Nutrient sensing and hexokinases in T. brucei

T. brucei 中的营养感应和己糖激酶

• 批准号: 7454845
• 负责人: JAMES Culvin MORRIS
• 金额: $ 21.32万
• 依托单位: CLEMSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7454845
• 关键词: African Trypanosomiasis; Amino Acids; Anabolism; Biochemical; Biology; Blood Circulation; Cell physiology; Cells; Complex; Condition; Cues; Development; Enzymes; Exhibits; Figs - dietary; Fostering; Fumaric acid; Glucose; Glycolysis; Goals; Hexoses; In Vitro; Mammals; Mediator of activation protein; Messenger RNA; Metabolic; Metabolic Pathway; Metabolism; Molecular; Myristic Acids; Nutrient; Parasites; Pathway interactions; Phosphorylation Inhibition; Play; Production; Proteins; Public Health; Publishing; Regulation; Research; Role; Staging; Students; Surface; Therapeutic; Trypanosoma brucei brucei; Tsetse Flies; Work; base; detection of nutrient; environmental change; enzyme mechanism; fatty acid biosynthesis; glucose metabolism; hexokinase; innovation; novel strategies; novel therapeutics; planetary Atmosphere; response; size; sugar; therapeutic target; vector

DESCRIPTION (provided by applicant): The sugar glucose is essential to the protozoan parasite Trypanosoma brucei, the causative agent of African sleeping sickness. Heretofore, we have known very little about the regulation of a key enzyme in glucose metabolism, hexokinase (TbHK1). Recently, our group has identified a second HK (TbHK2) that regulates the first. This observation, along with our finding that products from other cellular processes can alter HK activity, suggest that HK serves as a central mediator of metabolism in the cell. Here, we propose to explore how TbHK2 regulates TbHK1 at both the mRNA and protein levels. Further, we will consider how the enzyme is regulated by other mechanisms, including phosphorylation and inhibition by other cellular metbolites. Our long-term goal is to carefully characterize the roles of the two HKs in the biology of T. brucei, with a particular emphasis on understanding the role of these proteins in regulation of metabolism. We hypothesize that the proteins may regulate the cells' response to environmental changes in nutrient availability that occurs as the parasites move from one host to another. PUBLIC HEALTH RELEVANCE: Trypanosoma brucei, the causative agent of African sleeping sickness, infects an estimated 500,000 people annually and is fatal if untreated. The research proposed here will further our understanding of the regulation of a metabolic pathway that is essential to the parasite suggesting that we may identify novel therapeutic targets.

描述（由申请人提供）：葡萄糖对于原生动物寄生虫布氏锥虫（非洲昏睡病的病原体）至关重要。迄今为止，我们对葡萄糖代谢中关键酶己糖激酶（TbHK1）的调节知之甚少。最近，我们的团队确定了第二个 HK（TbHK2）来规范第一个 HK。这一观察结果，加上我们发现其他细胞过程的产物可以改变 HK 活性，表明 HK 是细胞代谢的中心介质。在这里，我们建议探索 TbHK2 如何在 mRNA 和蛋白质水平上调节 TbHK1。此外，我们将考虑其他机制如何调节酶，包括磷酸化和其他细胞代谢物的抑制。我们的长期目标是仔细描述这两种 HK 在 T. brucei 生物学中的作用，特别强调了解这些蛋白质在代谢调节中的作用。我们假设这些蛋白质可能调节细胞对营养可用性环境变化的反应，这种变化是寄生虫从一个宿主转移到另一个宿主时发生的。 公共卫生相关性：布氏锥虫是非洲昏睡病的病原体，每年估计有 50 万人感染，如果不及时治疗会致命。这里提出的研究将进一步了解对寄生虫至关重要的代谢途径的调节，这表明我们可能会确定新的治疗靶点。