BIOSYNTHESES OF BIOTIN AND LIPOIC ACID

生物素和硫辛酸的生物合成

• 批准号: 3467631
• 负责人: GARY W ASHLEY
• 金额: $ 9.01万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-04-01 至 1994-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3467631
• 关键词: Escherichia coli; biochemistry; biotin; carboxylate; drug design /synthesis /production; fatty acid metabolism; fluorine; hydrocarbons; microorganism genetics; mutant; sulfur compounds; vitamin biosynthesis

The introduction of sulfur into the enzyme cofactors biotin and lipoic acid has been studied for many years using classical labeling techniques, yet the chemistry behind these reactions remains elusive. We are attempting to develop new approaches towards understanding this important yet uncharted area of sulfur metabolism which will provide information concerning not only the specific pathways of biotin and lipoic acid biosynthesis but also the chemistry by which organisms from bacteria to animals use to metabolize molecules lacking in reactive functionality. Using the unique chemical properties of fluorine (very strong C-F bonds, high electronegativity, and steric size similar to hydrogen) we are designing analogs of the biosynthetic precursors of lipoic acid and biotin which have rationally modified properties at specific reaction centers, thus providing a series of probes for use in whole-cell bacterial systems. As even the basic outlines of the biosynthesis of lipoic acid are unclear, we are first using our o-fluorinated carboxylic acid probes to gain more detailed information on the nature of the octanoic acid precursor. These fluorinated analogs will also be used to study inhibition of the lipoic acid activation system, resulting in a potential screen for lipoate overproducing mutants and a potential method for the design of antimicrobial agents based on inhibition of enzyme cofactor activation. The technique may also prove useful for probing more general features of fatty acid metabolism. For biotin, long-sought details concerning the sequence of events involved in sulfur introduction may be obtained, allowing further design of potential reaction intermediates and inhibitors for use as probes of the chemistry of C-S bond formation.

将硫引入酶辅因子生物素和 使用经典的方法已经对硫辛酸进行了多年的研究 标记技术，然而这些反应背后的化学 仍然难以捉摸 我们正在尝试开发新的方法 了解这片重要但未知的硫磺区域 代谢，这将提供信息，不仅有关 生物素和硫辛酸生物合成的特定途径， 从细菌到动物的有机体所使用的化学物质 代谢缺乏反应功能的分子。 使用 氟的独特化学性质（非常强的C-F键，高 电负性，空间尺寸类似于氢），我们是 设计硫辛酸的生物合成前体的类似物， 在特定条件下具有合理修饰性质的生物素 反应中心，从而提供了一系列用于 全细胞细菌系统。 即使是基本的轮廓， 硫辛酸的生物合成尚不清楚，我们首先使用我们的 邻氟羧酸探针，以获得更详细的 关于辛酸前体性质的信息。 这些 氟化的类似物也将用于研究 硫辛酸活化系统，导致潜在的筛选 硫辛酸高产突变体及其设计方法 基于酶辅因子抑制的抗微生物剂 activation. 这项技术也可能被证明是有用的探测更多 脂肪酸代谢的一般特征。 对于生物素，长期寻求 关于硫所涉及的事件顺序的细节 可以获得引入，允许进一步设计潜在的 用作探针的反应中间体和抑制剂 C-S键形成的化学过程