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PubMed1980

Multivalent feedback regulation of HMG CoA reductase, a control mechanism coordinating isoprenoid synthesis and cell growth.

The availability of compactin (ML-236B), a potent competitive inhibitor of 3-hydroxy-3-methylglutaryl Coenzyme A reductase, has permitted the demonstration of a hitherto unsuspected aspect of mevalonate metabolism and isoprenoid synthesis in cultured mammalian cells. 3-Hydroxy-3-methylglutaryl Coenzyme A reductase, the enzyme that synthesizes mevalonate, appears to be regulated through a multivalent feedback mechanism. Full suppression of the reductase requires the presence of at least two regulators: 1) cholesterol, which is normally derived exogenously from plasma low density lipoprotein (LDL), and 2) a nonsterol product, which is normally synthesized endogenously from mevalonate. Evidence indicates that both of these regulators of the reductase may be essential for the growth of mammalian cells in culture. The multivalent feedback regulation of 3-hydroxy-3-methylglutaryl Coenzyme A reductase, together with secondary regulatory changes in other enzymes of the sterol synthetic pathway, coordinates the branched pathway of mevalonate metabolism so as to assure a constant supply of cholesterol and nonsterol products. These new findings have important implications for the understanding of isoprenoid metabolism and its relation to cell growth.

Animals↗
PubMed1997

Regulatory adaptation of isoprenoid biosynthesis and the LDL receptor pathway in fibroblasts from patients with mevalonate kinase deficiency.

In a search for the pathophysiologic mechanisms, we estimated isoprenoid synthesis and concentration, cellular growth, and the activity of the LDL receptor pathway in fibroblasts from patients with mevalonate kinase deficiency (MKD), a severe multisystemic disorder of cholesterol and non-sterol isoprenoid biosynthesis. In response to different concentrations of LDL and non-lipoprotein-bound cholesterol, MKD cells partially counteracted their enzyme defect by increased activities of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase (results from earlier studies) and the LDL receptor pathway, responses similar to the pharmacologic effects seen upon administration of HMG-CoA reductase inhibitors. Rates of N-linked protein glycosylation, estimated as the amount of [14C]galactose-labeled macromolecules secreted into cell culture medium, were significantly decreased in MKD fibroblasts in comparison with control cells which may indicate alterations in the dolichol or dolichol phosphate pool. In response to exogenous cholesterol, the major feedback inhibitor of isoprenoid biosynthesis, growth velocities of MKD fibroblasts declined in comparison with control cells, further suggesting an impairment of non-sterol isoprenoid biosynthesis in MKD. Our results suggest an imbalance in the multilevel regulation of the biosynthesis of cholesterol and non-sterol isoprenoids in MKD, representing an additional causative factor responsible for the pre- and postnatal pathology of MKD.

Adaptation, Physiological↗
PubMed1966

Conversion of mevalonic acid to gamma, gamma-dimethylallyl pyrophosphate by Mycoplasma.

Henrikson, Carl V. (University of South Dakota, Vermillion), and Paul F. Smith. Conversion of mevalonic acid to gamma,gamma-dimethylallyl pyrophosphate by Mycoplasma. J. Bacteriol. 92:701-706. 1966.-Three representative strains of Mycoplasma, M. laidlawii strain B, Mycoplasma sp. avian strain J, and M. hominis type 2 strain O7, were examined for the presence or absence of enzymes associated with the biosynthetic pathway from mevalonic acid to gamma,gamma-dimethylallyl pyrophosphate. M. laidlawii served as a control organism, since it is capable of de novo biosynthesis of carotenoids. All four enzymes, namely, adenosine triphosphate (ATP)-mevalonate 5-phosphotransferase (EC 2.7.1.36), ATP-5-phosphomevalonate phosphotransferase (EC 2.7.4.2), ATP-5-pyrophosphomevalonate carboxy-lyase (EC 4.1.1.33), and isopentenylpyrophosphate Delta(3),Delta(2)-isomerase (EC 5.3.3.2), were demonstrated in this organism. Mycoplasma sp. avian strain J, which contains all enzymes necessary for the biosynthesis of mevalonic acid, lacks the first three of the above enzymes but contains isopentenyl pyrophosphate Delta(3),Delta(2)-isomerase. M. hominis, which lacks the enzymes necessary for the biosynthesis of mevalonic acid, also is deficient in the enzymes involved in its conversion to gamma,gamma-dimethylallyl pyrophosphate.

Carbon Isotopes↗
PubMed1982

The effects of phosphate on the biosynthesis of cholesterol in rat liver homogenates.

The biosyntheses of cholesterol from acetate and mevalonate were determined in rat liver homogenates that were prepared and incubated in buffers containing varying concentrations of phosphate. Relatively little acetate or mevalonate was incorporated into cholesterol in the absence of added phosphate. When phosphate was added, there was an increase in incorporation of both substrates. The addition of phosphate resulted in an increase in the incorporation of mevalonate to a maximum, whereas phosphate appeared to increase the incorporation of acetate at low phosphate levels and decrease the incorporation at higher phosphate levels. The results appear to be consistent with the possibility that, at low phosphate levels, the biosynthesis of cholesterol is limited by some phosphate-requiring reaction(s) in the pathway after mevalonate, and at higher phosphate levels, the biosynthesis is limited by the 3-hydroxy-3-methylglutaryl coenzyme A reductase-catalyzed step.

Acetates↗
PubMed2026

High-level terpene production via a novel Actinomycetota-derived MVA pathway in E. coli.

The heterologous production of terpene in microbial hosts is often limited by inefficient and unstable pathway expression, creating a major bottleneck for industrial-scale synthesis. While E. coli as a chassis offers significant advantages, such as rapid growth, ease of cultivation, and genetic tractability. Its endogenous supply of terpenoid precursors remains a critical constraint, fundamentally restricting high-yield production. To address this challenge, we developed a genomically integrated Mevalonate (MVA) pathway from Actinomycetota in E. coli BL21(DE3) to enhance terpene precursor supply. Our approach began with an in silico multi-layer global genome mining analysis of 25,261 Actinomycetota genomes to identify a series of MVA pathway enzymes with potentially high catalytic efficiency, created a high-efficiency chassis E. coli MVA platform (ecMVA-1 and ecMVA-2) for terpene precursor synthesis. Its functionality was validated by testing eight distinct TSs. Among them, the fermentation of artemisinin precursor amorphadiene using a 5-liter bioreactor yielded 947.80 mg/L. These results indicated that E. coli (MVA) is well-suited for TS studies in the laboratory as well as holding significant promise for industrial applications. In addition, this in silico approach offers a new perspective for metabolic engineering and provides potential reservoir of diverse chassis for the industrial production of terpenoid-derived compounds.

Actinomycetota↗
PubMed2003

Lovastatin inhibits bone marrow-derived dendritic cell maturation and upregulates proinflammatory cytokine production.

Statins are a group of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors which are most effective as lipid lowering agents, and are currently extensively used clinically. Recently, it was also shown that statins affect the immune response. We investigated the effects of lovastatin on the maturation and functional changes of bone marrow-derived dendritic cells (BM-DC). Lovastatin inhibited MHC class II and CD40 expression on DC in a dose-dependent manner, but had lesser effects on CD16, CD80, CD86, and CD11b expression. Nuclear extracts of lovastatin treated DC had decreased NF-kappaB DNA binding activity. Although antigen capture capacity of DC was not affected by lovastatin, the T-cell stimulatory activity of DC was inhibited. Lovastatin up-regulated DC pro-inflammatory cytokine production induced by LPS as measured by intracellular cytokine staining, ELISA and cDNA microarrays. Mevalonate, added in vitro, prevented these effects. These results indicate that lovastatin may inhibit BM-DC maturation and up-regulate cytokine production through a mevalonate dependent pathway, and may cause adverse effects on either innate or adaptive immunity.

Animals↗
PubMed2006

Biosynthesis of mono- and sesquiterpenes in strawberry fruits and foliage: 2H labeling studies.

The biosynthesis of the monoterpene (S)-linalool and the sesquiterpene trans-(S)-nerolidol in fruits of Fragaria x ananassa Duch. cv. Eros and Florence and of the monoterpene (-)-alpha-pinene in Fragaria vesca was investigated by in vivo feeding experiments with [5,5-2H2]mevalonic acid lactone (d2-MVL) and [5,5-2H2]-1-deoxy-d-xylulose (d2-DOX). The feeding experiments indicate that (S)-linalool and trans-(S)-nerolidol in Fragaria x ananassa Duch. and (-)-alpha-pinene in F. vesca are exclusively synthesized via the cytosolic mevalonic acid pathway without any contribution from the plastidial 1-deoxy-D-xylulose/2-C-methyl-D-erythritol 4-phosphate (DOXP/MEP) route. Inhibition experiments revealed that even the presence of mevastatin, an export of plastid-derived isopentyl diphosphate/dimethylallyl diphosphate, cannot be induced. However, the enantioselective analysis shows that in Fragaria x ananassa Duch. cv. Eros and Florence both linalool enantiomers are present and that only (S)-linalool is labeled after administration of d2-MVL. Therefore, the origin of (R)-linalool in these fruits remains unknown. Contrarily, in Fragaria x ananassa Duch. foliage (R)-linalool is the dominant enantiomer. Feeding experiments revealed an incorporation of d2-MVL and d2-DOX at equal rates exclusively into (S)-linalool. Only in F. vesca foliage, where (R)-linalool is present at high enantiomeric purity (ee > 90%), is a de novo biosynthesis of the (R)-enantiomer via the DOXP/MEP pathway detectable. These results demonstrate a complex intraplant variation of (R)- and (S)-linalool biosynthesis via the cytosolic and plastidial route.

Acyclic Monoterpenes↗
PubMed1999

Differential effects of pravastatin, simvastatin, and atorvastatin on Ca2+ release and vascular reactivity.

The direct effects of the cholesterol-lowering agents, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) reductase inhibitors, on vascular smooth muscle responsiveness were examined by incubation of isolated aorta from normocholesterolemic rats with simvastatin, atorvastatin, or pravastatin. The smooth muscle contractions caused by phenylephrine were progressively inhibited with increasing concentrations of simvastatin. Similarly, atorvastatin at the higher concentration caused decreased responses to phenylephrine. In contrast, incubation with pravastatin had no significant effect at all concentrations studied. In Ca2+-free buffer, the transient contraction caused by phenylephrine, which results from intracellular release of Ca2+, also was inhibited by simvastatin and atorvastatin but not by pravastatin. In cultured rat aortic smooth muscle cells loaded with fura-2, increases in intracellular free-Ca2+ concentration ([Ca2+]i) induced by angiotensin II were markedly inhibited in cells incubated with simvastatin and atorvastatin but not pravastatin. The inhibitory effects of simvastatin and atorvastatin were reversed by mevalonate. These findings demonstrate that inhibition of HMG CoA reductase by using simvastatin and atorvastatin, but not pravastatin, has effects on vascular smooth muscle cell responsiveness that involve alteration of Ca2+ homeostasis through a mevalonate-dependent pathway.

Animals↗
PubMed2004

A high-performance liquid chromatography method for the analysis of intermediates of the deoxyxylulose phosphate pathway.

A sensitive and versatile ion pair radio high-performance liquid chromatography (HPLC) method for the investigation of the deoxyxylulose phosphate (DXP) pathway has been developed, allowing the simultaneous separation of phosphorylated, nonphosphorylated, and nucleotide moieties bearing intermediates. Moreover, this method addresses the problem of separating the isomers isopentenyl diphosphate (IDP) and dimethylallyl diphosphate (DMADP). Because the majority of the intermediates of this isoprenoid pathway lack a chromophore, the combination with an on-line radiodetector provides a highly sensitive tool for their detection. Chromoplasts isolated from Capsicum annuum and Narcissus pseudonarcissus served as model systems for the testing of the analytical procedures after the application of radiolabeled precursors. This HPLC system, which represents an improvement in analytical methods developed for the analysis of the mevalonic acid pathway, should be easily adaptable to other plant and bacterial systems and should permit further elucidation of the regulatory mechanisms that control the flow of intermediates through the DXP pathway and the coordination with related metabolic pathways. Moreover, the system can serve as an analytical tool in the screening for inhibitors of this pathway, allowing the development of new antibiotics as well as herbicides, because this pathway is absent in vertebrates.

Capsicum↗
PubMed2001

LytB, a novel gene of the 2-C-methyl-D-erythritol 4-phosphate pathway of isoprenoid biosynthesis in Escherichia coli.

The mevalonate-independent 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway for isoprenoid biosynthesis is essential in many eubacteria, plants, and the malaria parasite. Using genetically engineered Escherichia coli cells able to utilize exogenously provided mevalonate for isoprenoid biosynthesis by the mevalonate pathway we demonstrate that the lytB gene is involved in the trunk line of the MEP pathway. Cells deleted for the essential lytB gene were viable only if the medium was supplemented with mevalonate or the cells were complemented with an episomal copy of lytB.

Animals↗
PubMed1972

Development of the activities of enzymes of the isoprenoid pathway during early stages of pea-seed germination.

The activities of individual enzymes of the isoprenoid pathway from mevalonate kinase to squalene synthetase in homogenates of seeds germinated up to 32h were assayed. Changes in the activity of each enzyme were observed and compared with the activity at the 2h germination stage. Activities of alkaline phosphatase and fructose 1,6-diphosphate aldolase were similarly measured to provide a reference for changes in the general metabolic activity of seeds during imbibition of water. Water uptake reached a plateau after 12h. The reference enzymes almost doubled in activity between 2 and 8h and thereafter their activities steadily declined. All of the enzymes of the isoprenoid pathway increased in activity between 2 and 6h and, thereafter, with the exception of the prenyltransferase, their activities remained relatively constant. With the prenyltransferase activity the initial increase was followed by a short plateau between 6 and 9h and then a second increase to a maximum between 14 and 16h. After 16h the activity declined. The relative activities of the isoprenoid enzymes at 16h of germination were mevalonate kinase>phosphomevalonate kinase>pyrophosphomevalonate decarboxylase approximately isopentenyl pyrophosphate isomerase>squalene synthetase>isopentenyl pyrophosphate/dimethylallyl pyrophosphate prenyltransferase. The finding that the prenyltransferase may be the rate-limiting enzyme in squalene synthesis from mevalonate is discussed in relation to regulation of isoprenoid synthesis during pea-seed germination.

Alkaline Phosphatase↗
PubMed2006

Growth inhibition of Candida species and Aspergillus fumigatus by statins.

Statins are a class of drugs widely used for lowering high cholesterol levels through their action on 3-hydroxy-3-methylglutaryl-CoA reductase, a key enzyme in the synthesis of cholesterol. We studied the effects of two major statins, simvastatin and atorvastatin, on five Candida species and Aspergillus fumigatus. The statins strongly inhibited the growth of all species, except Candida krusei. Supplementation of Candida albicans and A. fumigatus with ergosterol or cholesterol in aerobic culture led to substantial recovery from the inhibition by statins, suggesting specificity of statins for the mevalonate synthesis pathway. Our findings suggest that the statins could have utility as antifungal agents and that fungal colonization could be affected in those on statin therapy.

Antifungal Agents↗
PubMed2004

The metabolic imbalance underlying lesion formation in Arabidopsis thaliana overexpressing farnesyl diphosphate synthase (isoform 1S) leads to oxidative stress and is triggered by the developmental decline of endogenous HMGR activity.

Overexpression of Arabidopsis thaliana farnesyl diphosphate synthase isoform 1S (FPS1S) in transgenic A. thaliana (L.) Heynh. leads to necrotic lesion formation in leaves in planta and to premature senescence in detached leaves [A. Masferrer et al. (2002) Plant J 30:123-132]. Here we report that leaves of plants overexpressing FPS1S with symptoms of necrosis show increased H2O2 formation and induction of both the pathogenesis-related 1 (PR-1) and the alternative oxidase 1a (AOX1a) genes. These findings indicate that plants overexpressing FPS1S should be considered as lesion-mimic mutants and lead us to propose that H2O2 is the main inducing agent of necrosis in these plants. The onset of necrosis appears in a developmentally regulated manner that correlates with the developmental decline of endogenous 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) activity. Accordingly, constitutive overexpression of HMGR in plants overexpressing FPS1S prevents both necrosis and premature senescence. These observations demonstrate that both phenotypes are due to an insufficient supply of mevalonic acid and support the notion that the metabolic imbalance associated with FPS1S overexpression is, in fact, triggered by the developmental decline of HMGR activity. We also show that overexpression of FPS1S alleviates growth inhibition caused by overexpression of the catalytic domain of isoform HMGR1S. Overall, our results reinforce the view that the levels of specific intermediates of the mevalonic acid pathway must be strictly controlled, particularly those located at branch-point positions, in order to avoid deleterious effects on plant growth and development.

Alkyl and Aryl Transferases↗
PubMed2002

Antileukemia activity of perillyl alcohol (POH): uncoupling apoptosis from G0/G1 arrest suggests that the primary effect of POH on Bcr/Abl-transformed cells is to induce growth arrest.

In hematopoietic cells, the Bcr/Abl tyrosine kinase that is encoded by the Philadelphia chromosome translocation both stimulates proliferation and activates an anti-apoptotic program that is associated with a G2/M delay upon exposure to various apoptotic stimuli. We recently reported that the monocyclic monoterpene, perillyl alcohol (POH) selectively induces in Bcr/Abl transformed cells, G0/G1 arrest and apoptosis. Therefore, POH activates anti-proliferative and apoptotic pathways against which the Bcr/Abl kinase does not protect. In this report, we show that in Bcr/Abl-transformed cells, POH induces cytoplasmic acidification, redistribution of phosphatidylserine in the plasma membrane along with DNA fragmentation, all of which can be prevented by the phorbol ester, TPA. The ability of TPA to protect against POH-induced cytotoxicity was blocked by inhibitors of protein kinase C (PKC) and the Na(+)/H(+) antiport. In contrast, TPA does not protect the cells from POH-mediated G0/G1 arrest. While POH inhibits a distal step in the mevalonate biosynthesis pathway, lovastatin, also a potential anticancer agent, inhibits the initial step in this pathway. Not surprisingly, lovastatin also induces G0/G1 arrest and apoptosis in Bcr/Abl-transformed cells, however, TPA protects cells from both apoptosis and G0/G1 arrest caused by lovastatin. Thus, in Bcr/Abl-transformed cells, POH and lovastatin cause growth arrest by different mechanisms. Together, these observations demonstrate that POH-mediated cell cycle arrest precedes apoptosis and raises the possibility that that the primary effect of POH is to induce G0/G1 arrest with apoptosis being a consequence of the growth arrest.

Amiloride↗
PubMed2001

Simvastatin and Ca(2+) signaling in endothelial cells: involvement of rho protein.

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor simvastatin is able to produce endothelium-dependent relaxation in addition to its lipid-lowering properties. The underlying mechanisms were investigated in bovine aortic endothelial cells (BAEC). Simvastatin induced an increase in cytosolic calcium ([Ca(2+)](i)) in BAEC, by releasing Ca(2+) from intracellular stores sensitive to thapsigargin and ryanodine, and increasing Ca(2+) entry. Simvastatin response was not altered by the phospholipase A(2) inhibitor ONO-RS-082, or the combination of superoxide dismutase plus catalase. However, the response to simvastatin was reduced by the product of HMG-CoA reductase, mevalonate or by the inhibitor of small G proteins of the Rho family, Clostridium botulinum C3 toxin. Thus, increase in [Ca(2+)](i) involving the activation of Rho protein through mevalonate-dependent pathway is essential for the action of simvastatin and might contribute to its beneficial effects against vascular diseases. This study helps elucidate the mechanisms of endothelial factor generation by simvastatin in BAEC.

Aminobenzoates↗
PubMed2003

Acyloxyalkyl ester prodrugs of FR900098 with improved in vivo anti-malarial activity.

FR900098 represents an improved derivative of the new antimalarial drug fosmidomycin and acts through inhibition of the 1-deoxy-D-xylulose 5-phosphate (DOXP) reductoisomerase, an essential enzyme of the mevalonate independent pathway of isoprenoid biosynthesis. Prodrugs with increased activity after oral administration were obtained by chemical modification of the phosphonate moiety to yield acyloxyalkyl esters. The most successful compound demonstrated 2-fold increased activity in mice infected with the rodent malaria parasite Plasmodium vinckei.

Animals↗
PubMed1987

Modulation of the enzymic activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase by multiple kinase systems involving reversible phosphorylation: a review.

This report summarizes the current concepts regarding the in vitro and in vivo modulation of the enzymic activity of HMG-CoA reductase and mevalonate formation in rat and human liver, as well as in cultured fibroblasts from normal and familial hypercholesterolemic subjects. Three separate mechanisms for the short-term modulation of hepatic HMG-CoA reductase activity by covalent phosphorylation have been described. These mechanisms involved three separate specific kinase systems including reductase kinase, protein kinase C, and a Ca+2, calmodulin-dependent kinase. The conceptual schemes presented in this report will provide a basis for future research as well as an overview for improved understanding of the complex and multifaceted short-term regulation of this key enzyme in the biosynthetic pathways of mevalonate, ubiquinones, dolichols, isopentenyl-tRNAs, and cholesterol.

AMP-Activated Protein Kinases↗
PubMed1968

Stimulation of liver cholesterol synthesis by actinomycin D.

1. An eightfold increase in the incorporation of [2-(14)C]acetate into liver cholesterol in vivo was observed 24hr. after starved rats had been given actinomycin D (0.5mg./kg. of body wt.). Liver cholesterol radioactivity declined faster in the treated animals, suggesting a greater rate of cholesterol turnover. 2. Liver slices from treated animals showed a tenfold increase in the incorporation of [2-(14)C]acetate into cholesterol; conversion into CO(2) and into fatty acids was less markedly increased, and conversion into ketone bodies was not significantly affected. 3. The patterns of conversion into liver cholesterol in vivo of the lactone and the sodium salt of mevalonic acid differed markedly. The former was converted at a faster rate and to a greater extent than the latter. Treatment with actinomycin D increased the conversion of both forms of mevalonic acid into liver cholesterol, but only to a small extent. 4. Stimulation of the incorporation of acetate into cholesterol occurred at 4hr. after the administration of actinomycin D but not at 2hr. The response was abolished by the simultaneous administration of dl-ethionine or puromycin. 5. Pre-feeding with a cholesterol-rich diet greatly diminished the stimulation of conversion of acetate into cholesterol caused by actinomycin D, though it did not completely suppress it. Adrenalectomized animals responded to the drug, but much less markedly. 6. It is concluded that actinomycin D stimulates the synthesis of cholesterol in the liver at a stage in the pathway before mevalonic acid, by a mechanism that probably requires protein synthesis. A likely site would be the beta-hydroxy-beta-methylglutaryl-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis. Some possible mechanisms by which the drug may lead to increased activity of this enzyme are considered.

Acetates↗