Toward understanding the chemistry and biology of microbial DXP synthase

项目总结 微生物的代谢功能和适应能力在人类健康的许多方面都很重要 疾病。本建议主要针对微生物代谢酶1-脱氧-D-木果糖进行研究。 5-磷酸合成酶(DXPs)。DXPS催化硫胺素二磷酸(ThDP)依赖 肠道微生物区系中发现的致病必需代谢物DXP的合成 细菌和寄生虫，但不存在于人类体内。定位于新陈代谢分支点，DxP充当 作为必需的类异戊二烯和维生素的前体，因此，我们推测DXPs起着关键作用 在微生物组功能和微生物代谢适应方面。我们的长期目标是学习如何 微生物在不同的环境中使用DXP，以了解其在微生物组和 它作为抗菌靶标的潜力。我们的团队发现了一种独特的配体门控机制 由DXP使用，为选择性抑制提供靶点，并可能使DXP能够检测和 对它的环境做出反应。这项提案的目标是剖析DXP如何应对 分子线索，在不同的化学环境中检查这种感知机制，并建立 针对DXP的这一独特特征的新的抑制策略。从中获得的洞察力 研究将指导我们对DXPS功能的思考，并指导化学探针的发展 需要研究DXPs在微生物中的作用。

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.