Mechanisms of polyketide, amino acid and Polypeptide biosynthesis

聚酮化合物、氨基酸及多肽生物合成机制

• 批准号: 845-2010
• 负责人: Vederas, John
• 金额: $ 11.66万
• 依托单位: University of Alberta
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2014
• 资助国家: 加拿大
• 起止时间: 2014-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=543905
• 关键词: Mechanisms; polyketide; amino; acid; Polypeptide

The major objectives of the proposed research in bioorganic chemistry and natural products chemistry include: a) development of new approaches to study secondary metabolism (especially polyketide and polypeptide biosynthesis); and b) study of the mechanism and inhibition of enzymes involved in amino acid and peptide metabolism. The program involves a combination of methods used in organic chemistry (e.g. synthesis, spectroscopic analysis) and biochemistry (e.g. molecular biology, protein characterization, enzyme inhibition, NMR solution structures and, in collaboration, x-ray crystallography of proteins). One part of the program focuses on the way fungi assemble polyketides, a class of secondary metabolites typically built from acetate, that often have important biological activity. In particular, the details of assembly of lovastatin, a cholesterol-lowering agent and precursor to the drug simvastatin (Zocor) will be examined. Construction of this molecule requires the polyketide synthase (PKS) enzyme LovB and the enoyl reductase enzyme LovC, which together produce most of the skeleton of lovastatin in 35 highly programmed steps. We will study the step by step transformations of this remarkable molecular machine with the goal of elucidating its mechanism and generating new analogs of the drug. Similar approaches will be used to study biosynthesis of three other biologically active fungal polyketide compounds. A second part of the program targets bacteriocins, which are antimicrobial peptides produced by bacteria that occur naturally in food. They are many orders of magnitude more potent than conventional antibiotics and are effective against pathogens resistant to current therapy. In particular, chemical synthesis of lantibiotics, a class of bacteriocins that contain monosulfide lanthionine rings, will be investigated with the goal of understanding structure-activity relationships and making more stable derivatives. Targets include lacticin 3147 and gallidermin. Another aspect involves determination of the details of biosynthesis of thuricins, which are active against the dangerous pathogen, Clostridium difficile ribotype 027. Their the 3D structures will also be examined by new approaches

生物有机化学和天然产物化学研究的主要目标包括：a)开发研究次生代谢（特别是聚酮和多肽生物合成）的新方法；b)氨基酸和肽代谢相关酶的机制和抑制研究。该计划涉及有机化学（如合成，光谱分析）和生物化学（如分子生物学，蛋白质表征，酶抑制，核磁共振溶液结构和合作，蛋白质的x射线晶体学）中使用的方法的组合。该项目的一部分重点关注真菌聚集聚酮的方式，聚酮是一类通常由醋酸酯形成的次级代谢物，通常具有重要的生物活性。特别是，洛伐他汀（一种降胆固醇剂和药物辛伐他汀（Zocor）的前体）的组装细节将被检查。该分子的构建需要聚酮合成酶（PKS）酶LovB和烯酰还原酶LovC，它们在35个高度程序化的步骤中共同产生洛伐他汀的大部分骨架。我们将研究这一非凡的分子机器的一步一步转化，目的是阐明其机制并产生新的药物类似物。类似的方法将用于研究其他三种具有生物活性的真菌聚酮化合物的生物合成。该计划的第二部分针对细菌素，细菌素是由细菌产生的抗菌肽，自然存在于食物中。它们的效力比传统抗生素强好几个数量级，对对当前治疗有耐药性的病原体有效。特别是，l抗生素（一类含有单硫代硫氨酸环的细菌素）的化学合成将被研究，目的是了解结构-活性关系并制造更稳定的衍生物。靶点包括乳酸素3147和镓脂素。另一个方面涉及确定苏云金素生物合成的细节，这些苏云金素对危险的病原体艰难梭状芽胞杆菌核型027有活性。它们的三维结构也将通过新的方法进行检查