Allosteric Inhibition of Acinetobacter baumannii ATP Phosphoribosyltransferase by Protein:Dipeptide and Protein:Protein Interactions
Allosteric Inhibition of Acinetobacter baumannii ATP Phosphoribosyltransferase by Protein:Dipeptide and Protein:Protein Interactions
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蛋白质：二肽和蛋白质：蛋白质相互作用对鲍曼不动杆菌 ATP 磷酸核糖转移酶的变构抑制
DOI：
10.1021/acsinfecdis.1c00539
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发表时间：
2021
影响因子：
5.3
通讯作者：
Read B
中科院分区：
文献类型：
--
作者：
Read B
三磷酸腺苷磷酸核糖转移酶催化细菌内组氨酸生物合成的第一步，即三磷酸腺苷与5-磷酸-α-d-核糖基-1-焦磷酸缩合生成N-(5-磷酸-β-d-核糖基)-三磷酸腺苷和焦磷酸。催化亚基(HisGS)和调节亚基(HISZ)组装在一个异八聚体中，其中HisZ激活HisGS，并介导组氨酸对变构的抑制。在鲍曼不动杆菌中，HisGS是肺炎期间细菌在肺内持续存在所必需的。因此，抑制ATPPRT是一种有希望的特定抗生素开发策略。与其他ATPPRT不同的是，鲍曼曲霉遵循快速平衡随机动力学机制。组氨酸非竞争性抑制ATPPRT。结合动力学表明，组氨酸与游离ATPPRT和ATPPRT：PRPP和ATPPRT：ATPPRT具有相似亲和力的二元复合体的结合遵循两步结合机制，但与起始酶：抑制物复合体具有明显的动力学分配。组氨酸-脯氨酸二肽分别对PRPP和ATP竞争性地和可能非竞争性地抑制ATPPRT。快速动力学分析表明，His-Pro通过两步结合机制与ATPPRT：ATP复合体结合。与a有43%序列同源性的相关hisz。BaumanniiHisZ是一种紧密结合的变构抑制剂OFA。鲍曼尼·希格斯。这些发现为抗A抑制剂的设计奠定了基础。鲍曼尼ATPPRT。
ATP phosphoribosyltransferase (ATPPRT) catalyzes the first step of histidine biosynthesis in bacteria, namely, the condensation of ATP and 5-phospho-α-d-ribosyl-1-pyrophosphate (PRPP) to generateN1-(5-phospho-β-d-ribosyl)-ATP (PRATP) and pyrophosphate. Catalytic (HisGS) and regulatory (HisZ) subunits assemble in a hetero-octamer where HisZ activates HisGSand mediates allosteric inhibition by histidine. InAcinetobacter baumannnii, HisGSis necessary for the bacterium to persist in the lung during pneumonia. Inhibition of ATPPRT is thus a promising strategy for specific antibiotic development. Here,A. baumanniiATPPRT is shown to follow a rapid equilibrium random kinetic mechanism, unlike any other ATPPRT. Histidine noncompetitively inhibits ATPPRT. Binding kinetics indicates histidine binds to free ATPPRT and to ATPPRT:PRPP and ATPPRT:ATP binary complexes with similar affinity following a two-step binding mechanism, but with distinct kinetic partition of the initial enzyme:inhibitor complex. The dipeptide histidine-proline inhibits ATPPRT competitively and likely uncompetitively, respectively, against PRPP and ATP. Rapid kinetics analysis shows His-Pro binds to the ATPPRT:ATP complex via a two-step binding mechanism. A related HisZ that shares 43% sequence identity withA. baumanniiHisZ is a tight-binding allosteric inhibitor ofA. baumanniiHisGS. These findings lay the foundation for inhibitor design againstA. baumanniiATPPRT.