ABSTRACT
Genetic predisposition in MS, influence of fat consumption on the disease, and excretion of lipid metabolites in urine led us to investigate isoprenoid metabolism in this disease. Ubiquinone concentration and biosynthesis was normal in lymphocytes. Cytochrome oxidase, which contains an isoprenoid side chain, was normal in activity. Cholesterol biosynthesis from acetate was found to be elevated in MS, and so was triglyceride biosynthesis. Increased biosynthesis may offer a very simple explanation to all the metabolites excreted (3-methylglutaconic acid, 2-hydroxy-2-methyl-3-butenoic acid and adipic acid). Increased biosynthesis may be caused by an elevated NADPH/NADP ratio, since such an elevation may also account for many other biochemical anomalies in MS. Elevated NADPH/NADP ratio may be of direct importance in the pathogenesis.
Subject(s)
Multiple Sclerosis/enzymology , NADP/metabolism , Terpenes/biosynthesis , Cholesterol/biosynthesis , Electron Transport Complex IV/metabolism , Humans , Lymphocytes/enzymology , NADPH-Ferrihemoprotein Reductase/metabolism , Triglycerides/biosynthesis , Ubiquinone/metabolismABSTRACT
Recently discovered metabolites in urine have suggested a defect of isoprenoid metabolism in multiple sclerosis. Lymphocyte HMG-CoA reductase was found unaffected however, and so was lymphocyte biosynthesis of geraniol, farnesol and squalene from mevalonolactone. The level of dolichol in white matter of an MS brain was similar to that of a control sample. Serum ubiquinone, on the other hand, was decreased in multiple sclerosis. Ubiquinone in serum was both age-dependent and related to serum cholesterol. Active as well as stable MS displayed a decreased level of serum ubiquinone, and a reduced ubiquinone-cholesterol ratio. These results are compatible with a deficient ubiquinone biosynthesis in multiple sclerosis.