Glyceraldehyde-3-phosphate dehydrogenase inhibitors

A novel extremely potent inhibitor of trypanosomal glyceraldehyde phosphate dehydrogenase has been reported. V -Naphthalenemethyl-2 -methoxybenzamido-P-NAD (114) was synthesised by selective phosphitylation of V -naphthalenemethyl-2 -methoxybenzamido-adenosine using bis(2-cy-anoethoxy)(diisopropylamino)phosphine in the presence of 5-ethylthio-lH-tet-razole. The resulting phosphotriester was purified by silica chromatography... 

The inhibitory effects of heavy metals, and of cyanide on cytochrome oxidase and of arsenate on glyceraldehyde phosphate dehydrogenase, are examples of non-competitive inhibition. This type of inhibitor acts by combining with the enzyme in such a way that for some reason the active site is rendered inoperative. The inhibition may or may not be reversible but it is not affected by the addition of extra substrate. 

FIGURE 6.34 Sheet structures formed from andparallel arrangements of /3-strands, (a) Streptomyces suh i x Xu inhibitor, (b) glutathione reductase domain 3, and (c) the second domain of glyceraldehyde-3-phosphate dehydrogenase represent minimal andparallel /S-sheet domain structures. In each of these cases, an andparallel /S-sheet is largely exposed to solvent on one face and covered by helices and random coils on the other face. (Jane Richardson)... 

Li, Y.-K. Byers, L.D. Phosphonate inhibitors of glyceraldehyde-3-phosphate dehydrogenase and phosphoglycerate kinase. Biochim. Biophys. Acta, 1164, 17-21 (1993)... 

Irreversible inhibitors often provide clues to the nature of the active site. Enzymes that are inhibited by iodo-acetamide, for example, frequently have a cysteine in the active site, and the cysteinyl sulfhydryl group often plays an essential role in the catalytic mechanism (fig. 7.18). An example is glyceraldehyde 3-phosphate dehydrogenase, in which the catalytic mechanism begins with a reaction of the cysteine with the aldehyde substrate (see fig. 12.21). As we discuss in chapter 8, trypsin and many related proteolytic enzymes are inhibited irreversibly by diisopropyl-fluorophosphate (fig. 7.18), which reacts with a critical serine residue in the active site. 

A compound is an inhibitor of glyceraldehyde-3-phosphate dehydrogenase. If this compound were added to liver cells where o-glucose was the only substrate, what effect would it have on the concentrations of the glycolytic intermediates ... 

Aronov, A.M., Suresh, S., Buckner, F.S., Van Voorhis, W.C., Verlinde, C.L.M.J., et al. (1999) Structure-based design of submicromolar, biologically active inhibitors of trypanosomatid glyceraldehyde-3-phosphate dehydrogenase. Proc. Natl Acad. Sci. USA 96 4273-4278. 

Bressi JC, Verlinde CL, Aronov AM et al. Adenosine analogues as selective inhibitors of glyceraldehyde-3-phosphate dehydrogenase of Trypanosomatidae via structure-based drug design. J Med Chem 2001 44(13) 2080-93. 

A similar displacement of a 2 -triflate was used in the synthesis of amides such as 60, related to a known inhibitor of trypanosomal glyceraldehyde-3-phosphate dehydrogenase, from ara-A. 2 -Amino-2 -deoxyuridine has been linked through an amide to a coumarin the resultant derivative was incorporated into oligonucleotides to act as a fluorescence energy donor to DNA. ... 

Bero, J., Beaufay, C., Hannaert, V., Herent, M. E., Michels, P. A.. Quetin-Leclercq, J. 2013. Antitrypanosomal compounds from the essential oil and extracts of Keetia leucantha leaves with inhibitor activity on Trypanosoma brucei glyceraldehyde-3-phosphate dehydrogenase. 20(3-4) 270-274. 

Bovine Albumin, 66 kD, Egg Albumin, 45 kD, Glyceraldehyde-3-Phosphate Dehydrogenase, 36 kD, Carbonic Anhydrase, 29 kD, Trypsinogen, 24 kD, Trypsin Inhibitor, 20 kD and a-Lactalbumin,... 

Molecular modeling studies on selective inhibitors of trypanosomatids glyceraldehyde-3-phosphate dehydrogenase... 

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