Discovery and Mechanism of Biosynthetic Enzymes

项目摘要 生物合成途径富含酶促转化， 多种天然产物，如次级代谢产物、修饰的核酸，以及 修饰肽。发现和理解这些的分子基础 变革是努力深入了解各种因素的基础， 或者掩盖许多疾病过程，或者它们在治疗剂开发中的用途。 NIGMS资助的两个主要研究领域是在密歇根大学的班达里实验室， 犹他州的重点是（1）发现吡咯并嘧啶生物成因的分子基础 在各种次级代谢产物中发现的核心结构，以及在高度修饰的 碱，肌苷，和（2）阐明酶参与的机制， 转录后修饰的核糖体合成的生物合成途径 多肽（RiPPs），其作为一组新的天然产物而出现， 作为治疗剂的巨大潜力。这些途径通常利用复杂的自由基- 介导的酶促转化，其机制尚不清楚。发现 这些酶的机制研究被提议作为该R35应用的一部分。 !

PROJECT SUMMARY Biosynthetic pathways are rich in enzymatic transformations that produce structurally diverse natural products, such as secondary metabolites, modified nucleic acids, and modified peptides. Discovering and understanding the molecular basis for these transformations underpins efforts towards development of deep insights into factors that either belie many disease processes, or their use in development of therapeutic agents. The two major NIGMS-funded research areas in the Bandarian lab at the University of Utah focus on (1) discovering the molecular basis of biogenesis of the pyrrolopyrimidine core structure found in a variety of secondary metabolites, as well as in the hypermodified base, queuosine, and (2) elucidating the mechanism of enzymes involved in the biosynthetic pathways of ribosomally synthesized posttranscriptionally modified polypeptides (RiPPs), which are emerging as a new group of natural products with substantial potential as therapeutic agents. These pathways often utilize complex radical- mediated enzymatic transformations whose mechanisms are not known. The discovery and mechanistic studies of these enzymes are proposed as part of this R35 application. !