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 生物素是用于执行各种羧化，脱羧和执行各种酶的普遍重要辅助因子 转羧酸反应。这包括脂肪酸生物合成中的关键酶，代谢物的补充 在三核酸周期和氨基酸代谢中。如果有的话，结核分枝杆菌（MTB） 可以利用外源生物素，但MTB无法从宿主那里清除生物素。在主机中成长和生存 因此，MTB需要合成生物素。参与合成生物素，结扎生物素或使用生物素的MTB酶 该组和其他人都将其识别为有吸引力的药物靶标，因为它们的抑制作用具有潜力 缩短结核病化疗。但是，需要更好地了解MTB中生物素的生物学才能完全 并有效利用MTB对生物素饥饿对药物开发的敏感性。这个项目解决了这个问题 需要（i）识别和在功能上分类的基因MTB需要合成和利用生物素，（ii） 定义活动MTB需要进口生物素或回收生物素，并且（iii）确定生物素饥饿如何影响 MTB对宿主相关压力的反应。这些活动直接有助于总体计划的目标 了解MTB生物学中的关键途径对于适应与疾病相关的压力源很重要。