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PubMed1988

Physiological aspects and mechanism of action of mevalonate 5-diphosphate decarboxylase.

1. This work reviews the present knowledge of the physiological role and mechanism of action of mevalonate 5-diphosphate decarboxylase, the third enzyme involved in the biosynthesis of cholesterol from mevalonic acid. 2. Published evidence indicates that this and other enzymes of the cholesterol biosynthetic pathway present coordinate fluctuations in activity in rat liver. A possible regulatory role for the brain decarboxylases from chicken and rat has been proposed. 3. From kinetic and stereochemical studies with the chicken liver enzyme it has been proposed that the reaction is initiated by the abstraction of a proton from the 3-hydroxyl group of mevalonate 5-diphosphate by a basic group in the enzyme, followed by the nucleophilic attack of the C-3 oxygen on P gamma of the lambda isomer of the beta, gamma bidentate MgATP2- in a SN2(P) reaction that goes with inversion of configuration at P.

Animals↗
PubMed1982

Isolation of an inhibitor of hepatic cholesterolgenesis from human milk.

Two preparations active in reducing hepatic cholesterolgenesis in vitro were demonstrated in human milk. These appear to affect the cholesterol synthetic pathway at different loci. One inhibits the synthesis before the formation of mevalonic acid and has been isolated and subsequently identified as uric acid. The other inhibitor has yet to be identified. The apparent paradox of the active component being uric acid, of which high levels are known to cause gout, is discussed.

Animals↗
PubMed1983

Overproduction of a Mr 92,000 protomer of 3-hydroxy-3-methylglutaryl-coenzyme A reductase in compactin-resistant C100 cells.

We describe a cell line, designated C100, that displays a 100-fold increase in the major regulatory enzyme of the cholesterol biosynthetic pathway, 3-hydroxy-3-methylglutaryl-coenzyme A reductase [HMG-CoA; mevalonate:NADP(+) oxido-reductase (CoA-acylating), EC 1.1.1.34]. Immunoprecipitation of [(35)S]methionine-labeled enzyme from C100 microsomal membranes prepared in the presence of the protease inhibitors phenyl-methylsulfonyl fluoride and leupeptin revealed two up regulated proteins: a major band of M(r) 92,000 and a minor band of M(r) 63,000. We conclude that the M(r) 92,000 protein is probably the intact form of HMG-CoA reductase protomer based on the following criteria. (i) It is a highly up regulated microsomal membrane protein that coincides with the increase in HMG-CoA reductase specific activity in this cell line. (ii) It is recognized by a specific HMG-CoA reductase antiserum under a variety of stringencies. (iii) Isolation and solubilization of [(35)S]methionine-labeled C100 microsomal membranes in the absence of protease inhibitors resulted in the disappearance of the M(r) 92,000 protein and the appearance of two proteins of M(r) 52,000 and 38,000. (iv) Analysis of cells labeled for 30 min with [(35)S]methionine, well under the half-life of HMG-CoA reductase, revealed only the M(r) 92,000 protein to be present in total cell extract. (v) The previously reported single immunoprecipitation polypeptide for HMG-CoA reductase of M(r) 62,000 [Chin, D. J., Luskey, K. L., Anderson, R. G. W., Faust, J. R., Goldstein, J. L. & Brown, M. S. (1982) Proc. Natl. Acad. Sci. USA 79, 1185-1189] can be isolated and appears to be the result of both proteolysis and sample preparation for NaDodSO(4) gel electrophoresis. Analysis of C100 cells labeled with [(35)S]methionine for 24 hr indicates that the predominant steady-state form of the enzyme is the M(r) 92,000, rather than the M(r) 63,000, protein, further suggesting that the two proteins do not have a classical precursor-product relationship.

Animals↗
PubMed1987

New developments in lipid-lowering therapy: the role of inhibitors of hydroxymethylglutaryl-coenzyme A reductase.

HMG-CoA reductase catalyzes the conversion of hydroxymethylglutarate to mevalonate, an important early rate-limiting step in the cholesterol biosynthesis pathway. Since the discovery of compactin, the first HMG-CoA reductase inhibitor, by Endo et al. in 1976, several other inhibitors have been described. Those that have been investigated in the clinic include mevastatin (compactin), lovastatin (mevinolin), simvastatin (synvinolin), eptastatin (CS-514, SQ-31,000), and SRI-62320. These compounds are competitive inhibitors, with Ki values of the hydroxyacid forms of around 10(-9) M. Lovastatin (mevinolin, Mevacor), which is in the late stages of clinical development and has been administered to over 1000 subjects for up to 4 years, is the inhibitor on which the most information is available. It is given in single or divided doses of 20 to 80 mg/day, and is a very effective and usually well-tolerated lipid-lowering agent. At 40 mg bid, lovastatin produces the following approximate mean changes: total plasma cholesterol, -33%; low-density lipoprotein (LDL) cholesterol, -40%; very low-density lipoprotein cholesterol, -35%; plasma triglycerides, -25%; high-density lipoprotein cholesterol, +10%; apolipoprotein B, -20%. The substantial reduction in both LDL cholesterol and apolipoprotein B (the principal protein component of LDL) indicates a reduction in the number of circulating LDL particles. The mechanism probably involves both decreased LDL production and increased LDL clearance.

Animals↗
PubMed1999

Effect of simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, on alpha-fetoprotein gene expression through interaction with the ras-mediated pathway.

BACKGROUND/AIMS: The ras proto-oncogene encodes a small GTP-binding protein (Ras) which regulates cell growth and differentiation by relaying signals from the cell surface to the nucleus. In the present study, the role of Ras signal transduction pathway in alpha-fetoprotein (AFP) gene expression was evaluated in HuH-7 human hepatoma cells using simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, which blocks Ras function through inhibition of farnesylation, and the ras(val-12) expression vector. METHODS: The HuH-7 cells were treated with simvastatin (10 micromol/l), or both simvastatin and mevalonate (300 micromol/l), and numbers of viable cells were counted after treatment. To elucidate the effects of simvastatin on AFP gene expression and the interactive effect of simvastatin on Ras signal transduction pathway, Northern blotting and transient chloramphenicol acetyltransferase plasmid transfection assays were performed. RESULTS: Cell growth was inhibited by simvastatin, and this growth inhibition was restored by addition of mevalonate. Levels of AFP mRNA but not albumin mRNA were elevated by simvastatin in a dose-dependent manner (1-10 micromol/l). AFP promoter and enhancer activities were stimulated by simvastatin. In contrast, both activities were repressed by transfection with the ras(val-12) expression vector. The ras(val-12)-mediated repression was restored by simvastatin and returned to the repressed level by simvastatin plus mevalonate. CONCLUSIONS: These results indicate that the Ras signal transduction pathway functions to down-regulate the AFP gene transcription in human hepatoma cells.

Carcinoma, Hepatocellular↗
PubMed2003

Mortalin-MPD (mevalonate pyrophosphate decarboxylase) interactions and their role in control of cellular proliferation.

Mortalin (mot-2/GRP75/PBP74/mthsp70) is a member of the hsp70 family of proteins and is differentially distributed in normal and immortal cells. It was shown to be involved in pathways to cell senescence and immortalization. To elucidate its functional aspects, a yeast interactive screen for mortalin (mot-2) binding proteins was performed. Mevalonate pyrophosphate decarboxylase (MPD) was identified as one of the mortalin binding partners. The interactions were confirmed in mammalian cells by two-hybrid assay and in vivo coimmunoprecipitation. MPD is known to furnish prenyl groups required for prenylation, protein modification that is essential for the activity of many proteins including p21(Ras) (Ras). We have examined the effect of MPD-mot-2 interactions on the level and activity of p21(Ras) and its downstream effectors, p44 and p42 MAP kinases (ERK1/ERK2), in Ras-Raf pathway. An overexpression of mot-2 resulted in reduced level of Ras and phosphorylated ERK2. These were rescued by co-expression of MPD from an exogenous promoter demonstrating a functional link between mot-2, MPD, and Ras. Ras and its oncogenic forms act as key players in controlling proliferation of normal and cancerous cells. Assigning mot-2 upstream of p21(Ras) offers an important mechanism for influence over cell proliferation.

Animals↗
PubMed1996

Farnesyl analogues inhibit vasoconstriction in animal and human arteries.

Recent studies have suggested that nonsterol, mevalonate-derived metabolites are implicated in the control of vascular tone and blood pressure. Because of the metabolic importance of farnesyl pyrophosphate, a 15-carbon (C15) intermediate of the cholesterol pathway, the vasoactive properties of the farnesyl motif were investigated. Two farnesyl analogues were used: farnesol, the natural dephosphorylated form of farnesyl pyrophosphate, and N-acetyl-S-trans,trans-farnesyl-L-cysteine (AFC), a synthetic mimic of the carboxyl terminus of farnesylated proteins. Both compounds inhibited NE-induced vasoconstriction in rat aortic rings at micromolar concentration. Their action was rapid, dose dependent, and reversible. Shorter (C10) and longer (C20) isoprenols as well as N-acetyl-S-geranyl-L-cysteine (C10) did not inhibit the response to NE. In contrast, N-acetyl-S-geranylgeranyl-L-cysteine (C20), exhibited vasoactive properties similar to AFC. It was further demonstrated that AFC and farnesol inhibited KCl and NaF-induced contractions, suggesting a complex action on Ca2+ channels and G protein-dependent pathways. Finally, the effect of farnesol and AFC on the NE response was reproduced in human resistance arteries. In conclusion, mevalonate-derived farnesyl analogues are potent inhibitors of vasoconstriction. The study suggests that farnesyl cellular availability is an important determinant of vascular tone in animals and humans, and provides a basis for exploring farnesyl metabolism in humans with compromised vascular function as well as for using farnesyl analogues as regulators of arterial tone in vivo.

Animals↗
PubMed1989

Role of mevalonic acid in the regulation of natural killer cell cytotoxicity.

Considerable evidence has accumulated for a role of a nonsteroidal mevalonate product in the regulation of DNA replication and cell division. We report here a similar requirement for mevalonate in a nonreplicative function, that of natural killer (NK) cell cytotoxicity. Treatment of NK cells with 10 microM compactin for 48 hr results in a significant inhibition of cytotoxicity which can be completely reversed by treatment with 1 mM mevalonate, but not cholesterol, dolichol, or isopentenyl adenine. Protein and RNA synthesis appear to be involved in this reversal. Treatment with compactin and reversal with mevalonate do not affect the phenotypic distribution of the effector cell population, and the cell type involved in the inhibition and reversal of cytotoxicity is a CD16 (Leu 11)-, Leu 19-positive, large granular lymphocyte. The conjugation of the target and effector cell early in the lytic pathway is inhibited by compactin treatment of the effector cell population, and this inhibition is reversed by mevalonate.

Cell Line↗
PubMed1984

A possible regulatory role of squalene epoxidase in Chinese hamster ovary cells.

Growth of Chinese Hamster Ovary (CHO) cells in the presence of 20% lipid depleted serum (LDS) for only 2 hr results in an increase in the synthesis of [14C]sterols from [14C]mevalonate and from [14C]squalene compared with cells grown under normal growth conditions in the presence of 10% fetal calf serum (FCS). This enhanced sterol synthesis increases with time of exposure of the cells to LDS. However, exposing these cells for time periods up to 42.5 hr to a growth medium containing 20% LDS did not result in enhanced [14C]sterol synthesis from [14C]2,3-oxidosqualene. Incubation of these cells with [14C]mevalonate resulted in the accumulation of [14C]squalene regardless of the presence of either LDS or FCS. These results suggest that squalene epoxidase is a regulatory enzyme in the cholesterol biosynthetic pathway in CHO.

Animals↗
PubMed2001

The pathway of biosynthesis of abscisic acid in vascular plants: a review of the present state of knowledge of ABA biosynthesis.

The pathway of biosynthesis of abscisic acid (ABA) can be considered to comprise three stages: (i) early reactions in which small phosphorylated intermediates are assembled as precursors of (ii) intermediate reactions which begin with the formation of the uncyclized C40 carotenoid phytoene and end with the cleavage of 9'-cis-neoxanthin (iii) to form xanthoxal, the C15 skeleton of ABA. The final phase comprising C15 intermediates is not yet completely defined, but the evidence suggests that xanthoxal is first oxidized to xanthoxic acid by a molybdenum-containing aldehyde oxidase and this is defective in the aba3 mutant of Arabidopsis and present in a 1-fold acetone precipitate of bean leaf proteins. This oxidation precludes the involvement of AB-aldehyde as an intermediate. The oxidation of the 4'-hydroxyl group to the ketone and the isomerization of the 1',2'-epoxy group to the 1'-hydroxy-2'-ene may be brought about by one enzyme which is defective in the aba2 mutant and is present in the 3-fold acetone fraction of bean leaves. Isopentenyl diphosphate (IPP) is now known to be derived by the pyruvate-triose (Methyl Erythritol Phosphate, MEP) pathway in chloroplasts. (14C)IPP is incorporated into ABA by washed, intact chloroplasts of spinach leaves, but (14C)mevalonate is not, consequently, all three phases of biosynthesis of ABA occur within chloroplasts. The incorporation of labelled mevalonate into ABA by avocado fruit and orange peel is interpreted as uptake of IPP made in the cytoplasm, where it is the normal precursor of sterols, and incorporated into carotenoids after uptake by a carrier in the chloroplast envelope. An alternative bypass pathway becomes more important in aldehyde oxidase mutants, which may explain why so many wilty mutants have been found with this defect. The C-1 alcohol group is oxidized, possibly by a mono-oxygenase, to give the C-1 carboxyl of ABA. The 2-cis double bond of ABA is essential for its biological activity but it is not known how the relevant trans bond in neoxanthin is isomerized.

Abscisic Acid↗
PubMed1998

A sterol biosynthetic pathway in Mycobacterium.

The genome sequence of Mycobacterium tuberculosis (and also M. leprae) revealed a significant number of homologies to Saccharomyces cerevisiae sterol biosynthetic enzymes. We addressed the hypothesis of a potential sterol biosynthetic pathway existing in Mycobacterium using cultures of Mycobacterum smegmatis. Non-saponifiable lipid extracts subjected to analysis by gas chromatography-mass spectrometry (GC-MS) showed cholesterol was present. Sterol synthesis by M. smegmatis was confirmed using 14C-radiolabelled mevalonic acid and incorporation into C4-desmethyl sterol co-migrating with authentic cholesterol on TLC. The sterol biosynthetic pathway has provided a rich source of targets for commercially important bioactive molecules and such agents represent new opportunities for Mycobacteria chemotherapy.

Cholesterol↗
PubMed2000

Molecular cloning and expression analysis of the mevalonate kinase gene from Arabidopsis thaliana.

Mevalonate kinase (MVK), the enzyme that catalyzes the phosphorylation of mevalonate to produce mevalonate 5-phosphate, is considered as a potential regulatory enzyme of the isoprenoid biosynthetic pathway. The Arabidopsis thaliana MVK gene corresponding to the MVK cDNA previously isolated has been cloned and characterized. RNAse protection analysis indicated that the expression of the MVK gene generates three mRNA populations with 5' ends mapping 203, 254 and 355 nt upstream of the MVK ATG start codon. Northern blot analysis showed that the MVK mRNA accumulates preferentially in roots and influorescences. Histochemical analysis, with transgenic A. thaliana plants containing a translational fusion of a 1.8 kb fragment of the 5' region of the MVK gene to the beta-glucuronidase (GUS) reporter gene, indicated that the MVK 5'-flanking region directs widespread expression of the GUS gene throughout development, although the highest levels of GUS activity are detected in roots (meristematic region) and flowers (sepals, petals, anthers, style and stigmatic papillae). The expression pattern of the MVK gene suggests that the role of the encoded MVK is the production of a general pool of mevalonate-5-phosphate for the synthesis of different classes of isoprenoids involved in both basic and specialized plant cell functions. Functional promoter deletion analysis in transfected A. thaliana protoplasts indicated that regulatory elements between positions -295 and -194 of the MVK 5'-flanking region are crucial for high-level MVK gene expression.

Amino Acid Sequence↗
PubMed1976

A novel pathway for the synthesis of solanidine in the isolated chloroplast from greening potatoes.

Synthesis of chlorophyll always preceded the synthesis of solanine in cold-stored potatoes in the presence of dim light (30--40 lux). Isolated chloroplasts from green peelings were able to fix CO2. The evidence obtained showed a direct reduction of CO2 to formate, which was the primary product of fixation. Apart from this the chloroplasts were capable of incorporating NaH14CO3, [14C]formate, [2-14/C]glycine, [2-14C]pyruvate, [2-14C]acetate, [2-14C]mevalonate and [U-14C]serine into the solanidine moiety of the alkaloid. The intermediates in the pathway between CO2 and acetate have been identified as formate, glycine, serine and pyruvate. The localization of the enzymes involved in the reaction sequence viz. serine hydroxymethyl-transferase, and pyruvic dehydrogenase complex, in the isolated chloroplast has been established.

Chlorophyll↗
PubMed2005

Induction of macrophage elastase (MMP-12) gene expression by statins.

The statins (including mevastatin and lovastatin) are a widely prescribed class of serum-cholesterol lowering drugs that function by inhibiting 3-hydroxymethylglutaryl coenzyme A (HMG CoA) reductase activity and cellular sterol synthesis. Statins are also widely being appreciated for their inhibitory effects upon inflammation, primarily mediated through direct regulation of inflammatory gene expression. Here we report that statins are also capable of increasing the expression of macrophage elastase (MMP-12). The induction of MMP-12 in mouse macrophages by statins is specific for HMG CoA reductase inhibition, rescued by mevalonate and not observed after inhibition of subsequent steps in the cholesterol biosynthetic pathway. Modulation of cholesterol metabolism may lead to changes in MMP-12 expression and subsequent impacts during physiological and pathophysiological states. We conclude that statins, in addition to their previously described anti-inflammatory properties, may promote the production of some proteinases from activated macrophages.

Animals↗
PubMed1999

Identification of a mutation cluster in mevalonate kinase deficiency, including a new mutation in a patient of Mennonite ancestry.

Mevalonate kinase (MKase) deficiency (MKD) is a rare autosomal recessive disorder in the pathway of cholesterol and nonsterol isoprenoid biosynthesis. Thus far, two disease-causing missense alleles have been identified, N301T and A334T. We report four additional mutations associated with MKD: L264F, T243I, L265P, and I268T, the last found in a patient of Mennonite ancestry. Electrophoretic analysis of bacterially expressed wild-type and mutant MKase indicated that I268T and T243I mutants produced normal or somewhat reduced amounts of MKase protein; conversely, L264F and L265P mutations resulted in considerably decreased, or absent, MKase protein. Immunoblot analysis of MKase from all patients suggested that the MKase polypeptide was grossly intact and produced in amounts comparable to control levels. Three mutations resulted in significantly diminished MKase enzyme activity (<2%), whereas the I268T allele yielded approximately 20% residual enzyme activity. Our results should allow more-accurate identification of carriers and indicate a mutation "cluster" within amino acids 240-270 of the mature MKase polypeptide.

Alleles↗
PubMed1989

Genetic and pharmacological suppression of oncogenic mutations in ras genes of yeast and humans.

The activity of an oncoprotein and the secretion of a pheromone can be affected by an unusual protein modification. Specifically, posttranslational modification of yeast a-factor and Ras protein requires an intermediate of the cholesterol biosynthetic pathway. This modification is apparently essential for biological activity. Studies of yeast mutants blocked in sterol biosynthesis demonstrated that the membrane association and biological activation of the yeast Ras2 protein require mevalonate, a precursor of sterols and other isoprenes such as farnesyl pyrophosphate. Furthermore, drugs that inhibit mevalonate biosynthesis blocked the in vivo action of oncogenic derivatives of human Ras protein in the Xenopus oocyte assay. The same drugs and mutations also prevented the posttranslational processing and secretion of yeast a-factor, a peptide that is farnesylated. Thus, the mevalonate requirement for Ras activation may indicate that attachment of a mevalonate-derived (isoprenoid) moiety to Ras proteins is necessary for membrane association and biological function. These observations establish a connection between the cholesterol biosynthetic pathway and transformation by the ras oncogene and offer a novel pharmacological approach to investigating, and possibly controlling, ras-mediated malignant transformations.

Amino Acid Sequence↗