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Trypanosoma cruzi glycosomal glyceraldehyde‐3‐phosphate dehydrogenase: structure, catalytic mechanism and targeted inhibitor design
Author(s) -
Souza D.H.F,
Garratt R.C,
Araújo A.P.U,
Guimarães B.G,
Jesus W.D.P,
Michels P.A.M,
Hannaert V,
Oliva G
Publication year - 1998
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(98)00154-9
Subject(s) - glyceraldehyde 3 phosphate dehydrogenase , dehydrogenase , chemistry , trypanosoma cruzi , salt bridge , cofactor , biochemistry , active site , enzyme , nad+ kinase , conformational change , stereochemistry , protein structure , parasite hosting , mutant , gene , world wide web , computer science
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 Arg 249 which as a consequence forms a salt bridge to Asp 210 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 Asp 210 is a leucine in the mammalian enzymes.