Anderson H
Laboratório de Planejamento e Desenvolvimento de Fármacos, Instituto de Ciências Exatas e Naturais, Universidade Federal do Pará, Belém, Brazil.
Institute of Biodiversity, Federal University of Western Pará, Santarém, Brazil.
Front Mol Biosci. 2022 Jul 20;9:889825. doi: 10.3389/fmolb.2022.889825. eCollection 2022.
Peptidoglycan is a cross-linked polymer responsible for maintaining the bacterial cell wall integrity and morphology in Gram-negative and Gram-positive bacteria. The peptidoglycan pathway consists of the enzymatic reactions held in three steps: cytoplasmic, membrane-associated, and periplasmic. The Mur enzymes (MurA-MurF) are involved in a cytoplasmic stage. The UDP-N-acetylglucosamine enolpyruvyl transferase (MurA) enzyme is responsible for transferring the enolpyruvate group from phosphoenolpyruvate (PEP) to UDP-N-acetylglucosamine (UNAG) to form UDP-N-acetylglucosamine enolpyruvate (EP-UNAG). Fosfomycin is a natural product analogous to PEP that acts on the MurA target enzyme via binding covalently to the key cysteine residue in the active site. Similar to fosfomycin, other MurA covalent inhibitors have been described with a warhead in their structure that forms a covalent bond with the molecular target. In MurA, the nucleophilic thiolate of Cys115 is pointed as the main group involved in the warhead binding. Thus, in this minireview, we briefly describe the main recent advances in the design of MurA covalent inhibitors.
肽聚糖是一种交联聚合物，负责维持革兰氏阴性菌和革兰氏阳性菌的细胞壁完整性和形态。肽聚糖途径由三个步骤中的酶促反应组成：细胞质、膜相关和周质。Mur酶（MurA-MurF）参与细胞质阶段。UDP-N-乙酰葡糖胺烯醇丙酮酸转移酶（MurA）负责将烯醇丙酮酸基团从磷酸烯醇丙酮酸（PEP）转移到UDP-N-乙酰葡糖胺（UNAG），形成UDP-N-乙酰葡糖胺烯醇丙酮酸（EP-UNAG）。磷霉素是一种类似于PEP的天然产物，通过与活性位点的关键半胱氨酸残基共价结合作用于MurA靶酶。与磷霉素类似，其他MurA共价抑制剂的结构中也有一个弹头，可与分子靶点形成共价键。在MurA中，Cys115的亲核硫醇盐被认为是参与弹头结合的主要基团。因此，在本综述中，我们简要描述了MurA共价抑制剂设计方面的主要最新进展。
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