title: 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.
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 enzymes which strongly suggests that peroxisomes play a major role in cholesterol biosynthesis.
authors.affiliation: Department of Clinical Chemistry, University of Amsterdam, Academic Medical Centre, The Netherlands. wanders@amc.uva.nl
authors.forename: R J
authors.initials: RJ
authors.lastname: Wanders
authors.forename: G J
authors.initials: GJ
authors.lastname: Romeijn
mesh_terms: D000595:Amino Acid Sequence; D002478:Cells, Cultured; D002784:Cholesterol / Q000096:biosynthesis*; D018902:Chondrodysplasia Punctata, Rhizomelic / Q000503:physiopathology*; D016384:Consensus Sequence / Q000235:genetics; D006801:Humans; D008099:Liver / Q000201:enzymology; D008830:Microbodies / Q000201:enzymology* / Q000502:physiology; D008969:Molecular Sequence Data; D000074437:Peroxisomal Targeting Signal 2 Receptor; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000172:deficiency*; D017856:Phosphotransferases (Phosphate Group Acceptor) / Q000172:deficiency*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D015211:Zellweger Syndrome / Q000201:enzymology*
chemical_list: D000074437:Peroxisomal Targeting Signal 2 Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D002784:Cholesterol; D017853:Phosphotransferases (Alcohol Group Acceptor); C021796:mevalonate kinase; D017856:Phosphotransferases (Phosphate Group Acceptor); C022371:phosphomevalonate kinase