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At least 37 records · Page 2Linked to original sources
PubMed1984

Evidence for post-translational incorporation of a product of mevalonic acid into Swiss 3T3 cell proteins.

Previous studies have identified several cellular requirements for mevalonic acid that appear unrelated to cholesterol, dolichol, or ubiquinone. To search for other products of mevalonic acid that might account for these requirements we cultured Swiss 3T3 cells in the presence of mevinolin, an inhibitor of mevalonic acid biosynthesis, then labeled the cells with exogenous radioactive mevalonic acid. Upon analyzing the radioactive material formed, we found that 40-50% of it was not extractable into lipid solvents, and that most of the lipid-insoluble material behaved like protein when treated with sodium dodecyl sulfate:chloroform:phenol, RNase, or proteinase K. Further analysis by electrophoresis revealed that radioactivity was associated with a few specific proteins that had apparent molecular weights of 13,000-58,000. Control experiments indicated that authentic radioactive (R)-mevalonic acid was the active precursor. Other lines of evidence suggested that mevalonate was first converted to an isoprenoid compound, then covalently incorporated into proteins by way of a cycloheximide-insensitive mechanism. These results suggest that Swiss 3T3 cells possess novel metabolic products of mevalonic acid metabolism that are formed by post-translational incorporation of isoprenoids into specific cell proteins.

Animals↗
PubMed1982

Mevalonic acid as an initiator of cell growth. Studies using human lymphocytes and inhibitors of endogenous mevalonate biosynthesis.

Mevalonic acid (5 x 10(-4)-1 x 10(-2) M) stimulates DNA synthesis, morphologic transformation and cell cycling in peripheral blood human lymphocytes. Other organic acid anions which serve as cholesterol and mevalonate precursors are devoid of such effects. Both ML-236B and 25-hydroxycholesterol, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, inhibit concanavalin A-induced lymphocyte transformation, but only the inhibition by ML-236B can be overcome by exogenous mevalonate. In contrast, only 25-hydroxycholesterol inhibits mevalonate-induced lymphocyte DNA synthesis. The effects of mevalonic acid on lymphocytes cannot be reproduced by isopentenyl adenine or isopentenyl adenosine. Unregulated endogenous cellular synthesis of mevalonic acid may contribute to uncontrolled growth in certain malignant cell lines.

Concanavalin A↗
PubMed1978

Metabolism of Mevalonic Acid in Vegetative and Induced Plants of Xanthium strumarium.

The metabolism of mevalonic acid in Xanthium strumarium L. Chicago plants was studied to determine how mevalonate was metabolized and whether metabolism was related to induction of flowering. Leaves of vegetative, photoperiodically induced, and chemically inhibited cocklebur plants were supplied with [(14)C]mevalonic acid prior to or during a 16-hour inductive dark period. Vegetative, induced, and Tris(2-diethylaminoethyl)phosphate trihydrochloride-treated plants did not differ significantly in the amount of [(14)C]mevalonic acid they absorbed, nor in the distribution of radioactivity among the leaf blade (97%), petiole (2.3%), or shoot tip (0.7%). [(14)C]Mevalonic acid was rapidly metabolized and transported out of the leaves. Possible metabolites of mevalonate were mevalonic acid phosphates and sterols. No detectable (14)C was found in gibberellins, carotenoids, or the phytol alcohol of chlorophyll. Chemically inhibited plants accumulated (14)C compounds not found in vegetative or induced plants. When ethanol extracts of leaves, petioles, and buds were chromatographed, comparisons of chromatographic patterns did not show significant differences between vegetative and induced treatments.

Journal Article↗
PubMed1985

The effect of excess mevalonic acid on ubiquinone and tetrahymanol biosynthesis in Tetrahymena pyriformis.

When T. pyriformis is grown in the presence of 10(-2)M-mevalonic acid, the uptake exceeds the cell's requirement for this biosynthetic intermediate. The majority of the excess mevalonic acid is diverted into ubiquinone-8 biosynthesis whereas the biosynthesis of tetrahymanol, the major product of the mevalonic acid pathway, is unchanged. In the presence of excess external mevalonic acid, the biosynthesis of mevalonic acid by the cell is inhibited. It is proposed that ubiquinone biosynthesis is normally regulated by mevalonic acid availability, whereas tetrahymanol biosynthesis is regulated primarily at a later point in the pathway.

Mevalonic Acid↗
PubMed1964

METABOLISM OF MEVALONIC ACID BY LACTOBACILLUS PLANTARUM.

Durr, I. F. (American University of Beirut, Beirut, Lebanon), and A. N. Shwayri. Metabolism of mevalonic acid by Lactobacillus plantarum. J. Bacteriol. 88:361-366. 1964.-Lactobacillus plantarum strain 8014-H(2), unlike other lactobacilli studied, does not require mevalonic acid for growth, but growing and resting cells utilize it only for the synthesis of nonsaponifiable lipids. Upon the incubation of washed cells with mevalolactone-2-C(14), the label appeared in the lipids but not in CO(2). On the other hand, when mevalolactone-1-C(14) was used, the label appeared in CO(2) but not in lipids. For every mole of CO(2) liberated, 1 mole of radioactive carbon was introduced in the lipids, suggesting that terpenic polymers were synthesized. Amino acids did not stimulate the utilization of mevalonic acid. Starved cells could not synthesize nonsaponifiable lipids from mevalonic acid unless glucose was supplied. Sodium fluoride (0.14 m), 2,4-dinitrophenol (0.003 m), p-hydroxymercuribenzoate (0.0013 m), potassium phosphate (0.1 m), and ammonium formate (0.04 m) were potent inhibitors. Cells metabolized only one isomer of dl-mevalonic, and utilized the salt form at least twice as efficiently as the lactone. Optimal synthesis of lipids from mevalonic acid occurred aerobically, at pH 5 and 30 C.

2,4-Dinitrophenol↗
PubMed2002

Mevalonic acid partially restores chloroplast and etioplast development in Arabidopsis lacking the non-mevalonate pathway.

Isopentenyl diphosphate (IPP) is produced via two independent biosynthetic pathways in higher plants: the mevalonate (MVA) pathway in the cytoplasm and the non-mevalonate 2-C-methyl- D-erythritol-4-phosphate (MEP) pathway in plastids. It has been previously suggested that IPP or IPP-derived products can be exchanged between the cytoplasm and plastids. However, the issue of whether the exchanged products reflect efficient synthesis of functional isoprenoids remains unresolved. We fed exogenous mevalonic acid to the Arabidopsis thaliana (L.) Heynh. albino mutant cla1-1, a null mutant of the first-step enzyme in the MEP pathway. This resulted in the recovery of thylakoid membrane stacking in chloroplasts in the light, and the formation of prolamellar bodies and plastoglobuli in etioplasts in the dark. By contrast, exogenous lovastatin, an inhibitor of mevalonic acid biosynthesis, induced complete depigmentation and further inhibition of plastid development in both the light and the dark. These results suggest that mevalonic acid-derived products contribute to the formation of functional plastidic isoprenoids, such as the chlorophylls and carotenoids required for plastid development.

Arabidopsis↗
PubMed1976

[Possible role of acetyl-CoA-carboxylase in biosynthesis of mevalonic acid and sterols in rat liver].

Effect of citrate on acetyl-CoA incorporation into mevalonic acid, sterols and fatty acids after preliminary incubation of rat liver extracts under conditions optimal for acetyl-CoA carboxylase activation, was studied. 30 min preincubation with the citrate at 37 degrees C results in a 2--3-fold stimulation of the mevalonic acid biosynthesis from acetyl-CoA in the microsomal and soluble (140 000 g) fraction, and in that of sterols precipitated by digitonin or isolated by TLC in the mitochondria--free fraction. 2-14C-malonyl-CoA incorporation into the mevalonic acid and sterols and biosynthesis of sterols from 2-14C-mevalonic acid were not stimulated under those conditions. A correlation was shown to exist between the activity of acetyl-CoA carboxylase and the rate of acetyl-CoA incorporation into mevalonate and sterols; the activity of beta-hydroxy-beta-methylglutaryl-CoA reductase, limiting the rate of the sterol biosynthesis, was not changed. The stimulating effect of citrate was found to depend on the concentration of acetyl-CoA and NADPH in the medium. The data obtained suggest that the mevalonic acid biosynthesis in rat liver may occur in the presence of acetyl-CoA carboxylase through the formation of malonyl-CoA.

Acetyl-CoA Carboxylase↗
PubMed1975

Incorporation of mevalonic Acid into ribosylzeatin in tobacco callus ribonucleic Acid preparations.

The incorporation of (14)C-2-mevalonic acid into transfer RNA and ribosomal RNA (high molecular weight RNA) in rapidly growing, cytokinin-dependent tobacco (Nicotiana tabacum var. Wisconsin No. 38) callus cultures has been investigated. Approximately 40% of the label incorporated into transfer RNA was present in a ribonucleoside with chromatographic properties identical to those of cis-ribosylzeatin. The remainder of the label in the transfer RNA appears to be nonspecific incorporation resulting from degradation and metabolism of (14)C-2-mevalonic acid by the tobacco callus tissue. Although the total radioactivity incorporated into ribosomal RNA was roughly the same as in transfer RNA, the specific radioactivity of the transfer RNA was about four times higher than that of the ribosomal RNA, and the ribosomal RNA labeling could be distinguished from the cytokinin labeling observed in transfer RNA. The distributions of the (14)C-2-mevalonic acid label and cytokinin activity in tobacco callus transfer RNA fractionated by benzoylated diethylaminoethylcellulose chromatography indicate that at least two cytokinin-containing transfer RNA species are present in this tissue.

Journal Article↗
PubMed2003

Liquid chromatography/tandem mass spectrometry methods for quantitation of mevalonic acid in human plasma and urine: method validation, demonstration of using a surrogate analyte, and demonstration of unacceptable matrix effect in spite of use of a stable isotope analog internal standard.

Selective, accurate, and reproducible liquid chromatography/tandem mass spectrometry (LC/MS/MS) methods were developed and validated for the determination of mevalonic acid, an intermediate in the biosynthesis of cholesterol and therefore a useful biomarker in the development of cholesterol lowering drugs, in human plasma and urine. A hepta-deuterated analog of mevalonic acid was used as the internal standard. For both methods, calibration standards were prepared in water, instead of human plasma and urine, due to unacceptably high levels of endogenous mevalonic acid. The lower quality control (QC) samples were prepared in water while the higher QC samples were prepared in the biological matrices. For the isolation/purification of mevalonic acid from the plasma and urine matrices, the samples were first acidified to convert the acid analyte into its lactone form. For the plasma samples, the lactone analyte was retained on and then eluted off a polymeric solid-phase extraction (SPE) sorbent. For the urine method, the sample containing the lactone analyte was passed through a C-18 SPE column, which did not retain the analyte, with the subsequent analyte retention on and then elution off a polymeric SPE sorbent. Chromatographic separation was achieved isocratically on a polar-endcapped C-18 analytical column with a water/methanol mobile phase containing 0.5 mM formic acid. Detection was by negative-ion electrospray tandem mass spectrometry. The standard curve range was 0.500-20.0 ng/mL for the plasma method and 25.0-1,000 ng/mL for the urine method. Excellent accuracy and precision were obtained for both methods at all concentration levels tested. It was interesting to note that for certain batches of urine, when a larger sample volume was used for analysis, a high degree of matrix effect was observed which resulted not only in the attenuation of the absolute response, but also in a change of analyte/internal standard response ratio. This demonstrated that, under certain conditions, the use of a stable isotope analog internal standard does not, contrary to conventional thinking, guarantee the constancy of the analyte/internal response ratio, which is a prerequisite for a rugged bioanalytical method. On the other hand, under conditions where the sample matrix does not have such a deleterious effect, we have found that a stable isotope analog could serve as a surrogate (substitute) analyte. Thus, we have shown that using calibration standards prepared by spiking plasma with tri-deuterated or tetra-deuterated mevalonic acid, instead of mevalonic acid itself (the analyte), plasma QC samples that contain mevalonic acid can be successfully analyzed for the accurate and precise quantitation of mevalonic acid. The use of a surrogate analyte provides the opportunity to gauge the daily performance of the method for the low concentration levels prepared in the biological matrix, which otherwise is not achievable because of the endogenous concentrations of the analyte in the biological matrices.

Chromatography, Liquid↗