Phosphonate inhibitors of glyceraldehyde-3-phosphate dehydrogenase and phosphoglycerate kinase.
Several bisphosphonates were examined as inhibitors of yeast GPD (glyceraldehyde-3-phosphate dehydrogenase, EC 1.2.1.12) and PGK (phosphoglycerate kinase, EC 2.7.2.3). The phosphonomethyl analog of 2-deoxy-1,3-bisphosphoglycerate (i.e., 2-oxo-1,5-bisphosphonopentane, 2-oxo-PC5P) is a good inhibitor of PGK (Ki = 0.2 +/- 0.08 mM at pH 8.5, 27 degrees C) and a poor inhibitor of GPD (Ki = 20 +/- 1 mM, pH 8.5). The shorter, butane, analog (2-oxo-PC4P) binds more tightly to PGK (Ki = 84 +/- 6 microM), and about equally well to GPD, as does 2-oxo-PC5P. The 2-oxo-bisphosphonates bind to PGK more tightly (by approx. 4 kJ/mol) than do the corresponding non-carbonyl analogues (1,4-bisphosphonobutane and 1,5-bisphosphonopentane).
Li
Y K
YK
Department of Chemistry, Tulane University, New Orleans, LA 70118.
Byers
L D
LD
D004163:Diphosphoglyceric Acids / Q000494:pharmacology*; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000037:antagonists & inhibitors*; D010735:Phosphoglycerate Kinase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D015003:Yeasts / Q000201:enzymology
D004163:Diphosphoglyceric Acids; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D010735:Phosphoglycerate Kinase