Removal of substrate inhibition in a lactate dehydrogenase from human muscle by a single residue change

FEBS Letters
C M EszesJ J Holbrook

Abstract

High concentrations of ketoacid substrates inhibit most natural hydroxyacid dehydrogenases due to the formation of an abortive enzyme-NAD+-ketoacid complex. It was postulated that this substrate inhibition could be eliminated from lactate dehydrogenases if the rate of NAD+ dissociation could be increased. An analysis of the crystal structure of mammalian LDHs showed that the amide of the nicotinamide cofactor formed a water-bridged hydrogen bond to S163. The LDH of Plasmodium falciparum is not inhibited by its substrate and, uniquely, in this enzyme the serine is replaced by a leucine. In the S163L mutant of human LDH-M4 pyruvate inhibition is, indeed, abolished and the enzyme retains high activity. However, the major contribution to this effect comes from a weakening of the interaction of pyruvate with the enzyme-coenzyme complex.

References

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May 29, 1991·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·C R DunnJ J Holbrook
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Citations

Jan 11, 2013·Journal of Medicinal Chemistry·Anna KohlmannDavid C Dalgarno
Aug 11, 2011·Journal of Biochemistry·Kazuhito AraiHayao Taguchi
Mar 19, 2014·Future Medicinal Chemistry·Luigi FiumeGiuseppina Di Stefano
Jul 2, 1999·Protein Engineering·C O HewittJ J Holbrook
Jan 30, 2003·American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics : the Official Publication of the International Society of Psychiatric Genetics·Robert A PhilibertWilliam H Coryell
Feb 14, 2019·The Journal of Biological Chemistry·Huabo WangEdward V Prochownik
May 1, 2004·The Journal of Biological Chemistry·Angus CameronFederico Gómez de las Heras
Apr 25, 2020·Nature Communications·Jung Ho AhnSang Yup Lee
Dec 24, 2019·Journal of Biotechnology·Yue-Peng ShangHui-Lei Yu
Apr 7, 2020·Journal of Medicinal Chemistry·Léopold ThabaultRaphaël Frédérick

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