Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Mevalonate pathway”

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 883 records · Page 49Linked to original sources
PubMed2002

Isoprenoid biosynthesis in Synechocystis sp. strain PCC6803 is stimulated by compounds of the pentose phosphate cycle but not by pyruvate or deoxyxylulose-5-phosphate.

The photosynthetic cyanobacterium Synechocystis sp. strain PCC6803 possesses homologs of known genes of the non-mevalonate 2-C-methyl-D-erythritol 2-phosphate (MEP) pathway for synthesis of isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). Isoprenoid biosynthesis in extracts of this cyanobacterium, measured by incorporation of radiolabeled IPP, was not stimulated by pyruvate, an initial substrate of the MEP pathway in Escherichia coli, or by deoxyxylulose-5-phosphate, the first pathway intermediate in E. coli. However, high rates of IPP incorporation were obtained with addition of dihydroxyacetone phosphate (DHAP) and glyceraldehyde 3-phosphate (GA3P), as well as a variety of pentose phosphate cycle compounds. Fosmidomycin (at 1 micro M and 1 mM), an inhibitor of deoxyxylulose-5-phosphate reductoisomerase, did not significantly inhibit phototrophic growth of the cyanobacterium, nor did it affect [(14)C]IPP incorporation stimulated by DHAP plus GA3P. To date, it has not been possible to unequivocally demonstrate IPP isomerase activity in this cyanobacterium. The combined results suggest that the MEP pathway, as described for E. coli, is not the primary path by which isoprenoids are synthesized under photosynthetic conditions in Synechocystis sp. strain PCC6803. Our data support alternative routes of entry of pentose phosphate cycle substrates derived from photosynthesis.

Carbon Radioisotopes↗
PubMed2001

Molecular characterization of Hmg2 gene encoding a 3-hydroxy-methylglutaryl-CoA reductase in rice.

Three genes encoding 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR, EC1.1.1.34), which converts HMG-CoA into mevalonate in the early key step of the plant isoprenoid pathway, were isolated by RT-PCR and rice cDNA and genomic library screening. A genomic Southern blot analysis confirmed that HMGR genes are present in three copies in rice. Of the three, the HMGR 2 gene (Hmg2) obtained as a cDNA clone and its genomic clone had 4 exons and 3 introns, and encoded a 576 amino acid peptide containing an open reading frame of 1,728 bp with a calculated Mw. of 61,150. The structure of rice Hmg2 had common features, based on its nucleotide and deduced amino acid sequence homologies, with other plant HMGR genes published to date. Rice Hmg2 transcripts were constitutively detected in all parts of the rice plant, except in lamina and their levels were high particularly in the leaf part of the dark-grown seedlings and mature flowers. Our result showed that mRNA levels of rice Hmg2 were strongly induced in seedlings and influorescence in the early development stage. Rice Hmg2 possibly has a housekeeping role involved in the sterol biosynthesis, among the possible roles of plant HMGR genes that have been suggested in other plants [Weissenborn et al. (1995)].

Amino Acid Sequence↗
PubMed1999

The Arabidopsis dwf7/ste1 mutant is defective in the delta7 sterol C-5 desaturation step leading to brassinosteroid biosynthesis.

Lesions in brassinosteroid (BR) biosynthetic genes result in characteristic dwarf phenotypes in plants. Understanding the regulation of BR biosynthesis demands continued isolation and characterization of mutants corresponding to the genes involved in BR biosynthesis. Here, we present analysis of a novel BR biosynthetic locus, dwarf7 (dwf7). Feeding studies with BR biosynthetic intermediates and analysis of endogenous levels of BR and sterol biosynthetic intermediates indicate that the defective step in dwf7-1 resides before the production of 24-methylenecholesterol in the sterol biosynthetic pathway. Furthermore, results from feeding studies with 13C-labeled mevalonic acid and compactin show that the defective step is specifically the Delta7 sterol C-5 desaturation, suggesting that dwf7 is an allele of the previously cloned STEROL1 (STE1) gene. Sequencing of the STE1 locus in two dwf7 mutants revealed premature stop codons in the first (dwf7-2) and the third (dwf7-1) exons. Thus, the reduction of BRs in dwf7 is due to a shortage of substrate sterols and is the direct cause of the dwarf phenotype in dwf7.

Alleles↗
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

HMG-CoA reductase inhibition and PPAR- alpha activation both inhibit cyclosporin A induced endothelin-1 secretion in cultured endothelial cells.

The use of cyclosporin A (CsA) in solid organ transplantation has been shown to be associated with the development of hypertension and nephrotoxicity. Several mechanisms, including endothelin (ET)-1-mediated systemic vasoconstriction, are considered to be responsible for CsA-induced hypertension. This study shows that: (i) incubation of CsA (1 microg) with bovine aortic endothelial cells leads to increased ET secretion by+40%; (ii) the use of compactin, the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor and fibric acid, the peroxisome-proliferator-activated receptor (PPAR)-alpha activator, inhibit the CsA-induced ET secretion to the level below the basal ET secretion, by -32% and -26% respectively; (iii) both inhibitions were reversed by the addition of mevalonate, suggesting communication between the HMG-CoA reductase product and PPAR-alpha pathway. The present findings may be of significant clinical relevance, since statins and fibrates beyond their hypolipidaemic action may represent a potential therapeutic tool in the treatment or prophylaxis of CsA-associated side effects. Furthermore, we suggest that the mevalonate metabolism would interfere with PPAR-alpha activity.

Animals↗
PubMed2004

The MEP pathway: a new target for the development of herbicides, antibiotics and antimalarial drugs.

Isoprenoids, a diverse group of compounds derived from the five-carbon building units isopentenyl diphosphate (IPP) and its isomer dimethylallyl diphosphate (DMAPP), are essential for survival in all organisms. Animals synthesize their isoprenoids from mevalonic acid (MVA), whereas most pathogenic bacteria and the malaria parasites utilize a completely different pathway for IPP and DMAPP synthesis, the methylerythritol phosphate (MEP) pathway. Plants use both pathways for the synthesis of isoprenoid precursors. The recent elucidation of the MEP pathway has opened the possibility to develop new strategies against microbial pathogens. Novel immunotherapeutic agents can be developed based on the MEP pathway intermediates known to activate the proliferation of human V-delta-9 V-gamma-2 T-cells after infection by many pathogenic bacteria and protozoa. Moreover, the design of specific inhibitors of MEP pathway enzymes (which are highly conserved but show no homology to mammalian proteins) should result in herbicides and drugs with broad-spectrum antimicrobial activity without mechanism-based toxicity to humans. A good example is the cure of bacterial infections and malaria with fosmidomycin, a highly stable inhibitor of the MEP pathway. The use of plants as test systems has led to the identification of additional inhibitors such as ketoclomazone. Biochemical, genetic and crystallographic approaches with the MEP pathway enzymes are now starting to characterize the inhibition kinetics and identify which residues play a structural or catalytic role. Current efforts should eventually contribute to an effective drug designed to fight against microbial pathogens that show resistance to currently available agents.

Anti-Bacterial Agents↗
PubMed1992

Fibric acid derivatives: effects on the synthesis of isoprenoid lipids in cultured human lymphocytes.

Fibric acid derivatives have been demonstrated to reduce circulating lipoprotein and triacylglycerol concentrations and to inhibit hydroxymethylglutaryl CoA reductase, a key regulatory enzyme of cholesterol biosynthesis. This study describes the effect of four fibric acid derivatives on the biosynthesis of isoprenoid products from acetate and mevalonate in Molt-4 cells, a human leukemic T-lymphocyte cell line. The isoprenoids analyzed were cholesterol as well as dolichol and ubiquinone, alternative products of the branched isoprenoid biosynthetic pathway. None of the fibric acid derivatives showed significant effects on the synthesis of cholesterol from acetate or mevalonate and there was little change in the flux of these metabolites into either dolichol and ubiquinone compared to cells grown in drug-free medium. Therefore, in contrast to the reported inhibitory effects of fibric acids on hepatic sterol synthesis in rats and humans and on hydroxymethylglutaryl CoA reductase activity in human nonmalignant lymphocytes, our results show that these drugs do not significantly affect any of the post-reductase enzymes in the branched metabolic pathways leading from acetate to dolichol, ubiquinone and cholesterol in short term culturing of human malignant lymphocytes.

Acetates↗
PubMedDate not supplied

Ubiquinone synthesis by Pneumocystis carinii: incorporation of radiolabeled polyprenyl chain and benzoquinone ring precursors.

Radiolabeled mevalonic acid was incorporated in vitro into Pneumocystis carinii ubiquinone homologs, CoQ9 and CoQ10, demonstrating the isoprenoid branch pathway forming the polyprenyl chain of ubiquinone is functional in the organism. Radiolabeled shikimic acid, tyrosine and p-hydroxybenzoic acid were also incorporated into the two ubiquinone homologs, indicating that P. carinii also possessed the biochemical pathway for de novo synthesis of the CoQ benzoquinone ring.

Coenzymes↗
PubMed1984

Isolation and characterization of yeast mutants blocked in mevalonic acid formation.

Yeast mutants defective in beta-hydroxy-beta-methylglutaryl-CoA synthase and acetoacetyl-CoA thiolase have been isolated. Mutants impaired in acetoacetyl-CoA thiolase range into two linked complementation units, erg 10 A and erg 10 B. Mutants deficient in beta-hydroxy-beta-methylglutaryl-CoA synthase belong to two unlinked complementation groups, erg 11 and erg 13. In strictly anaerobic growth conditions, mutants impaired in beta-hydroxy-beta-methylglutaryl-CoA synthase require mevalonic acid in addition to sterol and oleic acid, pointing out the role of mevalonic acid in other physiological function than ergosterol precursor. Growth of mutants impaired in acetoacetyl-CoA thiolase cannot be recovered by mevalonic acid supplementation, suggesting a role of acetoacetyl-CoA or thiolase not linked to sterol pathway.

Acetyl-CoA C-Acetyltransferase↗
PubMed1996

Regulation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase degradation by the nonsterol mevalonate metabolite farnesol in vivo.

We have previously reported that degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, the rate-limiting enzyme in the isoprenoid pathway leading to cholesterol production, can be accelerated in cultured cells by the addition of farnesyl compounds, which are thought to mimic a natural, nonsterol mevalonate metabolite(s). In this paper we report accelerated reductase degradation by the addition of farnesol, a natural product of mevalonate metabolism, to intact cells. We demonstrate that this regulation is physiologically meaningful, shown by its blockage by several inhibitory conditions that are known to block the degradation induced by mevalonate addition. We further show that intracellular farnesol levels increase significantly after mevalonate addition. Based on these results, we conclude that farnesol is a nonsterol, mevalonate-derived product that plays a role in accelerated reductase degradation. Our conclusion is in agreement with a previous report (Correll, C. C., Ng, L., and Edwards, P. A. (1994) J. Biol. Chem. 269, 17390-17393), in which an in vitro system was used to study the effect of farnesol on reductase degradation. However, the apparent stimulation of degradation in vitro appears to be due to nonphysiological processes. Our findings demonstrate that in vitro, farnesol causes reductase to become detergent insoluble and thus lost from immunoprecipitation experiments, yielding apparent degradation. We further show that another resident endoplasmic reticulum protein, calnexin, similarly gives the appearance of protein degradation after farnesol addition in vitro. However, after the addition of farnesol to cells in vivo, calnexin remains stable, whereas reductase is degraded, providing further evidence that the in vivo effects of farnesol are physiologically meaningful and specific for reductase, whereas the in vitro effects are not.

Animals↗
PubMed1988

Discovery, biochemistry and biology of lovastatin.

Cholesterol is a 27-carbon steroid that is an essential component of the cell membrane, the immediate precursor of steroid hormones, the substrate for the formation of bile acids, and is required for the assembly of very low density lipoprotein in the liver. Because as much as two-thirds of total body cholesterol in patients is of endogenous origin, an effective means to control cholesterogenesis may occur by inhibition of its biosynthesis. Cholesterol is biosynthesized in a series of more than 25 separate enzymatic reactions that initially involve the formation of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA). Early attempts to pharmacologically block cholesterol synthesis focused only on steps later in the biosynthetic pathway and resulted in compounds with unacceptable toxicity. Recent research had identified that HMG CoA reductase is a key rate-limiting enzyme in this pathway and is responsible for the conversion of HMG CoA to mevalonate. Additional research with fungal metabolites identified a series of compounds with potent inhibiting properties for this target enzyme, from which lovastatin was selected for clinical development. A reduction in cholesterol synthesis by lovastatin has been subsequently confirmed in cell culture, animal studies and in humans. A resultant decrease in circulating total and low-density lipoprotein (LDL) cholesterol has also been demonstrated in animals and humans. Because hepatic LDL receptors are the major mechanism of LDL clearance from the circulation, further animal research has confirmed that these declines in cholesterol are accompanied by an increase in hepatic LDL receptor activity. Lovastatin effectively diminishes endogenous cholesterol synthesis providing useful therapeutic properties for patients with hypercholesterolemia.

Animals↗
PubMedDate not supplied

Cholesterol metabolism and colon cancer.

While epidemiologic and concordant experimental data indicate a direct relationship between dietary fat (and presumably caloric) intake and the development of colon cancer, the effect of dietary cholesterol on this disease is still not clear. However, there appears to be a developing literature concerning an inverse relationship between serum and plasma cholesterol levels, and the risk for colon cancer. Findings that low serum cholesterol levels are apparent as early as ten years prior to the detection of colon cancer implies that sub clinical disease is probably not involved initially in this process. The possibility of low serum cholesterol as a bio-marker was considered in epidemiologic studies which focused upon obese men with lower than normal serum cholesterol levels who were found to be at increased risk to colon cancer. While the relationship between low serum cholesterol and colonic or intestinal cholesterol metabolism is presently not understood, current genetic studies provide a promising though as yet unexplored potential association. Alterations which occur during the developmental progression of colonic cancer include changes in chromosome 5, which also carries two genes vital to the biosynthesis and regulation of systemic and cellular cholesterol metabolism, 3-hydroxy-3-methylglutaryl coenzyme A synthase, and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCoA R). Regulation of cholesterol metabolism in intestinal cells in vivo and in vitro varies from that seen in normal fibroblasts or hepatocytes in terms of exogenous sources of cholesterol and how these sources regulate internal synthesis. Colonic cancer cells have been used to assess small bowel enterocyte cholesterol metabolism, which has been possible because of their ability to differentiate in culture, however information regarding true colonic enterocyte cholesterol metabolism is relatively scarce. Colonic cancer cells have been shown to possess a diminished or nonexistent ability to use low density lipoprotein to support cellular growth, unlike normal fibroblasts. Diminished low density lipoprotein (LDL) receptor (LDL-R) activity is a significant alteration in a metabolic pathway with such fundamental ties to cellular growth and activation (via mevalonate effects on isoprenylation of G-proteins for example), that it is selected for in the development of certain tumors--among them human colonic carcinomas. It would be expected that such a loss would provide a growth advantage to the tumor cell. Preliminary investigation of this hypothesis has shown that LDL will inhibit the proliferative capacity of certain human colonic adenocarcinomas, and that these cells possess a high rate of cholesterol synthesis relative to fibroblasts.(ABSTRACT TRUNCATED AT 400 WORDS)

Cholesterol↗
PubMed2006

Inhibition of mevalonate 5-diphosphate decarboxylase by fluorinated substrate analogs.

Mevalonate 5-diphosphate decarboxylase (MDD) is a peroxisomal enzyme in the cholesterol biosynthetic pathway, which plays an important role in regulating cholesterol biosynthesis. In the present study, rat MDD was cloned and purified to apparent homogeneity. Two fluorinated MDD substrate analogs, P'-geranyl 2-fluoromevalonate 5-diphosphate (4) and 2-fluoromevalonate 5-diphosphate (6), were synthesized, and both were found to be irreversible inhibitors of rat MDD. These two inhibitors were characterized, and mechanisms of the inactivation process were proposed. Kinetic studies indicate both analogs only bind into mevalonate binding-site of MDD. Compound 4 shows competitive inhibition on mevalonate kinase (MVK), and its IC(50) value was determined to be comparable with that of geranyl diphosphate. Further kinetic studies indicate compound 4 only bind into ATP binding-site of MVK. These studies provide an example for a single inhibitor to carry out sequential blocking of two enzymes in cholesterol biosynthesis, which may provide useful information for drug discovery for the purpose of treating cardiovascular disease and cancer or for pest control.

Animals↗
PubMed1991

Role of isoprenoid metabolism in IgE receptor-mediated signal transduction.

In the 2H3 subline of rat basophilic leukemia cells (RBL-2H3), IgE receptor cross-linking stimulates a signal transduction pathway that leads to the secretion of histamine, serotonin, and other inflammatory mediators; the assembly of F-actin; and the transformation of the cell surface from a microvillous to a lamellar or ruffled architecture. We report here that 20 h incubation of RBL-2H3 cells with 10 microM lovastatin, an inhibitor of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMG CoA reductase), inhibits both the secretory and morphologic responses to IgE receptor cross-linking. Ag-induced Ca2+ mobilization, determined from the influx and efflux of 45Ca2+, and Ag-induced 1,4,5-inositol trisphosphate production are also inhibited in lovastatin-treated RBL-2H3 cells. Under the same conditions, lovastatin does not alter cell proliferation or IgE receptor expression, and it causes only a small impairment of responses initiated by drugs that bypass the earliest steps in the receptor-activated transduction pathway (ionomycin-induced secretion and PMA-induced membrane ruffling). Receptor-mediated Ca2+ mobilization, secretion, and ruffling are all restored by 0.5- to 4-h incubation of lovastatin-treated cells with mevalonic acid, the product of HMG CoA reductase and the first committed intermediate of the isoprenoid biosynthetic pathway. In contrast, dolichol and cholesterol, which are synthesized from products of the isoprenoid pathway, do not restore receptor-activated responses. These data implicate an isoprenoid pathway intermediate in an early step in the IgE receptor-activated signal-transduction sequence. We postulate that this intermediate is required for a newly described post-translational modification of proteins, their post-synthetic isoprenylation. The substrates for this modification include the ras family of GTP-binding proteins and the gamma subunits of the heterotrimeric guanine nucleotide-binding protein.

Animals↗
PubMed2004

Human mevalonate pyrophosphate decarboxylase is localized in the cytosol.

In the past decade several reports have claimed that peroxisomes play a critical role in the isoprenoid/cholesterol biosynthetic pathway based on the finding of a predominant peroxisomal localization of several of the enzymes involved. Other reports, however, do not support the peroxisomal localization of these enzymes. In this study we have studied the subcellular localization of one of the enzymes, human mevalonate pyrophosphate decarboxylase, by conventional subcellular fractionation and digitonin permeabilization studies, immunofluorescence microscopy, and immunoelectron microscopy. We found a cytosolic localization for both endogenous human mevalonate pyrophosphate decarboxylase (in human fibroblasts, liver, CV1 and HEK293 cells) and overexpressed mevalonate pyrophosphate decarboxylase (in human fibroblasts, HEK293 and CV1 cells) but no indication for a peroxisomal localization. Our results do not support a central role of peroxisomes in the isoprenoid/cholesterol biosynthetic pathway.

Carboxy-Lyases↗
PubMed1994

Presqualene metabolism in two species of Lagenidium.

The fate of precursors of the isoprenoid pathway was studied in the sterol auxotroph Lagenidium giganteum and in the positive control organism Lagenidium callinectes. Acetate derived from glucose and mevalonic acid was converted to sterols and fatty acids in L. callinectes. Lagenidium giganteum converted mevalonic acid to sterols and fatty acids, but glucose-derived acetate was not utilized for sterol synthesis. The results showed that the defect in the isoprenoid pathway of L. giganteum occurs at the level of the beta-hydroxy-beta-methylglutarylcoenzyme A reductase-synthase complex. Various aspects of this defect are discussed relative to metabolism of the organism.

Acetates↗
PubMed2004

Simvastatin treatment for inflammatory attacks of the hyperimmunoglobulinemia D and periodic fever syndrome.

Hyperimmunoglobulinemia D (hyper-IgD) and periodic fever syndrome, a hereditary autoinflammatory syndrome, is characterized by lifelong recurrent episodes of fever and inflammation. No effective treatment is known. It is caused by a defect of mevalonate kinase, an enzyme that follows 3'-hydroxy-3'-methylglutaryl-coenzyme A (HMG-CoA) reductase in the isoprenoid pathway. We wanted to test the hypothesis that inhibition of HMG-CoA reductase would ameliorate the inflammatory attacks. Six patients with hyper-IgD syndrome and proven mevalonate kinase deficiency were followed up for 2 treatment periods with either simvastatin, 80 mg/d, or placebo for 24 weeks, separated by a 4-week washout period in a double-blind fashion. Simvastatin resulted in a drop in urinary mevalonic acid concentration in all patients and decreased the number of febrile days in 5 of 6 patients. No side effects were observed. These data offer preliminary evidence for the hypothesis that simvastatin may improve inflammatory attacks in the hyper-IgD syndrome. This highlights the anti-inflammatory properties of HMG-CoA reductase inhibition.

Adolescent↗
PubMed1979

Inhibition of rat liver mevalonate pyrophosphate decarboxylase and mevalonate phosphate kinase by phenyl and phenolic compounds.

1. Mevalonate pyrophosphate decarboxylase of rat liver is inhibited by various phenyl and phenolic acids. 2. Some of the phenyl and phenolic acids also inhibited mevalonate phosphate kinase. 3. Compounds with the phenyl-vinyl structure were more effective. 4. Kinetic studies showed that some of the phenolic acids compete with the substrates, mevalonate 5-phosphate and mevalonate 5-pyrophosphate, whereas others inhibit umcompetitively. 5. Dihydroxyphenyl and trihydroxyphenyl compounds and p-chlorophenoxyisobutyrate, a hypocholesterolaemic drug, had no effect on these enzymes. 6. Of the three mevalonate-metabolizing enzymes, mevalonate pyrophosphate decarboxylase has the lowest specific activity and is probably the rate-determining step in this part of the pathway.

Animals↗