Post-translational regulation of mevalonate kinase by intermediates of the cholesterol and nonsterol isoprene biosynthetic pathways

Debra D. Hinson, Ken L. Chambliss, Matthew J. Toth, Richard D. Tanaka, K. Michael Gibson

Research output: Contribution to journalArticlepeer-review

89 Scopus citations


To assess the potential for feedback inhibition by isoprene intermediates in the cholesterol and nonsterol isoprene biosynthetic pathway, we expressed human cDNAs encoding mevalonate kinase (MKase), phosphomevalonate kinase (PMKase), and mevalonate diphosphate decarboxylase (MDDase) as fusion proteins in Escherichia coli DH5α, and purified these proteins by affinity chromatography. Several phosphorylated and non- phosphorylated isoprenes were analyzed as inhibitors of the enzymes using a standard spectrophotometric assay. Of the three proteins, only MKase was inhibited through competitive interaction at the ATP-binding site. The intermediates studied (and their relative inhibitory capacity) were: geranylgeranyl-diphosphate (GGPP, C20) > farnesyl-diphosphate (FPP, C15) > geranyl-diphosphate (GPP, C10) > isopentenyl-diphosphate (IPP, C5) ≤ 3,3-dimethylallyl-diphosphate (DMAPP, C5) > farnesol (C15) > dolichol- phosphate (DP, C80-100). Mevalonate-diphosphate, geraniol, and dolichol were not inhibitors. Our data further define the spectrum of physiologic inhibitors of MKase, and provide the first evidence for feedback inhibition of MKase by a nonsterol isoprene produced by the branched pathway, dolichol- phosphate. These results provide additional evidence that MKase may occupy a central regulatory role in the control of cholesterol and nonsterol isoprene biosynthesis.

Original languageEnglish (US)
Pages (from-to)2216-2223
Number of pages8
JournalJournal of lipid research
Issue number11
StatePublished - Nov 1997
Externally publishedYes


  • ATP- binding site
  • Cholesterol
  • Competitive inhibition
  • Isoprenes
  • Mevalonate diphosphate decarboxylase
  • Mevalonate kinase
  • Phosphomevalonate kinase
  • Regulation

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology


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