Toward understanding the chemistry and biology of microbial DXP synthase

了解微生物 DXP 合酶的化学和生物学

• 批准号: 10317255
• 负责人: Caren L. Freel Meyers
• 金额: $ 44.4万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10317255
• 关键词: Active Sites; Binding; Binding Sites; Biochemical Pathway; Biology; Chemicals; Chemistry; Complex; Cues; Decarboxylation; Development; Diphosphates; Disease; Environment; Enzymatic Biochemistry; Enzymes; Glyceraldehyde; Goals; Health; Human; Human Microbiome; Infection; Knowledge; Learning; Ligands; Link; Metabolic; Metabolism; Microbe; Molecular; Molecular Conformation; Movement; Nature; Oximes; Parasites; Pathogenesis; Physiological; Play; Positioning Attribute; Pyruvate; Reaction; Research; Role; Structure; Thiamine; Thinking; Vitamins; antimicrobial; base; biophysical tools; carbanion; computerized tools; enzyme activity; gut microbiota; human microbiota; inhibitor/antagonist; insight; isoprenoid; microbial; microbial host; microbiome; mutant; novel; pathogen; pathogenic bacteria; prevent; resilience; scaffold; xylulose-5-phosphate

PROJECT SUMMARY Microbial metabolic function and adaptability are important in many facets of human health and disease. This proposal centers on studies of the microbial metabolic enzyme 1-deoxy-D-xylulose 5-phosphate synthase (DXPS). DXPS catalyzes the thiamin diphosphate (ThDP)-dependent synthesis of the essential metabolite DXP, which is found in the gut microbiota, pathogenic bacteria and parasites, but not in humans. Positioned at a metabolic branchpoint, DXP serves as a precursor to indispensable isoprenoids and vitamins, thus, we postulate DXPS plays key roles in microbiome function and microbial metabolic adaptation. Our long-term goal is to learn how microbes use DXPS in different contexts, toward understanding its roles in the microbiome and its potential as an antimicrobial target. Our group discovered a unique ligand-gated mechanism used by DXPS that bestows targets for selective inhibition and may enable DXPS to sense and respond to its environment. The goals of this proposal are to dissect how DXPS responds to molecular cues, examine this sensing mechanism in different chemical contexts, and establish novel inhibition strategies that target this distinctive feature of DXPS. Insights gained from this research will direct our thinking about DXPS function, and guide development of chemical probes needed to study DXPS roles in microbes.

项目摘要 微生物代谢功能和适应性在人类健康的许多方面都很重要， 疾病该建议集中于微生物代谢酶1-脱氧-D-木酮糖的研究 5-磷酸合酶（DXPS）。DXPS催化二磷酸硫胺素（ThDP）依赖性 在肠道微生物群中发现的必需代谢物DXP的合成，致病性 细菌和寄生虫，但不是在人类。DXP位于代谢分支点， 是不可或缺的类异戊二烯和维生素的前体，因此，我们假设DXPS起着关键作用 微生物组功能和微生物代谢适应。我们的长期目标是 微生物在不同的背景下使用DXPS，以了解其在微生物组中的作用， 其作为抗微生物靶标的潜力。我们的团队发现了一种独特的配体门控机制 由DXPS使用，赋予选择性抑制的靶点，并使DXPS能够感测和 对其环境做出反应。本提案的目标是剖析DXPS如何应对 分子线索，在不同的化学背景下检查这种传感机制，并建立 针对DXPS的这种独特特征的新型抑制策略。从中获得的见解 这一研究将指导我们对DXPS功能的思考，并指导化学探针的开发 研究DXPS在微生物中的作用