177902-90-8Relevant academic research and scientific papers
O-alkyl hydroxamates as metaphors of enzyme-bound enolate intermediates in hydroxy acid dehydrogenases. Inhibitors of isopropylmalate dehydrogenase, isocitrate dehydrogenase, and tartrate dehydrogenase
Pirrung, Michael C.,Han, Hyunsoo,Chen, Jrlung
, p. 4527 - 4531 (2007/10/03)
The inhibition of Thermus thermophilus isopropylmalate dehydrogenase by O-methyl oxalohydroxamate was studied for comparison to earlier results of Schloss with the Salmonella enzyme. It is a fairly potent (1.2 μM), slow-binding, uncompetitive inhibitor against isopropylmalate and is far superior to an oxamide (25 mM Ki competitive) that is isosteric with the ketoisocaproate product of the enzyme. This improvement in inhibition was attributed to its increased NH acidity, which presumably is due to the inductive effect of the hydroxylamine oxygen. This principle was extended to the structurally homologous enzyme isocitrate dehydrogenase from E. coli, for which the compound O-(carboxymethyl) oxalohydroxamate is a 30 nM inhibitor, uncompetitive against isocitrate. The pH dependence of its inhibition supports the idea that it is bound to the enzyme in the anionic form. Another recently discovered homologous enzyme, tartrate dehydrogenase from Pseudomonas putida, was studied with oxalylhydroxamate. It has a relatively low affinity for the enzyme, though it is superior to tartrate. On the basis of these leads, squaric hydroxamates with increased acidity compared to squaric amides directed toward two of these enzymes were prepared, and they also show increased inhibitory potency, though not approaching the nanomolar levels of the oxalylhydroxamates.
