Crystal structure of the Anopheles gambiae 3-hydroxykynurenine transaminase.
In 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.
Dipartimento di Scienze Chimiche, Alimentari Farmaceutiche e Farmacologiche-Drug and Food Biotechnology Center, University of Piemonte Orientale "Amedeo Avogadro," Via Bovio 6, 28100 Novara, Italy.
Franca
F
Rossi
Silvia
S
Garavaglia
Giovanni Battista
GB
Giovenzana
Bruno
B
Arcà
Jianyong
J
Li
Menico
M
Rizzi
D000818:Animals; D000852:Anopheles / Q000201:enzymology*; D000962:Antimalarials; D018360:Crystallography, X-Ray; D015195:Drug Design; D007700:Kinetics; D008958:Models, Molecular; D017433:Protein Structure, Secondary; D000637:Transaminases / Q000737:chemistry*
D000962:Antimalarials; D000637:Transaminases; C021481:kynurenine-oxoglutarate transaminase