The structure of a Trypanosoma cruzi glucose-6-phosphate dehydrogenase reveals differences from the mammalian enzyme

Gustavo F. Mercaldi, Alice Dawson, William N. Hunter, Artur T. Cordeiro (Lead / Corresponding author)

Research output: Contribution to journalLetter

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Abstract

The enzyme glucose-6-phosphate dehydrogenase from Trypanosoma cruzi (TcG6PDH) catalyses the first step of the pentose phosphate pathway 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 glucose-6-phosphate 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. This article is protected by copyright. All rights reserved.

Original languageEnglish
Pages (from-to)2776-2786
Number of pages11
JournalFEBS Letters
Volume590
Issue number16
Early online date19 Jul 2016
DOIs
Publication statusPublished - 19 Aug 2016

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Glucosephosphate Dehydrogenase
Trypanosoma cruzi
NADP
Pentoses
Pentose Phosphate Pathway
Glucose-6-Phosphate
Chagas Disease
Substrates
Enzymes
Parasites
Crystal structure
Phosphates
Binding Sites
Pharmaceutical Preparations
Proteins

Cite this

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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 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 glucose-6-phosphate 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. This article is protected by copyright. All rights reserved.",
author = "Mercaldi, {Gustavo F.} and Alice Dawson and Hunter, {William N.} and Cordeiro, {Artur T.}",
note = "Funded by FAPESP (Funda{\cc}{\~a}o de Amparo {\`a} Pesquisa do Estado de S{\~a}o Paulo) Grant Number: 2013/03983-5; BEPE Fellowship Grant Number: 2014/07533-7; Wellcome Trust Grant Number: 094090.",
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The structure of a Trypanosoma cruzi glucose-6-phosphate dehydrogenase reveals differences from the mammalian enzyme. / Mercaldi, Gustavo F.; Dawson, Alice; Hunter, William N. ; Cordeiro, Artur T. (Lead / Corresponding author).

In: FEBS Letters, Vol. 590, No. 16, 19.08.2016, p. 2776-2786.

Research output: Contribution to journalLetter

TY - JOUR

T1 - The structure of a Trypanosoma cruzi glucose-6-phosphate dehydrogenase reveals differences from the mammalian enzyme

AU - Mercaldi, Gustavo F.

AU - Dawson, Alice

AU - Hunter, William N.

AU - Cordeiro, Artur T.

N1 - Funded by FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo) Grant Number: 2013/03983-5; BEPE Fellowship Grant Number: 2014/07533-7; Wellcome Trust Grant Number: 094090.

PY - 2016/8/19

Y1 - 2016/8/19

N2 - The enzyme glucose-6-phosphate dehydrogenase from Trypanosoma cruzi (TcG6PDH) catalyses the first step of the pentose phosphate pathway 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 glucose-6-phosphate 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. This article is protected by copyright. All rights reserved.

AB - The enzyme glucose-6-phosphate dehydrogenase from Trypanosoma cruzi (TcG6PDH) catalyses the first step of the pentose phosphate pathway 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 glucose-6-phosphate 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. This article is protected by copyright. All rights reserved.

U2 - 10.1002/1873-3468.12276

DO - 10.1002/1873-3468.12276

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