FARNESYL-DIPHOSPHATE SYNTHASE IS LOCALIZED IN PEROXISOMES

In this study, we have investigated the subcellular localization of fa rnesyl-diphosphate synthase (FPP synthase). FPP synthase produces FPP, which is utilized in the synthesis of squalene, cholesterol, farnesyl ated and geranylgeranylated proteins, dolichols, coenzyme Q, and the i soprenoid moiety of heme a. This enzyme is found in the 100,000 x g su pernatant fraction of cells or tissues and has been considered to be a cytoplasmic protein. In this study, analysis of FPP synthase activity and protein in fractionated rat liver together with immunofluorescent and immunoelectron microscopy studies demonstrated unequivocally that FPP synthase is largely localized in peroxisomes. These data, in comb ination with the previous observation that mevalonate kinase is predom inantly localized in peroxisomes, suggest that peroxisomes are the maj or site of synthesis of FPP from mevalonate. We also demonstrate that in liver tissue obtained from patients with peroxisomal deficiency dis eases (Zellweger syndrome and neonatal adrenoleukodystrophy), the acti vities of five enzymes involved in isoprenoid synthesis, namely mevalo nate kinase, phosphomevalonate kinase, mevalonate-diphosphate decarbox ylase, isopentenyl-diphosphate isomerase, and FPP synthase, are signif icantly reduced, consistent with a peroxisomal localization of these e nzymes.