Tryptophan Metabolism in Mosquitoes

描述（由申请人提供）：蚊子传播疾病，如疟疾；继续对人类健康造成破坏性影响。近年来，西尼罗河病毒在世界上几个地区出现，它在美国的迅速传播表明它有可能在美国永久存在。为了预防蚊媒疾病的传播，迫切需要开发新的蚊虫控制方法，而深入了解蚊虫媒介的生物化学和生理特征是开发新的和创新的媒介控制策略的必要条件。我们对埃及伊蚊色氨酸代谢的研究揭示了蚊子色氨酸分解代谢的一些独特方面。犬尿氨酸、3-羟基犬尿氨酸（3-HK）、犬尿氨酸酸（KA）和黄嘌呤酸（XA）是色氨酸分解代谢的关键成分，犬尿氨酸转KA和3-HK转XA途径由犬尿氨酸转氨酶（KAT）和3-羟基犬尿氨酸转氨酶（HKT）介导，在蚊子发育过程中起重要的生理作用。我们的数据表明，KA对于维持蚊子中枢神经系统的正常生理功能至关重要，3-HK到XA通路是蚊子解毒3-HK的机制，KAT和HKT的分子调控为平衡蚊子色氨酸分解代谢的各个分支通路提供了一种机制。蚊子的KAT和HKT与哺乳动物的KAT和HKT具有较高的序列同源性，但它们的底物特异性和动力学性质与哺乳动物的类似酶有很大的不同。基于我们的研究结果，我们假设蚊子的KAT和HKT都经历了大量的功能进化，以满足蚊子在发育过程中特定的代谢需求。本研究的目的是：(1)明确KAT和HKT在蚊子中的作用，(2)与其他物种的对应物酶相比，了解这些蚊子转氨酶的功能进化，(3)阐明埃及伊蚊KAT和HKT催化功能的结构基础。拟议的研究将有助于我们对蚊子色氨酸代谢的全面了解。由于KAT和HKT在蚊子发育过程中都很重要，它们可能是未来蚊子控制的潜在目标。

DESCRIPTION (provided by the applicant): Mosquito transmitted diseases, such as malaria; continue to have a devastating impact on human health. In recent years, the West Nile virus has emerged in several regions around the world and its rapid spread in the United States suggests its potential permanent establishment in the country. To prevent the transmission of mosquito-borne diseases, there is an urgent need for new mosquito control methods to be developed and a thorough understanding of the biochemistry and physiology of the mosquito vectors is imperative to the development of new and innovative vector control strategies. Our studies dealing with tryptophan metabolism in Aedes aegypti revealed some unique aspects of tryptophan catabolism in mosquitoes. Kynurenine, 3-hydroxykynurenine (3-HK), kynurenic acid (KA) and xanthurenic acid (XA) are the key components in the tryptophan catabolism, and kynurenine to KA and 3-HK to XA pathways, mediated by kynurenine aminotransferase (KAT) and/or 3-hydroxykynurenine transaminase (HKT), play important physiological roles in mosquitoes during development. Our data suggest that KA is essential for maintaining the normal physiological function of mosquito central nervous system, that the 3-HK to XA pathway is the mechanism by which mosquitoes detoxify 3-HK, and that the molecular regulation of KAT and HKT provides a mechanism for balancing the individual branch pathways of tryptophan catabolism in the mosquitoes. Both mosquito KAT and HKT share high sequence identity with their mammalian counterparts, but their substrate specificity and kinetic properties seem quite different from those of similar mammalian enzymes. Based on our results, we hypothesize that both mosquito KAT and HKT have undergone substantial functional evolution to meet their specific metabolic requirements in mosquitoes during development. The objectives of this proposal are (1) to clearly define the roles both KAT and HKT play in mosquitoes, (2) to understand the functional evolution of these mosquito transaminases in comparison with counterpart enzymes from other species, and (3) to elucidate the structural basis of catalytic functions for both A. aegypti KAT and HKT. The proposed studies will contribute to our overall knowledge of tryptophan metabolism in mosquitoes. Because both KAT and HKT are critical during mosquito development, they could be potential targets for future mosquito controls.