Mevalonate kinase cholesterol biosynthesis

Houten, S.M., Schneiders, M.S., Wanders, R.J., and Waterham, H.R. (2003). Regnlation of isoprenoid/cholesterol biosynthesis in cehs from mevalonate kinase-deficient patients. J Biol Chem 278 5736-5743. 

This enzyme is not only crucial in plants, recent studies have suggested that mevalonate kinase also plays an important role in the regulation of the cholesterol biosynthesis in mammals. The significance of MVK has been further highlighted by the implication... 

Not all investigators are convinced that peroxisomes are involved in cholesterol biosynthesis. In contrast to Olivier and Krisans [4], Hogenboom and colleagues have found no deficiency in cholesterol biosynthesis in fibroblasts from patients with a peroxisomal biogenesis disorder (S. Hogenboom, 2003). In addition, using a variety of biochemical and microscopic techniques, they found that mevalonate kinase, phospho-mevalonate kinase, and mevalonate pyrophosphate decarboxylase are cytosolic, not peroxisomal enzymes (S. Hogenboom, 2004). 

The first recognized human metabolic defect in the biosynthesis of cholesterol and isoprenoids was mevalonic aciduria [10]. Mevalonic aciduria is an autosomal recessive disorder that is quite rare, with only 30 known patients (D. Haas, 2006). In normal individuals, a small amount of mevalonic acid diffuses from cells into the plasma at levels proportional to the rate of cellular cholesterol formation. Patients with the severe, classical form of mevalonic aciduria excrete 10,000-200,000 times the normal amount of mevalonic acid because they have severely reduced amounts of mevalonate kinase activity. Their clinical features include failure to thrive, anemia, gastroenteropathy, hepatosplenomegaly, psychomotor retardation, hypotonia, ataxia, cataracts, and dysmorphic features [10]. Surprisingly, patients with severe deficiencies in mevalonate kinase show normal plasma cholesterol levels and cultured mevalonic aciduria fibroblasts have a rate of cholesterol synthesis that is half that of normal cells. Close examination of cholesterogenic enzymes in mevalonic aciduria fibroblasts has revealed a 6-fold increase in HMG-CoA reductase activity, which is postulated to compensate for the low mevalonate kinase activity. Thus, mevalonate is overproduced. 

CXXXIX which has been found to be a potent inhibitor of mevalonic kinase [330]. Three analogs of famesinic acid, compounds CXL-CXLII, have been prepared in the Merck Laboratories [331, 332] and tested by Popjak and his associates [333]. The ethyl analog of famesinic acid (CXLIII) has been found to reduce serum and Hver concentration of cholesterol in the rat [334]. Bolhofer has prepared the famesinic acid analogs CXLIV [335] and CXLV [336] which have been reported to inhibit the biosynthesis of cholesterol in liver homogenates and as such are claimed to be useful in the treatment of arteriosclerosis. 

Bifunctional inhibitors of mevalonate kinase and mevalonate 5-diphosphate decarboxylase (15) have been synthesized. Both enzymes are in the cholesterol biosynthetic pathway and play an important role in the regulation of cholesterol biosynthesis. " ... 

Fig. 30.1. The pathway of cholesterol biosynthesis. 30. i, Mevalonate kinase 30.2, 3 -hydroxysteroid dehydrogenase of the 4a-methylsterol-4-demethylase complex 30.3, 3 -hydroxysteroid-A, A -isomerase (sterol-A -isomerase) 30.4, 3/ -hydroxysteroid-A - reductase (desmosterol reductase) 30.5, 3 -hydroxysteroid-A -reductase (7-dehydrocholesterol reductase)...

Levy, H. R., and G. Popjak Studies on the biosynthesis of cholesterol. 10. Mevalonic kinase and phosphomevalonic kinase from liver. Biochem. J. 76, 417 (1960). 

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