BIOSYNTHESES OF BIOTIN AND LIPOIC ACID

生物素和硫辛酸的生物合成

• 批准号: 3467634
• 负责人: GARY W ASHLEY
• 金额: $ 9.9万
• 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/3467634
• 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