Mosquitoes are important disease vectors, responsible for transmission of numerous viral, bacterial and parasitic diseases, such as malaria, dengue fever, yellow fever, and filariasis. Malaria, caused by infection with species of Plasmodium, is a devastating, disease which affects up to 500 million people world-wide, killing as many as 2 million a year. The development of drug resistant parasites, and insecticide resistant mosquito vectors urgently demands that new and innovative mosquito or parasite control strategies be developed. Disruption of the required physio-biochemical processes that are necessary for the normal development of either mosquitoes or malaria parasites is one approach for malaria control. A novel transaminase that is specific for the transamination of a chemically reactive and potentially toxic 3-hydroxykynurenine, formed during tryptophan oxidation, to stable xanthurenic acid is identified in Aedes aegypti mosquitoes, and this enzyme is tightly regulated with high activity in larvae and adult females after a bloodmeal. Our recent data show that xanthurenic acid also stimulates gametogenesis of Plasmodium parasites, suggesting this pathway may play critical role in initiating Plasmodium development in mosquito vectors. The long term goal of this research is to achieve a full understanding of the pathways and mechanisms governing the regulation of this enzyme in mosquito vectors.
The specific aims of the proposed research are (I) to purify and characterize the 3-hydroxykynurenine transaminase from mosquitoes by various biochemical techniques, (II) to initiate studies concerning the genetic regulation of this transaminase in mosquitoes during development with various molecular techniques, which includes preparation of a cDNA library from mosquito larvae, isolation of 3-hydroxykynurenine transaminase cDNA from the library, and study of gene expression of the 3-hydroxykynurenine transaminase in mosquitoes during development, and (III) to study the transamination pathway of 3-hydroxykynurenine to xanthurenic acid in Anopheles mosquitoes. Our hypotheses are that this transamination pathway is critical for the normal development of mosquitoes and also may play a critical role in stimulating Plasmodium development; consequently, understanding the mechanism controlling its regulation could have a significant impact on future efforts to negatively interfere with vector development through innovative mosquito control strategies and also may provide insight into developing novel tools for the control of malaria parasites by interrupting gametogenesis of Plasmodium in mosquito vectors.
| Han, Qian; Gao, Yi Gui; Robinson, Howard et al. (2008) Structural insight into the mechanism of substrate specificity of aedes kynurenine aminotransferase. Biochemistry 47:1622-30 |
| Han, Qian; Robinson, Howard; Li, Jianyong (2008) Crystal structure of human kynurenine aminotransferase II. J Biol Chem 283:3567-73 |
| Han, Qian; Beerntsen, Brenda T; Li, Jianyong (2007) The tryptophan oxidation pathway in mosquitoes with emphasis on xanthurenic acid biosynthesis. J Insect Physiol 53:254-63 |
| Li, Junsuo S; Han, Qian; Fang, Jianmin et al. (2007) Biochemical mechanisms leading to tryptophan 2,3-dioxygenase activation. Arch Insect Biochem Physiol 64:74-87 |
| Han, Qian; Robinson, Howard; Gao, Yi Gui et al. (2006) Crystal structures of Aedes aegypti alanine glyoxylate aminotransferase. J Biol Chem 281:37175-82 |
| Han, Qian; Kim, Seong Ryul; Ding, Haizhen et al. (2006) Evolution of two alanine glyoxylate aminotransferases in mosquito. Biochem J 397:473-81 |
| Beerntsen, Brenda T; Li, Jianyong (2006) Plasmodium development in white-eye (kh(w)) and transformed strains (kh43) of Aedes aegypti (Diptera: Culicidae). J Med Entomol 43:318-22 |
| Rossi, Franca; Garavaglia, Silvia; Giovenzana, Giovanni Battista et al. (2006) Crystal structure of the Anopheles gambiae 3-hydroxykynurenine transaminase. Proc Natl Acad Sci U S A 103:5711-6 |
| Han, Qian; Gao, Yi Gui; Robinson, Howard et al. (2005) Crystal structures of Aedes aegypti kynurenine aminotransferase. FEBS J 272:2198-206 |
| Rossi, Franca; Han, Qian; Li, Junsuo et al. (2004) Crystal structure of human kynurenine aminotransferase I. J Biol Chem 279:50214-20 |
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