Electrostatic and steric contributions to regulation at the active site of isocitrate dehydrogenase

Antony M. Dean, Daniel E. Koshland

Research output: Contribution to journalArticlepeer-review

99 Scopus citations

Abstract

The isocitrate dehydrogenase of Escherichia coli is regulated by covalent modification at the active site rather than, as expected, at an allosteric site. As a means of evaluating the mechanism of regulation, the kinetics of the substrate, 2R,3S-isocitrate, and a substrate analog, 2R-malate, were compared for the native, phosphorylated, and mutant enzymes. Phosphorylation decreases activity by more than a factor of 106 for the true substrate, but causes minor changes in the activity of the substrate analog. The kinetic results indicate that electrostatic repulsion and steric hindrance between the phosphoryl moiety and the γ carboxyl group of 2R,3S-isocitrate are the major causes of the inactivation, with a lesser contribution from the loss of a hydrogen bond.

Original languageEnglish (US)
Pages (from-to)1044-1046
Number of pages3
JournalScience
Volume249
Issue number4972
DOIs
StatePublished - 1990

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