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`0-Alkyl Hydroxamates as Metaphors of Enzyme-Bound Enolate
`Intermediates in Hydroxy Acid Dehydrogenases. Inhibitors of
`lsopropylmalate Dehydrogenase, lsocitrate Dehydrogenase, and
`Tartrate Dehydrogenase 1
`
`Michael C. Pirrung, Hyunsoo Han, and Jrlung Chen
`
`View Author Information v
`
`~ Cite this: J. Org. Chem. 1996, 61, 14, 4527-4531
`Publi cation Date: July 12, 1996 v
`https://doi.org/10.1021 /jo952090+
`Copyright © 1996 American Chemical Society
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`O-Alkyl Hydroxamates as Metaphors of Enzyme-Bound Enolate Interme...
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`https://pubs.acs.org/doi/full/10.1021/jo952090+
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`Abstract
`
`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 K competitive) that is isosteric with
`i
`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.
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