Differential deficiency of mevalonate kinase and phosphomevalonate kinase in patients with distinct defects in peroxisome biogenesis: evidence for a major role of peroxisomes in cholesterol biosynthesis

Biochemical and Biophysical Research Communications
Ronald J A Wanders, Gerrit Jan Romeijn

Abstract

Peroxisomes catalyze a number of essential metabolic functions especially related to lipid metabolism. There is increasing evidence suggesting that peroxisomes are also involved in the synthesis of isoprenoids via the mevalonate pathway at least in rat liver. In order to obtain independent evidence for a role of peroxisomes in isoprenoid synthesis in man, we have measured the activity of two key enzymes of the mevalonate pathway in patients suffering from certain defined defects in peroxisome biogenesis. We now report that mevalonate kinase is not only deficient in livers from Zellweger patients in which peroxisome biogenesis is defective, but also in livers from rhizomelic chondrodysplasia punctata (RCDP) Type 1 patients. In the latter group of patients there is a selective defect in peroxisome biogenesis due to a genetic defect in the PTS2-receptor, a mobile receptor-protein guiding peroxisomal proteins with a certain peroxisomal targeting signal (PTS2) to the peroxisome. Phosphomevalonate kinase was found to be strongly deficient in Zellweger patients thus suggesting that this enzyme is also peroxisomal. Taken together, our data indicate that in human liver mevalonate kinase and phosphomevalonate kinase are truly peroxisomal...Continue Reading

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Citations

Nov 10, 2001·Annual Review of Genomics and Human Genetics·R I Kelley, G E Herman
Nov 8, 2001·Proceedings of the National Academy of Sciences of the United States of America·J B BonannoS K Burley
Jun 16, 1999·Nature Genetics·D Valle
Jan 20, 2004·Journal of Cell Science·Sietske HogenboomHans R Waterham
Jul 23, 1999·Archives of Biochemistry and Biophysics·J Biermann, H van den Bosch
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Nov 25, 1998·Molecular Aspects of Medicine·R J Wanders, J M Tager
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Sep 11, 2008·Analytical Biochemistry·Linda HennemanHans R Waterham
Jun 29, 1999·European Journal of Cell Biology·J BiermannH van den Bosch

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