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鲁氏锥虫所必需的，布鲁氏锥虫是非洲昏睡病的病原体。迄今为止，我们对葡萄糖代谢的关键酶己糖激酶（TbHK1）的调控知之甚少。最近，我们的团队发现了调控第一个HK的第二个HK （TbHK2）。这一观察结果，以及我们发现来自其他细胞过程的产物可以改变HK的活性，表明HK是细胞代谢的中心介质。在这里，我们提出探索TbHK2如何在mRNA和蛋白质水平上调控TbHK1。此外，我们将考虑该酶如何受到其他机制的调节，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表征这两种HKs在布氏体生物学中的作用，特别强调理解这些蛋白质在调节代谢中的作用。我们假设这些蛋白质可能调节细胞对环境变化的反应，这些变化发生在寄生虫从一个宿主转移到另一个宿主的过程中。

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.