Cholesterol biosynthesis in Zellweger syndrome: normal activity of mevalonate kinase, mevalonate-5'-pyrophosphate decarboxylase and IPP-isomerase in patients' fibroblasts but deficient mevalonate kinase activity in liver

Cholesterol and dolichol are important constituents of cellular membranes but also serve other purposes. Cholesterol, for instance, is the precursor for bile acids and various hormones, whereas dolichol is involved in protein glycosylation in the form of dolichyl phosphate. Synthesis of all isoprenoids including dolichol and cholesterol follows a common pathway from acetyl-CoA to farnesyl pyrophosphate (FPP) which involves nine enzymic reactions, after which the pathways diverge. In the cholesterol biosynthetic pathway, for instance, two molecules of FPP condense to squalene, which is then further metabolized. With the exception of HMG-CoA reductase all enzymes involved in FPP formation from acetyl-CoA were believed to be cytosolic. Recent studies, notably by Krisans and co-workers, have shown this is not true and that at least some of these enzymes are localized in peroxisomes (Krisans 1992). The first indication for this came from immunoelectron-microscopy studies of Keller and co-workers (1986) showing the presence of HMG-CoA reductase in the matrix of peroxisomes. Later, other enzymes were also found to be localized in peroxisomes, including mevalonate kinase (Stamellos et al 1992), FPP synthase (Krisans et al 1994), dihydrolanosterol oxidase, steroid 14-reductase, steroid 8-isomerase, and steroid 3-ketoreductase (Appelkvist et al 1990). In apparent agreement with the important role of peroxisomes in cholesterol synthesis, patients affected by a disorder of peroxisome biogenesis often show hypocholesterolaemia (Poll-The et al 1987). Studies by Hodge and colleagues (1991) showed impaired de novo synthesis of cholesterol in fibroblasts from such patients (see, however, Malle et al 1995). In an important study, Mandel and co-workers (1995) recently reported reduced (Tab.) cholesterol levels in peroxisome-deficient fibroblasts. In addition, de novo cholesterol synthesis was found to be deficient and the patients' LDL showed adnormalities leading to deviant interaction between the LDL receptor and its ligand. We have studied the underlying basis for the impairment of cholesterol biosynthesis in peroxisome-deficient fibroblasts by measuring the activities of a number of candidate enzymes.