Project 2. Acquisition, synthesis and importance of biotin in Mtb.

项目 2. 结核分枝杆菌中生物素的获取、合成及其重要性。

• 批准号: 10426180
• 负责人: Dirk Schnappinger
• 金额: $ 29.28万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-12 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10426180
• 关键词: Acids; Address; Affect; Anabolism; Biochemical; Biology; Biotin; Biotin Metabolism Pathway; Biotinylation; Cessation of life; Citric Acid Cycle; Coenzymes; Collaborations; Decarboxylation; Disease; Drug Targeting; Enzymes; Fatty Acids; Genes; Genetic; Goals; Growth; In Vitro; Infection; Kinetics; Lipids; Liquid substance; Microbiology; Mus; Mycobacterium tuberculosis; Pathway Analysis; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Play; Predisposition; Protein Inhibition; Proteins; Reaction; Recycling; Rifampin; Role; Starvation; Stress; Testing; Tuberculosis; Vitamins; Work; amino acid metabolism; carboxylation; chemotherapy; cofactor; deprivation; drug development; experimental study; fatty acid biosynthesis; follow-up; mutant; mycobacterial; novel; programs; response; stressor; synergism; transposon sequencing

Project 2, Abstract Biotin is a universally essential cofactor for enzymes that perform various carboxylation, decarboxylation, and transcarboxylation reactions. This includes key enzymes in fatty acid biosynthesis, replenishment of metabolites in the tricarboxylic acid cycle, and amino acid metabolism. When available, Mycobacterium tuberculosis (Mtb) can utilize exogenous biotin but Mtb is unable to scavenge biotin from the host. To grow and survive in the host Mtb thus needs to synthesize biotin. Mtb enzymes involved in synthesizing biotin, ligating biotin, or utilizing biotin have been identified by this group and others as attractive drug targets because their inhibition has the potential to shorten TB chemotherapy. However, a better understanding of the biology of biotin in Mtb is required to fully and effectively exploit Mtb’s susceptibility to biotin starvation for drug development. This Project addresses this need by (i) identifying and functionally classifying the genes Mtb requires to synthesize and utilize biotin, (ii) defining activities Mtb requires to import biotin or recycle biotin, and (iii) determining how biotin starvation affects Mtb’s response to host relevant stresses. These activities directly contribute to the overall program goal of understanding key pathways in Mtb biology that are important in adaptation to disease-relevant stressors.

项目2，摘要 生物素是一种普遍存在的基本辅因子，对执行各种羧化、脱羧化和 转羧化反应。这包括脂肪酸生物合成中的关键酶，代谢产物的补充 在三羧酸循环中，和氨基酸代谢。如果有的话，结核分枝杆菌(Mtb) 可以利用外源生物素，但Mtb不能从寄主中清除生物素。在宿主中生长和生存 因此，MTB需要合成生物素。与合成生物素、连接生物素或利用生物素有关的MTB酶 已被该组织和其他组织确定为有吸引力的药物靶标，因为它们的抑制具有潜在的 缩短结核病化疗时间。然而，需要对结核分枝杆菌中生物素的生物学有更好的了解才能充分 并有效利用结核分枝杆菌对生物素饥饿的敏感性进行药物开发。本项目旨在解决这一问题 需要(一)鉴定和功能分类结核分枝杆菌合成和利用生物素所需的基因，(二) 确定Mtb进口生物素或回收生物素所需的活动，以及(Iii)确定生物素饥饿如何影响 MTB对东道主相关压力的回应。这些活动直接有助于实现总体方案目标 了解结核分枝杆菌生物学中的关键途径，这些途径在适应疾病相关应激源方面很重要。