2ch2 | pdb_00002ch2
Structure of the Anopheles gambiae 3-hydroxykynurenine transaminase in complex with inhibitor
Structural highlights
FunctionHKT_ANOGA Catalyzes the pyridoxal 5'-phosphate-dependent transamination of both 3-hydroxykynurenine and L-kynurenine to xanthurenic acid and kynurenic acid, respectively, preferentially using the alpha-ketoacid glyoxylate as the amino group acceptor (PubMed:16262702). Although glyoxylate is the preferred amino group acceptor, transamination of 3-hydroxykynurenine also works with pyruvate as the amino acceptor in vitro (PubMed:16262702). Involved in the detoxification of cytotoxic metabolite 3-hydroxykynurenine generated by the hydroxylation of L-kynurenine, an intermediate in the tryptophan catabolism pathway (PubMed:16262702). The Plasmodium parasite uses xanthurenic acid produced in the midgut to activate its gametocytes ingested during a blood meal (Probable). Also catalyzes, although with a lesser efficiency, the transamination of alanine with glyoxylate as an amino group acceptor (By similarity). May play a role in the detoxification of glyoxylate, a toxic plant metabolite from the diet (By similarity).[UniProtKB:Q0IG34][1] [2] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedIn Anopheles gambiae, the vector for the most deadly malaria parasite Plasmodium falciparum, xanthurenic acid (XA) plays a key role in parasite gametogenesis and fertility. In mosquitoes, XA is produced by transamination of 3-hydroxykynurenine (3-HK), a reaction that represents the main route to prevent the accumulation of the potentially toxic 3-HK excess. Interfering with XA metabolism in A. gambiae therefore appears an attractive avenue for the development of malaria transmission-blocking drugs and insecticides. We have determined the crystal structure of A. gambiae 3-HK transaminase in its pyridoxal 5'-phosphate form and in complex with a newly synthesized competitive enzyme inhibitor. Structural inspection of the enzyme active site reveals the key molecular determinants for ligand recognition and catalysis. Major contributions toward inhibitor binding are provided by a salt bridge between the inhibitor carboxylate and Arg-356 and by a remarkable hydrogen bond network involving the anthranilic moiety of the inhibitor and backbone atoms of residues Gly-25 and Asn-44. This study may be useful for the structure-based design of specific enzyme inhibitors of potential interest as antimalarial agents. Crystal structure of the Anopheles gambiae 3-hydroxykynurenine transaminase.,Rossi F, Garavaglia S, Giovenzana GB, Arca B, Li J, Rizzi M Proc Natl Acad Sci U S A. 2006 Apr 11;103(15):5711-6. Epub 2006 Apr 3. PMID:16585514[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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