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: 10641824
• 负责人: Caren L. Freel Meyers
• 金额: $ 40.33万
• 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/10641824
• 关键词: Active Sites; Binding; Binding Sites; Biochemical Pathway; Biology; Chemicals; Chemistry; Collaborations; Complex; Cues; Decarboxylation; Development; Diphosphates; Disease; Endowment; 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; Thiamine; Thinking; Vitamins; antimicrobial; biophysical tools; carbanion; computerized tools; enzyme activity; gut microbiota; human microbiota; inhibitor; insight; isoprenoid; microbial; 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-二甲套的研究 5-磷酸合酶（DXPS）。 DXP催化硫胺素双磷酸（THDP）依赖性 必需代谢物DXP的合成，该代谢物DXP在肠道菌群中发现，致病性 细菌和寄生虫，但不在人类中。 DXP位于代谢分支点处 必不可少的类异戊二烯和维生素的先驱，因此，我们假设DXP扮演着关键角色 在微生物组功能和微生物代谢适应中。我们的长期目标是了解如何 微生物在不同情况下使用DXP，以了解其在微生物组和 它作为抗菌靶标的潜力。我们的小组发现了独特的配体门控机制 由DXP使用的，授予目标抑制的目标，并且可以使DXPs感官和 回应其环境。该提案的目标是剖析DXP的回应 分子提示，在不同的化学环境中检查这种传感机制，并建立 针对DXP的这种独特特征的新型抑制策略。从中获得的见解 研究将指导我们对DXPS功能的思考，并指导化学探针的开发 需要研究微生物中的DXPS角色。

项目成果

Antibacterial Target DXP Synthase Catalyzes the Cleavage of d-Xylulose 5-Phosphate: a Study of Ketose Phosphate Binding and Ketol Transfer Reaction.

• DOI: 10.1021/acs.biochem.2c00274
• 发表时间: 2022-09-06
• 期刊: BIOCHEMISTRY
• 影响因子: 2.9
• 作者: Johnston, Melanie L.;Bonett, Eucolona M.;DeColli, Alicia A.;Meyers, Caren L. Freel
• 通讯作者: Meyers, Caren L. Freel