Tryptophan Metabolism in Mosquitoes

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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.