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PubMed1996

Mevalonic acid is limiting for N-linked glycosylation and translocation of the insulin-like growth factor-1 receptor to the cell surface. Evidence for a new link between 3-hydroxy-3-methylglutaryl-coenzyme a reductase and cell growth.

Depletion of mevalonic acid (MVA), obtained by inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase using lovastatin, depressed the biosynthesis of dolichyl-phosphate and the rate of N-linked glycosylation and caused growth arrest in the melanoma cell line SK-MEL-2. The growth arrest was partially prevented by addition of high concentrations of insulin-like growth factor-1 (IGF-1) to the cells, indicating that MVA depletion may inhibit cell growth through decreasing the number of IGF-1 receptors (IGF-1R) at the cell surface. Such a decrease in receptor number might be a result of a lowered translocation of de novo synthesized receptors to the cell membrane which in turn might be a result of a decreased N-linked glycosylation of the receptor proteins. We could also demonstrate that IGF-1R became underglycosylated and that the amount of de novo synthesized IGF-1R proteins at the cell membrane was drastically decreased upon MVA depletion. Analysis of receptor proteins cross-linked with IGF-1, as well as binding assays and immunocytostaining confirmed that the number of functional membrane-bound IGF-1R was substantially reduced. The N-linked glycosylation and the expression of de novo synthesized IGF-1R proteins at the cell surface as well as the number of IGF-1 binding sites were completely restored upon replenishment of MVA. These effects of MVA were efficiently abrogated by the glycosylation inhibitor tunicamycin. The translocation of IGF-1R to the cell membrane was shown to take place just prior to initiation of DNA synthesis in arrested cells stimulated with MVA. Additionally, there was a clear correlation between IGF-1 binding and initiation of DNA synthesis with regard to the MVA dose requirement. It was confirmed that inhibition of HMG-CoA reductase activity and N-linked glycosylation also depressed the expression of functional IGF-1R in other cell types (i.e. hepatoblastoma cells and colon cancer cells). Our data suggest that this mechanism is involved in MVA-regulated cell growth.

Base Sequence↗

PubMed1981

[Activities of 3-hydroxyl-3-methylglutaryl-CoA reductase and acetyl-CoA carboxylase and the rate of mevalonic acid, squalene, sterol and fatty acid biosynthesis from [1-14C]acetyl-CoA and [2-14C]malonyl-CoA in rat liver: effects of Triton WR 1339, starvation and cholesterol diet].

The effects of Triton WR 1339, starvation and cholesterol diet on the activities of 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase) and acetyl-CoA carboxylase and on the rates of mevalonic acid (MVA) biosynthesis from acetyl-CoA and malonyl-CoA in the soluble (140 000 g) and microsomal fractions of rat liver, on the rate of incorporation of these substrates into squalene, cholesterol and lanosterol in the rat liver postmitochondrial fraction and on the rate of fatty acid biosynthesis was studied. The administration of Triton WR 1339 (200 mg per 100 g of body weight twice) stimulated the activity of HMG-CoA reductase and MVA biosynthesis from acetyl-CoA and malonyl-CoA in the intact and solubilized microsomal fractions and had no effect on these parameters in the soluble fraction. Starvation for 36 hrs did not cause inhibition of the reductase activity or MVA biosynthesis from both substrates in the soluble fraction. Alimentary cholesterol significantly increased the activity of HMG-CoA reductase, had no effect on the rate of MVA biosynthesis from acetyl-CoA and stimulated the malonyl-CoA incorporation in to MVA in the soluble fraction. Starvation an alimentary cholesterol inhibited the HMG-CoA reductase activity and MVA biosynthesis from both substrates in the solubilized microsomal fraction. Triton WR 1339 stimulated 4--19-fold the lipid formation in the total unsaponified fraction and its components i.e. squalene, lanosterol, cholesterol, from acetyl-CoA and only insignificantly (1,2--1,7-fold) increased malonyl-CoA incorporation into these compounds. Starvation and alimentary cholesterol repressed lanosterol and cholesterol biosynthesis from acetyl-CoA, decreased malonyl-CoA incorporation into these sterols and had no influence on squalene biosynthesis from the two substrates. Triton WR 1339 and starvation inhibited the acetyl-CoA carboxylase activity, unaffected by alimentary cholesterol. No significant changes in the rate of fatty acid biosynthesis from the substrates were observed. The data obtained provide evidence for the existence of autonomic pathways of MVA biosynthesis localized in the soluble and microsomal fractions of rat liver. The pathway of MVA biosynthesis in the soluble fraction is less sensitive to regulatory factors. Sterol biosynthesis from malonyl-CoA is also more resistant to regulatory effects than sterol biosynthesis from acetyl-CoA. This suggests that HMG-CoA reductase localized in the soluble fraction takes part in MVA and sterol biosynthesis from malonyl-CoA.

Acetyl Coenzyme A↗

PubMed1994

Identification of farnesol as the non-sterol derivative of mevalonic acid required for the accelerated degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase.

The degradation of the microsomal enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase is highly regulated and is dependent on both a sterol and non-sterol derivative of mevalonic acid (MVA). We recently proposed that the non-sterol component is derived from farnesyl diphosphate (FPP), presqualene pyrophosphate, or squalene (Correll, C. C. and Edwards, P. A. (1994) J. Biol. Chem. 269, 633-638). In the current study, we have used digitonin-permeabilized cells to further define this MVA-derived non-sterol component required for the regulated degradation of HMG-CoA reductase. The addition of either FPP or farnesol to digitonin-permeabilized cells resulted in a rapid and dose-dependent degradation of HMG-CoA reductase. The effect of FPP, but not farnesol, was blocked by the phosphatase inhibitor sodium fluoride. The enhanced degradation of HMG-CoA reductase in permeabilized cells specifically required farnesol, since the addition of any of the structurally related isoprenoids geraniol, geranyl diphosphate, geranylgeranyl diphosphate, nerolidol, or all-cis-farnesol, or of the non-sterol squalene to the permeabilized cells did not stimulate enzyme degradation. The present studies demonstrate for the first time that the accelerated degradation of HMG-CoA reductase can be initiated in vitro. Further, since farnesol is shown to be specifically required for the enhanced degradation of the enzyme in vitro, we propose that this isoprenoid alcohol is important in this process in intact cells.

Animals↗

PubMed1998

Involvement of the mevalonic acid pathway and the glyceraldehyde-pyruvate pathway in terpenoid biosynthesis of the liverworts Ricciocarpos natans and Conocephalum conicum.

The incorporation of 13C-labeled glucose into borneol, bornyl acetate, the sesquiterpenes cubebanol and ricciocarpin A, phytol, and stigmasterol has been studied in axenic cultures of the liverworts Ricciocarpos natans and Conocephalum conicum. Quantitative 13C NMR spectroscopic analysis of the resulting labeling patterns showed that the isoprene building blocks of the sesquiterpenes and stigmasterol are built up via the mevalonic acid pathway, whereas the isoprene units of the monoterpenes and the diterpene phytol are exclusively derived from the glyceraldehyde-pyruvate pathway. These results indicate the involvement of both isopentenyl diphosphate biosynthetic pathways in different cellular compartments.

Camphanes↗

PubMed1982

A study of the Influence of mevalonic acid and its metabolites on the morphology of swiss 3T3 cells.

We used two model systems to investigate the effect of compactin, a competitive inhibitor of beta-hydroxy beta-methylglutarylcoenzyme A reductase, on the shape of Swiss 3T3 cells. We maintained cells in a quiescent state in medium deficient in platelet-derived growth factor (PDGF), or we added PDGF to quiescent cells to initiate traverse through a single cell cycle. In both systems, the cells responded to compactin by acquiring a characteristic rounded shape. Cell rounding seemed to depend on an induced deficiency of mevalonic acid (MVA) since the response could be prevented or reversed by adding MVA to the culture medium. Compactin-induced rounding appeared in PDGF-stimulated cells concomitantly with a compactin-mediated inhibition of DNA synthesis, and both effects had similar sensitivities to exogenous compactin and MVA. However, cell rounding seemed to be unrelated to other, previously observed effects of MVA deficiency. Compactin did not influence the total content of cell cholesterol, and little cholesterol was formed when we added radioactive MVA to round cells to effect shape change reversal. Measurement of the dolichol-dependent glycosylation of cell protein revealed no evidence of dolichol deficiency. In addition, reversal of cell rounding by MVA was not prevented by concentrations of tunicamycin that effectively blocked the incorporation of radioactive mannose into cell protein or by concentrations of cycloheximide that blocked protein synthesis. Taken together, our results suggest a new role for MVA or its products in the maintenance of cell shape.

Animals↗

PubMed1983

Metabolism of mevalonic acid in cell-free homogenates of bovine retinas. Formation of novel isoprenoid acids.

The metabolism of 3RS-[2RS-3H]mevalonate in the 10,000 x g supernatant fractions of homogenates of bovine retinas has been studied. Very efficient incorporation of the labeled mevalonate, approaching quantitative utilization of its 3R-isomer, into lipid products was observed. The extent of incorporation into saponifiable lipids was very substantial. Analysis of the labeled saponifiable lipids indicated that these lipids were composed almost exclusively of C15 and C20 isoprenoid acids. The major C15 acids corresponded chromatographically to trans,trans-farnesoic acid and cis,cis-farnesoic acid. The major C20 isoprenoid acids corresponded chromatographically to trans,trans,-trans-geranylgeranoic acid and an unidentified C20 isoprenoid acid containing at least one cis-double bond. Analyses of the nonsaponifiable lipids indicated the presence of labeled squalene, a C30 fraction containing lanosterol and/or 24,25-dihydrolanosterol, and a C27 fraction containing cholesterol, 5 alpha-cholest-7-en-3 beta-ol, 5 alpha-cholesta-8,24-dien-3 beta-ol, 5 alpha-cholesta-7,24-dien-3 beta-ol, and cholesta-5,24-dien-3 beta-ol. Trace components corresponding chromatographically to 5 alpha-cholest-8(14)-en-3 beta-ol and cholesta-5,7-dien-3 beta-ol were also detected.

Animals↗

PubMed1967

Bacterial metabolism of mevalonic acid.

Soluble cell-free extracts of actinomycete S4 grown on media containing mevalonate catalyze acetoacetate formation from mevalonate, mevaldate, and beta-hydroxy-beta-methylglutaryl-coenzyme A (CoA). Conversion of mevalonate to acetoacetate involves formation of free beta-hydroxy-beta-methylglutaryl-CoA, but not free mevaldate. The reaction favors mevalonate oxidation, and nicotinamide adenine dinucleotide, rather than nicotinamide adenine dinucleotide phosphate, acts as oxidant.

Acetoacetates↗

PubMed1975