Inhibition of mevalonate 5-diphosphate decarboxylase by fluorinated substrate analogs

Biochimica Et Biophysica Acta
Yongge Qiu, Ding Li

Abstract

Mevalonate 5-diphosphate decarboxylase (MDD) is a peroxisomal enzyme in the cholesterol biosynthetic pathway, which plays an important role in regulating cholesterol biosynthesis. In the present study, rat MDD was cloned and purified to apparent homogeneity. Two fluorinated MDD substrate analogs, P'-geranyl 2-fluoromevalonate 5-diphosphate (4) and 2-fluoromevalonate 5-diphosphate (6), were synthesized, and both were found to be irreversible inhibitors of rat MDD. These two inhibitors were characterized, and mechanisms of the inactivation process were proposed. Kinetic studies indicate both analogs only bind into mevalonate binding-site of MDD. Compound 4 shows competitive inhibition on mevalonate kinase (MVK), and its IC(50) value was determined to be comparable with that of geranyl diphosphate. Further kinetic studies indicate compound 4 only bind into ATP binding-site of MVK. These studies provide an example for a single inhibitor to carry out sequential blocking of two enzymes in cholesterol biosynthesis, which may provide useful information for drug discovery for the purpose of treating cardiovascular disease and cancer or for pest control.

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Citations

Nov 26, 2014·Protein Science : a Publication of the Protein Society·Jeffrey M VinokurJames U Bowie
Sep 25, 2007·Bioorganic & Medicinal Chemistry Letters·Yongge QiuDing Li
Oct 31, 2009·Journal of Enzyme Inhibition and Medicinal Chemistry·Andrew Agnew, David Timson
Apr 21, 2010·The Journal of Biological Chemistry·Scott T LefurgyThomas S Leyh
Dec 23, 2019·RSC Medicinal Chemistry·Pimyupa ManaswiyoungkulPatrick T Gunning
Oct 12, 2010·Archives of Biochemistry and Biophysics·Henry M Miziorko

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