1GYQ

CRYSTAL STRUCTURE OF GLYCOSOMAL GLYCERALDEHYDE FROM LEISHMANIA MEXICANA IN COMPLEX WITH N6-BENZYL-NAD

Summary for 1GYQ

• Entry DOI: 10.2210/pdb1gyq/pdb
• Descriptor: PROTEIN (GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE), N6-BENZYL-NICOTINAMIDE-ADENINE-DINUCLEOTIDE (2 entities in total)
• Functional Keywords: oxidoreductase (aldehyde(d)-nad+(a)), oxidoreductase
• Biological source: Leishmania mexicana
• Cellular location: Glycosome: Q27890
• Total number of polymer chains: 4
• Total formula weight: 157786.71

Authors

Suresh, S.,Hol, W. (deposition date: 1999-03-05, release date: 1999-03-16, Last modification date: 2023-08-09)

Primary citation

Aronov, A.M.,Suresh, S.,Buckner, F.S.,Van Voorhis, W.C.,Verlinde, C.L.,Opperdoes, F.R.,Hol, W.G.,Gelb, M.H.
Structure-based design of submicromolar, biologically active inhibitors of trypanosomatid glyceraldehyde-3-phosphate dehydrogenase.
Proc.Natl.Acad.Sci.USA, 96:4273-4278, 1999

PubMed Abstract: The bloodstream stage of Trypanosoma brucei and probably the intracellular (amastigote) stage of Trypanosoma cruzi derive all of their energy from glycolysis. Inhibiting glycolytic enzymes may be a novel approach for the development of antitrypanosomatid drugs provided that sufficient parasite versus host selectivity can be obtained. Guided by the crystal structures of human, T. brucei, and Leishmania mexicana glyceraldehyde-3-phosphate dehydrogenase, we designed adenosine analogs as tight binding inhibitors that occupy the pocket on the enzyme that accommodates the adenosyl moiety of the NAD+ cosubstrate. Although adenosine is a very poor inhibitor, IC50 approximately 50 mM, addition of substituents to the 2' position of ribose and the N6-position of adenosine led to disubstituted nucleosides with micromolar to submicromolar potency in glyceraldehyde-3-phosphate dehydrogenase assays, an improvement of 5 orders of magnitude over the lead. The designed compounds do not inhibit the human glycolytic enzyme when tested up to their solubility limit (approximately 40 microM). When tested against cultured bloodstream T. brucei and intracellular T. cruzi, N6-(1-naphthalenemethyl)-2'-(3-chlorobenzamido)adenosine inhibited growth in the low micromolar range. Within minutes after adding this compound to bloodstream T. brucei, production of glucose-derived pyruvate ceased, parasite motility was lost, and a mixture of grossly deformed and lysed parasites was observed. These studies underscore the feasibility of using structure-based drug design to transform a mediocre lead compound into a potent enzyme inhibitor. They also suggest that energy production can be blocked in trypanosomatids with a tight binding competitive inhibitor of an enzyme in the glycolytic pathway.

PubMed: 10200252
DOI: 10.1073/pnas.96.8.4273

Experimental method

X-RAY DIFFRACTION (3.4 Å)