Toward Understanding the Chemistry and Biology of 1-Deoxy-d-xylulose 5-Phosphate (DXP) Synthase: A Unique Antimicrobial Target at the Heart of Bacterial Metabolism.
Toward Understanding the Chemistry and Biology of 1-Deoxy-d-xylulose 5-Phosphate (DXP) Synthase: A Unique Antimicrobial Target at the Heart of Bacterial Metabolism.
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了解 1-脱氧-d-木酮糖 5-磷酸 (DXP) 合酶的化学和生物学：细菌代谢核心的独特抗菌靶点。
DOI：
10.1021/acs.accounts.8b00321
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发表时间：
2018-10-16
影响因子：
18.3
通讯作者：
Freel Meyers CL
中科院分区：
文献类型：
--
作者：
Bartee D;Freel Meyers CL
抗生素是现代医疗保健的基石。世纪磺胺类和β-内酰胺类抗生素的发现极大地改变了人类社会。简单的细菌感染不再是发病率和死亡率的主要原因，抗生素预防大大降低了手术感染的风险。目前的医疗保健系统需要有效的抗生素才能发挥作用。然而，抗生素耐药感染正变得越来越普遍，威胁着后抗生素时代的出现。为了预防这场公共卫生危机，需要具有新作用模式的抗生素。目前可用的抗生素仅针对少数细胞过程发挥其活性：DNA，RNA，蛋白质和细胞壁生物合成。细菌的中枢代谢未被充分利用，这提供了大量潜在的新靶点，可用于扩大抗微生物感染的药物。1-脱氧-d-木酮糖-5-磷酸（DXP）合酶是1997年发现的第一个磷酸甲基异戊糖（MEP）途径中的酶，它是一种二磷酸硫胺素（ThDP）依赖性酶，催化丙酮酸和d-甘油醛-3-磷酸（d-GAP）的脱羧缩合形成DXP。这种五碳代谢物进入细菌中枢代谢的三个独立的基本途径：ThDP合成，磷酸吡哆醛（PLP）合成和类异戊二烯合成的MEP途径。虽然它长期以来一直被确定为开发抗微生物剂的目标，但在开发该酶的选择性抑制剂方面取得的进展有限。该帐户强调了我们实验室在过去十年中为了解这种重要而独特的酶所取得的进展。与所有其他已知的ThDP依赖性酶不同，DXP合酶使用随机顺序机制，其需要在乳酰-ThDP中间体脱羧之前形成三元复合物。其大的活性位点容纳多种受体底物，使其自身具有许多替代活性，例如产生α-羟基酮、异羟肟酸盐、酰胺、乙酰乳酸盐和过乙酸盐。从机制和底物特异性研究中获得的知识指导了具有抗菌活性的选择性抑制剂的开发，并为理解细菌细胞中DXP合酶功能提供了生化基础。虽然是一个有前途的药物靶标，但DXP合酶在细菌代谢中的中心地位赋予了评估DXP合酶抑制剂的抗菌活性的特定挑战，并且大多数细菌对当前DXP合酶抑制剂的敏感性是显著的培养基依赖性。尽管存在这些挑战，但DXP合酶的研究有望揭示DXP合酶在感染期间细菌代谢适应性中的作用，最终提供如何抑制这种关键酶可用于开发新型抗生素的更完整的画面。
Antibiotics are the cornerstone of modern healthcare. The 20th century discovery of sulfonamides and β-lactam antibiotics altered human society immensely. Simple bacterial infections were no longer a leading cause of morbidity and mortality, and antibiotic prophylaxis greatly reduced the risk of infection from surgery. The current healthcare system requires effective antibiotics to function. However, antibiotic-resistant infections are becoming increasingly prevalent, threatening the emergence of a post-antibiotic era. To prevent this public health crisis, antibiotics with novel modes of action are needed. Currently available antibiotics target just a few cellular processes to exert their activity: DNA, RNA, protein, and cell wall biosynthesis. Bacterial central metabolism is underexploited offering a wealth of potential new targets that can be pursued toward expanding the armamentarium against microbial infections. Discovered in 1997 as the first enzyme in the methylerythritol phosphate (MEP) pathway, 1-deoxy-d-xylulose 5-phosphate (DXP) synthase is a thiamin diphosphate (ThDP)-dependent enzyme that catalyzes the decarboxylative condensation of pyruvate and d-glyceraldehyde 3-phosphate (d-GAP) to form DXP. This five-carbon metabolite feeds into three separate, essential pathways for bacterial central metabolism: ThDP synthesis, pyridoxal phosphate (PLP) synthesis, and the MEP pathway for isoprenoid synthesis. While it has long been identified as a target for the development of antimicrobial agents, limited progress has been made towards developing selective inhibitors of the enzyme. This Account highlights advances from our lab over the past decade to understand this important and unique enzyme. Unlike all other known ThDP-dependent enzymes, DXP synthase uses a random sequential mechanism which requires the formation of a ternary complex prior to decarboxylation of the lactyl-ThDP intermediate. Its large active site accommodates a variety of acceptor substrates lending itself to a number of alternative activities, such as the production of α-hydroxy ketones, hydroxamates, amides, acetolactate, and peracetate. Knowledge gained from mechanistic and substrate-specificity studies has guided the development of selective inhibitors with antibacterial activity and provides a biochemical foundation toward understanding DXP synthase function in bacterial cells. Although a promising drug target, the centrality of DXP synthase in bacterial metabolism imparts specific challenges to assessing antibacterial activity of DXP synthase inhibitors, and the susceptibility of most bacteria to current DXP synthase inhibitors is remarkably culture-medium-dependent. Despite these challenges, the study of DXP synthase is poised to reveal the role of DXP synthase in bacterial metabolic adaptability during infection ultimately providing a more complete picture of how inhibiting this crucial enzyme can be used to develop novel antibiotics.
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影响因子：
3.5
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通讯作者：
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作者：
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