title: The structure of a Trypanosoma cruzi glucose-6-phosphate dehydrogenase reveals differences from the mammalian enzyme.
abstract: The enzyme glucose-6-phosphate dehydrogenase from Trypanosoma cruzi (TcG6PDH) catalyses the first step of the pentose phosphate pathway (PPP) and is considered a promising target for the discovery of a new drug against Chagas diseases. In the present work, we describe the crystal structure of TcG6PDH obtained in a ternary complex with the substrate β-d-glucose-6-phosphate (G6P) and the reduced 'catalytic' cofactor NADPH, which reveals the molecular basis of substrate and cofactor recognition. A comparison with the homologous human protein sheds light on differences in the cofactor-binding site that might be explored towards the design of new NADP(+) competitive inhibitors targeting the parasite enzyme.
authors.affiliation: Brazilian Biosciences National Laboratory, Center of Research in Energy and Materials, Campinas, Brazil.|Institute of Biology, University of Campinas, Brazil.
authors.forename: Gustavo F
authors.initials: GF
authors.lastname: Mercaldi
authors.affiliation: Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, UK.
authors.forename: Alice
authors.initials: A
authors.lastname: Dawson
authors.affiliation: Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, UK.
authors.forename: Willian N
authors.initials: WN
authors.lastname: Hunter
authors.affiliation: Brazilian Biosciences National Laboratory, Center of Research in Energy and Materials, Campinas, Brazil.
authors.forename: Artur T
authors.initials: AT
authors.lastname: Cordeiro
mesh_terms: D000595:Amino Acid Sequence / Q000235:genetics; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D014355:Chagas Disease / Q000188:drug therapy* / Q000235:genetics; D003067:Coenzymes / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019298:Glucose-6-Phosphate / Q000378:metabolism; D005954:Glucosephosphate Dehydrogenase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009249:NADP / Q000378:metabolism; D010427:Pentose Phosphate Pathway / Q000235:genetics; D011487:Protein Conformation; D013379:Substrate Specificity; D014349:Trypanosoma cruzi / Q000201:enzymology* / Q000472:pathogenicity
chemical_list: D003067:Coenzymes; D004791:Enzyme Inhibitors; D009249:NADP; D019298:Glucose-6-Phosphate; D005954:Glucosephosphate Dehydrogenase
keywords: Chagas disease; drug discovery; ternary complex