Trypanosoma cruzi glycosomal glyceraldehyde‐3‐phosphate dehydrogenase: structure, catalytic mechanism and targeted inhibitor design

FEBS Letters

Garratt, R.C²  Souza, D.H.F²  Guimarães, B.G²  Hannaert, V¹  Araújo, A.P.U²  Jesus, W.D.P²  Oliva, G²  Michels, P.A.M¹ 

[1] Research Unit for Tropical Diseases, Christian de Duve Institute of Cellular Pathology (ICP) and Catholic University of Louvain, Ave. Hippocrate 74, B-1200 Brussels, Belgium;Instituto de Fı́sica de São Carlos, USP, P.O. Box 369, 13560-970 São Carlos, SP, Brazil

关键词: Glyceraldehyde-3-phosphate dehydrogenase;    Crystal structure;    Catalytic mechanism;    Conformational change;    Trypanosoma cruzi;   

DOI  :  10.1016/S0014-5793(98)00154-9

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

The structure of the enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) from glycosomes of the parasite Trypanosoma cruzi, causative agent of Chagas' disease, is reported. The final model at 2.8 Å includes the bound cofactor NAD⁺ and 90 water molecules per monomer and resulted in an R _factor of 20.1%, R _free=22.3%, with good geometry indicators. The structure has no ions bound at the active site resulting in a large change in the side chain conformation of Arg²⁴⁹ which as a consequence forms a salt bridge to Asp²¹⁰ in the present structure. We propose that this conformational change could be important for the reaction mechanism and possibly a common feature of many GAPDH structures. Comparison with the human enzyme indicates that interfering with this salt bridge could be a new approach to specific inhibitor design, as the equivalent to Asp²¹⁰ is a leucine in the mammalian enzymes.

【 授权许可】

Unknown