Differential inhibition of cytosolic PEPCK by substrate analogues. Kinetic and structural characterization of inhibitor recognition

Biochemistry
Rose Mary StiffinTodd Holyoak

Abstract

The mechanisms of molecular recognition of phosphoenolpyruvate (PEP) and oxaloacetate (OAA) by cytosolic phosphoenolpyruvate carboxykinase (cPEPCK) were investigated by the systematic evaluation of a variety of PEP and OAA analogues as potential reversible inhibitors of the enzyme against PEP. The molecules that inhibit the enzyme in a competitive fashion were found to fall into two general classes. Those molecules that mimic the binding geometry of PEP, namely phosphoglycolate and 3-phosphonopropionate, are found to bind weakly (millimolar Ki values). In contrast, those competitive inhibitors that mimic the binding of OAA (oxalate and phosphonoformate) coordinate directly to the active site manganese ion and bind an order of magnitude more tightly (micromolar Ki values). The competitive inhibitor sulfoacetate is found to be an outlier of these two classes, binding in a hybrid fashion utilizing modes of recognition of both PEP and OAA in order to achieve a micromolar inhibition constant in the absence of direct coordination to the active site metal. The kinetic studies in combination with the structural characterization of the five aforementioned competitive inhibitors demonstrate the molecular requirements for high affinity bi...Continue Reading

References

Feb 20, 2002·Journal of Molecular Biology·Pete DuntenStanley J Wertheimer
May 14, 2005·The International Journal of Biochemistry & Cell Biology·Julien J H CotelesageLouis T J Delbaere

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Citations

Jun 21, 2012·Journal of Chemical Information and Modeling·Richard D SmithHeather A Carlson
Sep 6, 2008·Proceedings of the National Academy of Sciences of the United States of America·Sarah M Sullivan, Todd Holyoak
Jul 30, 2009·The Journal of Biological Chemistry·Gerald M Carlson, Todd Holyoak
Sep 13, 2013·Journal of Biomedical Science·Mohammad Reza Dayer, Mohammad Saaid Dayer
Aug 14, 2012·The Journal of Physical Chemistry. B·Michael L DrummondThomas R Cundari
Nov 19, 2019·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Marc AragóJose C Perales

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