Nutrient sensing and hexokinases in T. brucei

描述（由申请人提供）：葡萄糖是原生动物寄生虫布氏锥虫（非洲昏睡病的病原体）所必需的。因此，我们对葡萄糖代谢中的关键酶己糖激酶（TbHK1）的调节知之甚少。最近，我们的小组已经确定了第二个HK（TbHK 2），它负责管理第一个HK。这一观察结果，沿着我们的发现，即来自其他细胞过程的产物可以改变HK活性，表明HK作为细胞中代谢的中心介质。在这里，我们建议探讨如何TbHK2调节TbHK1在mRNA和蛋白质水平。此外，我们将考虑酶是如何通过其他机制调节的，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两个HK在T.布鲁氏菌，特别强调了解这些蛋白质在代谢调节中的作用。我们推测，这些蛋白质可能调节细胞对寄生虫从一个宿主转移到另一个宿主时发生的营养可用性环境变化的反应。 公共卫生相关性：布氏锥虫是非洲昏睡病的病原体，估计每年感染50万人，如果不治疗是致命的。这里提出的研究将进一步我们对寄生虫所必需的代谢途径的调节的理解，这表明我们可以确定新的治疗靶点。

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.