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 生物素是进行各种羧化、脱羧和脱羧的酶的普遍必需的辅因子。 转羧反应。这包括脂肪酸生物合成的关键酶，代谢产物的补充 三羧酸循环和氨基酸代谢。如可用，结核分枝杆菌（Mtb） Mtb能利用外源生物素，但不能从宿主体内吸收生物素。在宿主体内生长和生存 结核分枝杆菌因此需要合成生物素。参与合成生物素、连接生物素或利用生物素的MTB酶 已经被这个小组和其他人确定为有吸引力的药物靶点，因为它们的抑制具有潜在的 来缩短结核病化疗的时间。然而，需要更好地了解结核分枝杆菌中生物素的生物学， 并有效地利用结核分枝杆菌对生物素饥饿的敏感性进行药物开发。该项目解决了这一问题 需要通过（i）鉴定和功能分类Mtb合成和利用生物素所需的基因，（ii） 确定Mtb需要输入生物素或回收生物素的活动，以及（iii）确定生物素饥饿如何影响 结核分枝杆菌对宿主相关压力的反应。这些活动直接有助于实现以下总体方案目标： 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压力方面很重要。