Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Mevalonic Acid”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 253 records · Page 14Linked to original sources
PubMed1974

Mevalonate metabolism by renal tissue in vitro.

Previous studies from this laboratory have demonstrated that the kidneys rather than the liver play the major role in the in vivo metabolism of circulating mevalonic acid. Kidneys, however, convert mevalonic acid primarily to the precursors of cholesterol, squalene and lanosterol, rather than to cholesterol. This study was designed to define the specific tissue site within the kidney responsible for mevalonic acid metabolism. Tissue slices from rat and dog renal cortex and medulla and glomeruli and tubules were isolated, and the incorporation of (14)C-labeled mevalonic acid into the nonsaponifiable lipids squalene, lanosterol, and cholesterol was determined in these tissues. The results demonstrate that the renal cortex is the primary site of mevalonic acid metabolism within the kidney and that the glomerulus is responsible for 95% of the mevalonic acid metabolized by the renal cortex. As was the case for the whole kidney, the major metabolites of mevalonate in the glomeruli are squalene and lanosterol.

Acetates↗
PubMed1993

Isoprenoid biosynthesis in bacteria: two different pathways?

The biosynthesis of isopentenylpyrophosphate, a central intermediate of isoprenoid formation, was investigated in six different bacterial organisms. Cell-free extracts of Myxococcus fulvus, Staphylococcus carnosus, Lactobacillus plantarum and Halobacterium cutirubrum converted [14C]acetyl-CoA or [14C]hydroxymethylglutaryl-CoA to [14C]mevalonic acid. Furthermore, [14C]mevalonic acid, [14C]mevalonate-5-phosphate and [14C]mevalonate-5-pyrophosphate were metabolized to [14C]isopentenylpyrophosphate. These data demonstrated the in vitro operation of acetoacetate pathway for the formation of isopentenylpyrophosphate in bacteria. In contrast, no intermediates of this reaction sequence could be detected using cell-free extracts of Zymomonas mobilis and Escherichia coli. These results indicate that at least two different pathways for the biosynthesis of isopentenylpyrophosphate are present in bacteria.

Acetyl Coenzyme A↗
PubMed2002

Lipid modification of proteins in Archaea: attachment of a mevalonic acid-based lipid moiety to the surface-layer glycoprotein of Haloferax volcanii follows protein translocation.

Once the newly synthesized surface (S)-layer glycoprotein of the halophilic archaeaon Haloferax volcanii has traversed the plasma membrane, the protein undergoes a membrane-related, Mg(2+)-dependent maturation event, revealed as an increase in the apparent molecular mass and hydrophobicity of the protein. To test whether lipid modification of the S-layer glycoprotein could explain these observations, H. volcanii cells were incubated with a radiolabelled precursor of isoprene, [(3)H]mevalonic acid. In Archaea, isoprenoids serve as the major hydrophobic component of archaeal membrane lipids and have been shown to modify other haloarchaeal S-layer glycoproteins, although little is known of the mechanism, site or purpose of such modification. In the present study we report that the H. volcanii S-layer glycoprotein is modified by a derivative of mevalonic acid and that maturation of the protein was prevented upon treatment with mevinolin (lovastatin), an inhibitor of mevalonic acid biosynthesis. These findings suggest that lipid modification of S-layer glycoproteins is a general property of halophilic archaea and, like S-layer glycoprotein glycosylation, lipid-modification of the S-layer glycoproteins takes place on the external cell surface, i.e. following protein translocation across the membrane.

Acids↗
PubMed1981

Biosynthesis of radiolabeled T-2 toxin by Fusarium tricinctum.

Incubation of Fusarium tricinctum NRRL 3299 on a solid rice medium in the presence of [1-14C]sodium acetate, [2-3H]mevalonic acid, [2-14C]mevalonic acid, or [5-3H]mevalonic acid yielded preparations of radiolabeled T-2 toxin with specific activities of 1.008, 1.64, 0.656, and 7.35 muCi/mmol, respectively.

Acetates↗
PubMed1994

Mevalonic acid-dependent degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase in vivo and in vitro.

The microsomal enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase is subject to rapid degradation when cells are incubated with sterols or mevalonic acid (MVA). It has been shown that this rapid degradation is dependent upon both a sterol and another MVA-derived metabolite (Nakanishi, M., Goldstein, J. L., and Brown, M. S. (1988) J. Biol. Chem. 258, 8929-8937). In the current study, inhibitors of the isoprene biosynthetic pathway were used to define further this mevalonic acid derivative involved in the accelerated degradation of HMG-CoA reductase. The accelerated degradation of HMG-CoA reductase in met-18b-2 cells, which is induced by the addition of MVA, was inhibited by the presence of the squalene synthase inhibitor, zaragozic acid/squalestatin, or the squalene epoxidase inhibitor, NB-598. Accelerated degradation of HMG-CoA reductase was observed when NB-598-treated cells were incubated with both MVA and sterols. In contrast, the addition of MVA and sterols to zaragozic acid/squalestatin-treated cells did not result in rapid enzyme degradation. This MVA- and sterol-dependent degradation of HMG-CoA reductase persisted in cells permeabilized with reduced streptolysin O. Finally, the selective degradation of HMG-CoA reductase was also observed in rat hepatic microsomes incubated in vitro in the absence of ATP and cytosol. We conclude that the MVA-derived component that is required for the accelerated degradation of HMG-CoA reductase is derived from farnesyl disphosphate and/or squalene in the isoprenoid biosynthetic pathway. We propose that this component has a permissive effect and does not, by itself, induce the degradation of HMG-CoA reductase. We also conclude that the degradation of HMG-CoA occurs in the endoplasmic reticulum, and, once the degradation of HMG-CoA reductase has been initiated by MVA and sterols, all necessary components for the continued degradation of HMG-CoA reductase reside in the endoplasmic reticulum.

Animals↗
PubMed1997

The orphan nuclear receptor LXRalpha is positively and negatively regulated by distinct products of mevalonate metabolism.

LXRalpha is an orphan member of the nuclear hormone receptor superfamily that displays constitutive transcriptional activity. We reasoned that this activity may result from the production of an endogenous activator that is a component of intermediary metabolism. The use of metabolic inhibitors revealed that mevalonic acid biosynthesis is required for LXRalpha activity. Mevalonic acid is a common metabolite used by virtually all eukaryotic cells. It serves as a precursor to a large number of important molecules including farnesyl pyrophosphate, geranylgeranyl pyrophosphate, cholesterol, and oxysterols. Inhibition of LXRalpha could be reversed by addition of mevalonic acid and certain oxysterols but not by other products of mevalonic acid metabolism. Surprisingly, the constitutive activity of LXRalpha was inhibited by geranylgeraniol, a metabolite of mevalonic acid. These findings suggest that LXRalpha may represent a central component of a signaling pathway that is both positively and negatively regulated by multiple products of mevalonate metabolism.

Cell Line↗
PubMed1966

Intracellular localization of mevalonate-activating enzymes in plant cells.

Mevalonate-activating enzymes are shown to be present in the chloroplasts of French-bean leaves. The chloroplast membrane is impermeable to mevalonic acid. Mevalonate-activating enzymes also appear to be found outside the chloroplast. These results support the view that terpenoid biosynthesis in the plant cell is controlled by a combination of enzyme segregation and specific membrane permeability.

Autoradiography↗
PubMed2001

Current prospects for controlling cancer growth with non-cytotoxic agents--nutrients, phytochemicals, herbal extracts, and available drugs.

In animal or cell culture studies, the growth and spread of cancer can be slowed by many nutrients, food factors, herbal extracts, and well-tolerated, available drugs that are still rarely used in the clinical management of cancer, in part because they seem unlikely to constitute definitive therapies in themselves. However, it is reasonable to expect that mechanistically complementary combinations of these measures could have a worthwhile impact on survival times and, when used as adjuvants, could improve the cure rates achievable with standard therapies. The therapeutic options available in this regard include measures that: down-regulate serum free IGF-I; suppress the synthesis of mevalonic acid and/or certain derivatives thereof; modulate arachidonate metabolism by inhibiting 5-lipoxygenase, 12-lipoxygenase, or COX-2; antagonize the activation of AP-1 transcription factors; promote the activation of PPAR-gamma transcription factors; and that suppress angiogenesis by additional mechanisms. Many of these measures appear suitable for use in cancer prevention.

Animals↗
PubMed1998

Seasonal variation of glycyrrhizin and isoliquiritigenin glycosides in the root of Glycyrrhiza glabra L.

The time courses of the glycyrrhizin and isoliquiritigenin glycoside contents in the thickening roots of licorice, Glycyrrhiza glabra L., have been determined. The glycyrrhizin content in 1-year-old roots rapidly increased from October to November, whereas the isoliquiritigenin glycoside content increased up to October. In 3-year-old plants, although the isoliquiritigenin glycoside content rapidly increased from June to July, the glycyrrhizin content did not show any significant increase from May to August. The glycyrrhizin content increased during the senescence of the aerial parts as well as during the early stage of shoot elongation. The incorporation of [14C]mevalonic acid into the glycyrrhizin fraction by the root segments was high in May, June and September, and low in August and winter. These results indicated that the biosynthesis of glycyrrhizin is differently regulated from that of isoliquiritigenin glycoside in the thickening root of G. glabra.

Carbon Radioisotopes↗
PubMed1997

Intestinal brush-border membrane transport of monocarboxylic acids mediated by proton-coupled transport and anion antiport mechanisms.

Intestinal brush-border membrane transport of monocarboxylic acids was investigated by using rabbit intestinal brush-border membrane vesicles (BBMVs) and isolated intestinal tissues mounted on Ussing-type chambers. [3H]Mevalonic acid uptake by BBMVs showed an overshoot phenomenon in the presence of an inwardly directed proton gradient, but not in the presence of an inwardly directed sodium gradient or an outwardly directed HCO3- or chloride gradient. Initial uptake of mevalonic acid was saturable in the presence of a proton gradient. Uptake of [3H]mevalonic acid was inhibited by various monocarboxylic acids, including acetic acid, benzoic acid, lactic acid, nicotinic acid, pravastatin, salicylic acid and valproic acid, but not by dicarboxylic acid or amino acids. Acetic acid, which is transported by both anion antiport and proton-coupled transport systems, induced serosal bicarbonate-dependent alkalinization in the mucosal-side bathing solution of rabbit jejunal tissues, when examined in Ussing-type chambers. Pravastatin, which is a structural analogue of mevalonic acid and is absorbed via proton-coupled transport like mevalonic acid, did not. The result demonstrates that acetic acid is transported by the bicarbonate-dependent anion antiport system, whereas pravastatin is not. So, it is suggested that monocarboxylic acids are transported by at least two independent transporters, namely, a proton-coupled transporter for most monocarboxylic acids, including mevalonic acid, pravastatin and acetic acid, and an anion antiporter for acetic acid, but not for mevalonic acid or pravastatin. Activation of anion antiporter can induce HCO3- secretion in intact intestine.

Acetic Acid↗
PubMed2002

The structure of a binary complex between a mammalian mevalonate kinase and ATP: insights into the reaction mechanism and human inherited disease.

Mevalonate kinase catalyzes the ATP-dependent phosphorylation of mevalonic acid to form mevalonate 5-phosphate, a key intermediate in the pathways of isoprenoids and sterols. Deficiency in mevalonate kinase activity has been linked to mevalonic aciduria and hyperimmunoglobulinemia D/periodic fever syndrome (HIDS). The crystal structure of rat mevalonate kinase in complex with MgATP has been determined at 2.4-A resolution. Each monomer of this dimeric protein is composed of two domains with its active site located at the domain interface. The enzyme-bound ATP adopts an anti conformation, in contrast to the syn conformation reported for Methanococcus jannaschii homoserine kinase. The Mg(2+) ion is coordinated to both beta- and gamma-phosphates of ATP and side chains of Glu(193) and Ser(146). Asp(204) is making a salt bridge with Lys(13), which in turn interacts with the gamma-phosphate. A model of mevalonic acid can be placed near the gamma-phosphoryl group of ATP; thus, the C5 hydroxyl is located within 4 A from Asp(204), Lys(13), and the gamma-phosphoryl of ATP. This arrangement of residues strongly suggests: 1) Asp(204) abstracts the proton from C5 hydroxyl of mevalonate; 2) the penta-coordinated gamma-phosphoryl group may be stabilized by Mg(2+), Lys(13), and Glu(193); and 3) Lys(13) is likely to influence the pK(a) of the C5 hydroxyl of the substrate. V377I and I268T are the most common mutations found in patients with HIDS. Val(377) is located over 18 A away from the active site and a conservative replacement with Ile is unlikely to yield an inactive or unstable protein. Ile-268 is located at the dimer interface, and its Thr substitution may disrupt dimer formation.

Adenosine Triphosphate↗
PubMed1989

Human lamin B contains a farnesylated cysteine residue.

We recently showed that HeLa cell lamin B is modified by a mevalonic acid derivative. Here we identified the modified amino acid, determined its mode of linkage to the mevalonic acid derivative, and established the derivative's structure. A cysteine residue is modified because experiments with lamin B that had been biosynthetically labeled with [3H]mevalonic acid or [35S]cysteine and then extensively digested with proteases yielded 3H- or 35S-labeled products that co-chromatographed in five successive systems. A thioether linkage rather than a thioester linkage is involved because the mevalonic acid derivative could be released from the 3H-labeled products in a pentane-extractable form by treatment with Raney nickel but not with methanolic KOH. The derivative is a farnesyl moiety because the Raney nickel-released material was identified as 2,6,10-trimethyl-2,6,10-dodecatriene by a combination of gas chromatography and mass spectrometry. The thioether-modified cysteine residue appears to be located near the carboxyl end of lamin B because treatment of 3H-labeled lamin B with cyanogen bromide yielded a single labeled polypeptide that mapped toward this end of the cDNA-inferred sequence of human lamin B.

Amino Acid Sequence↗
PubMed1985

Effect of 4-(4'-chlorobenzyloxy)benzyl nicotinate (KCD-232) on cholesterol metabolism in rats.

The effects of 4-(4'-chlorobenzyloxy)benzyl nicotinate (KCD-232), a new hypolipidemic agent, on serum cholesterol level and cholesterol biosynthesis were studied in normolipidemic rats. KCD-232 dose-dependently reduced the serum cholesterol level. The in vivo incorporation of [14C]-acetate and 3H from [3H]water into liver digitonin-precipitable sterols was inhibited by oral administration of KCD-232, while that of [14C]mevalonic acid into the sterols was not inhibited. Hepatic 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase activity was suppressed significantly by the oral administration of the drug. A KCD-232 metabolite, 4-(4'-chlorobenzyloxy)benzoic acid (MII), strongly inhibited [14C]acetate incorporation and weakly inhibited [14C]mevalonic acid incorporation into the sterols in liver slices. MII also significantly inhibited the sterol synthetic rate measured with [3H]water and the HMG-CoA reductase activity in dispersed hepatocytes. MII and its CoA thioester (MII-CoA) inhibited the incorporation of [14C]acetate, [14C]acetyl-CoA and [14C]HMG-CoA into nonsaponifiable lipids in a cell-free enzyme system from rat liver. MII-CoA further showed a weak inhibition of [14C]-mevalonic acid incorporation into nonsaponifiable lipids in the system, while MII showed no effect on mevalonic acid incorporation. These results indicate that KCD-232 possesses a major inhibitory site for sterol synthesis on HMG-CoA reductase due to both MII and MII-CoA, and a possible second site of action beyond mevalonic acid due to MII-CoA. The latter inhibitory site, however, is considered to play a minor role in the inhibition of sterol synthesis in vivo.

Acetates↗
PubMed1998

Probing cataractogenesis associated with mevalonic aciduria.

PURPOSE: Mevalonic aciduria in humans results from a genetic deficiency of mevalonate kinase and is characterized by very high plasma mevalonic acid levels, developmental malformations and cataracts. This study tested the possibility that the cataracts could result from direct toxicity of the accumulated mevalonate. METHODS: Young rat lenses were cultured for up to 4 days in medium TC199 containing 1 to 5 mM mevalonic acid. Changes in the water, sodium and potassium content of the lens were followed; electrolytes were measured by atomic absorption spectroscopy. The identities of proteins leaked from the lens were determined by sodium dodecylsulfate polyacrylamide electrophoresis and isoelectric focusing. Changes in cation flux were measured by 86Rb uptake. Lens concentrations of mevalonic acid were measured from uptake of 3H-mevalonolactone. RESULTS: Culture of young rat lenses with 3 to 5 mM mevalonic acid produced lens opacification and nuclear cataracts starting within 1 to 2 days of culture. Mevalonic acid did not concentrate in the lens. Treated lenses accumulated water and sodium and lost potassium and soluble gamma crystallin proteins. These changes were preceded by a loss of the len's capacity to concentrate 86Rb, a potassium analogue. The loss of 86Rb uptake might have been due to a slow poisoning of the cation pump, direct effects on membrane integrity or both. CONCLUSIONS: The results show that chronic exposure of the lens to mevalonic acid can induce cataracts, which appear caused by a progressive increase in the permeability of lens cell membranes. The cataracts associated with mevalonic aciduria could be due to toxicity from mevalonic acid.

Animals↗
PubMed1967

The stereospecific biosynthesis of phytoene and polyunsaturated carotenes.

1. The incorporation of [2-(14)C,(5R)-5-(3)H(1)]mevalonic acid and [2-(14)C,5-(3)H(2)]-mevalonic acid into phytoene, phytofluene, zeta-carotene, neurosporene, alpha-, beta-, gamma- and delta-carotene and lycopene by slices of fruit from two tomato mutants (delta and tangerine) and into alpha- and beta-carotene by bean leaves has been studied. 2. In the formation of phytoene, all the pro-R-hydrogen atoms from C-5 of mevalonic acid are retained whereas two pro-S-hydrogen atoms are lost. 3. Possible mechanisms for the condensation of two molecules of all-trans-geranylgeranyl pyrophosphate are outlined. 4. In each dehydrogenation step from phytoene to the fully unsaturated carotenes, one pro-R-hydrogen atom from C-5 of mevalonic acid is lost, indicating that the sequential dehydrogenation is stereospecific and in the same sense at each step.

Binding Sites↗
PubMed1992

Isopentenoid synthesis in isolated embryonic Drosophila cells: absolute, basal mevalonate synthesis rate determination.

Embryonic Drosophila cells (Kc cells) and [5-3H]mevalonate (less than or equal to 10 microM) were used to determine the absolute basal in vivo rate of total mevalonic acid synthesis/utilization. An absolute in vivo mevalonic acid synthesis rate of 0.69 nmol/h/mg total cell protein was measured. Absolute mevalonate utilization was obtained by correcting for the extent of endogenous dilution of exogenous [3H]mevalonate at isotopic equilibrium. Cellular [3H]farnesol specific radioactivity was used as representative of a rapidly turning over isopentenoid pool. Although our previous Kc cell study (Havel, C. M., Rector, E. R. II, Watson, J. A., 1986, J. Biol. Chem. 261, 10,150-10,156) demonstrated that greater than or equal to 40% of the metabolized [3H]mevalonate appeared as 3H-labeled media water, this report established that t,t-3,7,11-[3H]trimethyl-2,6,10-dodecatriene-1,12 dioic acid was also secreted. Media accumulation of the C15-alpha,omega-prenyl dioic acid and 3H2O was related directly to [3H]mevalonic acid availability. This is the first mevalonate carbon balance study reported for a eukaryotic organism. It was concluded that (i) Kc cells synthesized more mevalonate than needed for normal growth and essential isopentenoids and (ii) excess mevalonate carbon accumulated intra- and extracellularly as isopentenoid compounds distal to C5 products. Finally, this study emphasized the need to measure total mevalonate utilization and not mevalonate conversion to a single isopentenoid end product in carbon balance investigations.

Animals↗
PubMed1967

Biosynthesis of the prenyl side chains of plastoquinone and related compounds in maize and barley shoots.

The incorporation of (14)C by etiolated maize and barley shoots exposed to light of (14)CO(2) and [2-(14)C]mevalonic acid into phylloquinone, plastoquinone, ubiquinone, alpha-tocopherolquinone and alpha-tocopherol was examined. In maize (the principal tissue studied) it was demonstrated that (14)C from [2-(14)C]mevalonic acid is incorporated into phylloquinone, plastoquinone and ubiquinone. alpha-Tocopherol and alpha-tocopherolquinone, although undoubtedly labelled from this substrate, were not purified completely. As expected, (14)C from (14)CO(2) was incorporated into all components examined. Ozonolytic degradation studies showed that (14)C from [2-(14)C]mevalonic acid was incorporated specifically into the prenyl side chains of plastoquinone and ubiquinone, and from this it was inferred that mevalonic acid can be regarded as the specific distal precursor to the prenyl portions of all terpenoid quinones occurring in plant tissues. From a comparison of the relative incorporation of (14)C from (14)CO(2) and [2-(14)C]mevalonic acid into the intra- and extra-chloroplastidic terpenoids evidence was obtained consistent with the tenet that the prenyl portions of the chloroplastidic quinones phylloquinone and plastoquinone, along with beta-carotene, are biosynthesized within the confines of the chloroplast, the side chain of the extraplastidic ubiquinone and phytosterols being synthesized elsewhere within the cell. The results obtained for the incorporation of (14)C from (14)CO(2) and [2-(14)C]mevalonic acid into alpha-tocopherol and alpha-tocopherolquinone were not readily interpretable with regard to the site of synthesis of these compounds.

Carbon Dioxide↗
PubMed1997

Optimization of the culture medium for growth and the kinetics of lactate fermentation by Pediococcus sp. ISK-1.

The growth of a newly isolated strain of Pediococcus sp., designated ISK-1, was very slow and the concentration of cells in the medium remained low. Fermentation with an initial 30 g/liter glucose required about 60 h. To stimulate fermentation, we attempted to optimize the medium by flask culture and jar fermentation tests. Mevalonic acid and mieki (soy bean hydrolyzate) stimulated fermentation and increased the rate of formation of DL-lactate. Kinetic analysis of the fermentation showed that mevalonic acid markedly increased the specific glucose consumption rate and the specific lactate production rate. Mieki and mevalonic acid had a synergistic effect, but the effect of mevalonic acid was different from that of mieki.

Cell Division↗