Identification of peroxisomal targeting signals in cholesterol biosynthetic enzymes: AA-CoA thiolase, HMG-CoA synthase, MPPD, and FPP synthase

At least three different subcellular compartments, including peroxisomes, a re involved in cholesterol synthesis, The peroxisomal targeting signals for phosphomevalonate kinase and isopentenyl diphosphate isomerase have been i dentified. In the current study we identify the peroxisomal targeting signa ls required for four other enzymes of the cholesterol biosynthetic pathway: acetoacetyl-CoA (AA-CoA) thiolase, 3-hydroxy-3-methylglutaryl-coenzyme A ( HMG-CoA) synthase, mevalonate diphosphate decarboxylase (MPPD), and farnesy l diphosphate (FPP) synthase, Data are presented that demonstrate that mito chondrial AA-CoA thiolase contains both a mitochondrial targeting signal at the amino terminus and a peroxisomal targeting signal (PTS-1) at the carbo xy terminus. We also analyze a new variation of PTS-2 sequences required to target HMG-CoA synthase and MPPD to peroxisomes. In addition, we show that FPP synthase import into peroxisomes is dependent on the PTS-2 receptor an d identify at the amino terminus of the protein a lo-amino acid region that is required for the peroxisomal localization of the enzyme. These data pro vide further support for the conclusion that peroxisomes play a critical ro le in cholesterol biosynthesis.