2CH2

Structure of the Anopheles gambiae 3-hydroxykynurenine transaminase in complex with inhibitor

Summary for 2CH2

• Entry DOI: 10.2210/pdb2ch2/pdb
• Related: 2CH1
• Descriptor: 3-HYDROXYKYNURENINE TRANSAMINASE, PYRIDOXAL-5'-PHOSPHATE, 4-(2-AMINOPHENYL)-4-OXOBUTANOIC ACID, ... (4 entities in total)
• Functional Keywords: plp-enzyme, kynurenine pathway, transferase
• Biological source: ANOPHELES GAMBIAE (AFRICAN MALARIA MOSQUITO)
• Total number of polymer chains: 4
• Total formula weight: 179161.74

Authors

Rossi, F.,Garavaglia, S.,Giovenzana, G.B.,Arca, B.,Li, J.,Rizzi, M. (deposition date: 2006-03-10, release date: 2006-03-28, Last modification date: 2013-07-17)

Primary citation

Rossi, F.,Garavaglia, S.,Giovenzana, G.B.,Arca, B.,Li, J.,Rizzi, M.
Crystal Structure of the Anopheles Gambiae 3-Hydroxykynurenine Transaminase
Proc.Natl.Acad.Sci.USA, 103:5711-, 2006

PubMed Abstract: 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.

PubMed: 16585514
DOI: 10.1073/PNAS.0510233103

Experimental method

X-RAY DIFFRACTION (2.7 Å)