Nitrate esters, prepared by treatment of -hydroxy--amino acid derivatives with nitric acid, react with tributyltin hydride to give the corresponding alkoxyl radicals. These radicals readily undergo -scission, providing a convenient route for the regiocontrolled production of -carbon-centred amino acid radicals. By examining the partitioning of the alkoxyl radicals between the -scission process and the competing hydrogen transfer reaction, it has been possible to evaluate the influence of electronic and steric effects on the -scission reaction and the formation of the carbon-centred radicals.
We have previously reported dissociation constants for a range of bisphosphonate analogs of 1,3-bisphospho-D-glyceric acid binding to yeast phosphoglycerate kinase. Data for the unsymmetrical analogs were difficult to interpret because it was not clear in which of the two possible orientations these ligands bound. Here we report a novel NMR method for quantifying orientation preference based on relaxation effects induced by titration with CrADP, which is applied to these ligands. It is shown that all ligands can bind in both orientations but that the driving force for the orientational preference is to put the ␣,␣-difluoromethanephosphonate group in the "basic patch" (nontransferable phosphate) position. The relevance to the design of phosphoglycerate kinase inhibitors is discussed.Phosphoglycerate kinase (PGK) 1 (EC 2.7.2.3) is a glycolytic enzyme that catalyzes the following reaction, where MgADP and MgATP represent the magnesium complexes of ADP and ATP, respectively.
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