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PubMed1988

Influence of cholestyramine feeding on mevalonate-activating enzymes.

Phosphorylation and decarboxylation of mevalonic acid have been measured in different tissues of chicks fed a cholestyramine diet from hatching until 18 days of age. Hepatic and intestinal phosphorylation and decarboxylation of mevalonate were slightly although significantly increased from 15 days of treatment. Direct measurements of 5-pyrophosphomevalonate decarboxylase activity using the specific substrate of this enzyme corroborated these data. Brain enzymatic activities remained unaltered with respect to controls. These results suggest that enzymes responsible for the conversion of mevalonate to isopentenyl pyrophosphate from neonatal chick liver and intestine alter their activities in a coordinate fashion and may play an important role in the regulation of cholesterogenesis in these tissues.

Animals↗
PubMed1994

The HMG-CoA reductase inhibitor fluvastatin inhibits insect juvenile hormone biosynthesis.

Fluvastatin (Sandoz Compound XU 62-320), a synthetic HMG-CoA reductase inhibitor, was assayed in vitro and in vivo for its ability to suppress juvenile hormone (JH) biosynthesis by corpora allata of Locusta migratoria migratorioides. Fluvastatin inhibited JH biosynthesis by corpora allata in vitro. Exogenous mevalonic acid lactone restored JH biosynthesis in corpora allata inhibited by fluvastatin. Fluvastatin injected into locusts in vivo inhibited JH biosynthesis, but maximal inhibition lasted for only 6 hr. There were no discernible effects on either JH-regulated metamorphosis or oocyte maturation. Lengthening of the fourth larval stadium was observed and increased doses (single or repeated injections) were fatal.

Animals↗
PubMed2000

The effect of atorvastatin on serum lipids and lipoproteins in patients with homozyous familial hypercholesterolemia undergoing LDL-apheresis therapy.

The efficacy of atorvastatin, a new hydroxymethylglutaryl (HMG)-CoA reductase inhibitor, in reducing serum lipid levels, modifying lipoprotein composition, and suppressing cholesterol synthesis was evaluated in patients with homozygous familial hypercholesterolemia (homozygous FH) undergoing LDL-apheresis therapy. Atorvastatin was given in escalating doses (10, 20, and 40 mg/day) to nine patients with homozygous FH. Five of nine patients responded well to atorvastatin; four of these patients were receptor-defective and the remaining one was receptor-negative. The change in LDL-cholesterol in the receptor-defective patients averaged -20.6% compared to the baseline level at the highest dose of atorvastatin. Of five receptor-negative type patients, only one showed good response to atorvastatin therapy with a LDL-cholesterol reduction of 14.9%. Although the other four receptor-negative patients did not show a change in LDL-cholesterol, all of them exhibited a considerable increase in HDL-cholesterol. All patients showed reduced urinary excretion of mevalonic acid, suggesting that atorvastatin decreases LDL-cholesterol by inhibiting cholesterol biosynthesis even where LDL-receptor activity is not present. Atorvastatin also decreased serum triglycerides in both receptor-negative and defective patients, especially in the latter. As cholesterol level rebounds quickly after each apheresis procedure, a combination therapy using atorvastatin and apheresis may increase the efficacy of the apheresis treatment, improving cost-benefit effectiveness by reducing the frequency of the apheresis treatment.

Adolescent↗
PubMed1998

Inhibition of acyl coenzyme A:cholesterol acyltransferase blocks esterification but not uptake of cholesterol in Caco-2 cells.

The effects of cholesterol esterase (CEase) and acyl coenzyme A:cholesterol acyltransferase (ACAT) inhibitors on the uptake and esterification of cholesterol in Caco-2 cells were examined. CEase increased the uptake of [3H]cholesterol from bile salt mixed-micelles by 2.5- to 3.0-fold and its esterification by greater than 25-fold. Inhibition of cellular ACAT activity with CL277082 or CP113818 had little or no effect on cholesterol uptake measured in the presence or absence of CEase. The subsequent esterification of [3H]cholesterol was reduced greater than 90% by each ACAT inhibitor. Similar results were obtained in cells in which ACAT activity was induced by preincubation either with 25-hydroxycholesterol and mevalonic acid or with CEase and bile salt mixed-micelles containing 100 micromol/L cholesterol. Neither ACAT inhibitor had an effect on CEase-mediated synthesis or hydrolysis of cholesteryl oleate in vitro. Thus, the uptake of cholesterol from bile salt mixed-micelles in the presence or absence of CEase was not regulated by the level of cellular ACAT expression. The subsequent esterification of exogenous sterol was not due to CEase, but was completely dependent on ACAT activity. The dissociation of cholesterol uptake from ACAT activity suggests that the factors controlling the transfer of sterol from extracellular media to the cell are different from the factors regulating the cellular level of cholesterol esterification.

Bile Acids and Salts↗
PubMed2004

Molecular functions of conserved aspects of the GHMP kinase family.

The sequences and three-dimensional structures of the galactokinase, homoserine kinase, mevalonate kinase, and phosphomevalonate kinase (GHMP) family were compared to identify highly conserved surface residues. The functions of these solvent-accessible residues were assessed by determining the effects of their substitution, via mutagenesis, on the initial-rate parameters of a representative member of the GHMP kinase family, phosphomevalonate kinase from Streptococcus pneumoniae. What emerges from this study is a profile of the conserved surface-linked functions of the family. Certain substitutions produce highly selective effects on the steady-state affinity of a particular substrate, while one residue, Asp150, appears to be a pure k(cat) effector. Substitutions elsewhere affect multiple initial-rate parameters with varying, and sometimes compensatory, patterns. An alpha-helix that repositions during catalysis was substituted along its length to assess how its different segments contribute to catalysis-the substrate-proximal edge of the helix affects ATP recognition and k(cat), while the distal edge affects recognition of both substrates without affecting turnover. GHMP kinase mutations at the conserved surface residues corresponding to Ser291 and Ala293 in phosphomevalonate kinase are linked to mevalonic acid deficiency, which can lead to early fatality, and galactokinase deficiency, which causes cataracts. Our results suggest that the molecular basis for this particular galactokinase deficiency is an increase in the K(m) for galactose.

Alanine↗
PubMed1996

Effect of insulin on farnesyltransferase activity in 3T3-L1 adipocytes.

Activation of p21(ras) by GTP loading is a critical step in a cascade of intracellular insulin signaling. Farnesylation of p21(ras) protein is an obligatory event that facilitates Ras migration to the plasma membrane and subsequent activation. Farnesyltransferase (FTase) is a ubiquitous enzyme that catalyzes the lipid modification of p21(ras) by the addition of farnesyl to the C-terminal "CAAX" motif. In vitro and in vivo FTase activities were studied in 3T3-L1 adipocytes in response to insulin challenge. Insulin exerted a biphasic stimulatory effect on FTase activity measured in vitro with a 31% increase at 5 min and a 130% increase at 60 min. Insulin-stimulated farnesylation of p21(ras) pools in vivo correlated with FTase activity seen in vitro by displaying an increase in farnesylated p21(ras) from 40% of total cellular Ras in control cells to 63% by 5 min and 80% by 60 min (p < 0.05) in insulin-treated cells. Insulin challenge of 3T3-L1 adipocytes increased incorporation of tritiated mevalonic acid in p21(ras) in a dose-dependent manner and stimulated a 2-fold increase in phosphorylation of the alpha-subunit of FTase at 5 min and a 4-fold increase at 60 min.

3T3 Cells↗
PubMed2003

Terpene biosynthesis in the nudibranch Doriopsilla areolata.

Biogenesis of the enantiomeric sesquiterpenes 1 and 5 of the marine nudibranch Doriopsilla areolata was investigated by feeding of [1-(13)C]glucose, [1,2-(13)C(2)]glucose, and [1,2-(13)C(2)]acetate. Evidence is presented that supports de novo origin of both compounds via mevalonic acid.

Acetates↗
PubMed1997

Biosynthesis of the labdane diterpene marrubiin in Marrubium vulgare via a non-mevalonate pathway.

The biosynthesis of the furanic labdane diterpene marrubiin has been studied in plantlets and shoot cultures of Marrubium vulgare (Lamiaceae). The use of [2-14C]acetate, [2-14C]pyruvate, [2-14C]mevalonic acid and [U-14C]glucose incorporation experiments showed that the labelling of sterols in etiolated shoot cultures of M. vulgare was in accordance with their biosynthesis via the acetate-mevalonate pathway. In contrast, the incorporation rates of these precursors into the diterpene marrubiin could not be explained by biosynthesis of this compound via the acetate-mevalonate pathway. Cultivation of etiolated shoot cultures of M. vulgare on medium containing [1-13C]glucose and subsequent 13C-NMR spectroscopy of marrubiin led to the conclusion that the biosynthesis of marrubiin follows a non-mevalonate pathway. All isoprenic units of 13C-labelled marrubiin were enriched in those carbons that correspond to positions 1 and 5 of a putative precursor isopentenyl diphosphate. This labelling pattern from [1-13C]glucose is consistent with an alternative pathway via trioses, which has already been shown to occur in Eubacteria and Gymnospermae. The labdane skeleton is a precursor of many other skeletal types of diterpenes. Therefore it becomes obvious that in connection with the few known examples of a non-mevalonate pathway to isoprenoids the formation of some isoprenoids in plants via a non-mevalonate pathway might be quite common.

Acetates↗
PubMed1976

The in vitro metabolism of mevalonate by sterol and non-sterol pathways.

The metabolism of mevalonic acid by both sterol and non-sterol pathways has been evaluated in nine tissues of the rat. An in vitro estimation of the non-sterol, or "shunt", pathway of mevalonate metabolism was made possible by determining the conversion of [2-14C]mevalonate or [5-14C]mevalonate to 14CO2 in tissue slices. In confirmation of our previous results, the kidney was found to play a major role in the metabolism of mevalonate to sterols and sterol precursors. The shunt pathway accounted for a significant percentage of the mevalonate metabolized in kidney, ileum, spleen, lung and testes, but was of minor importance or undetectable in liver, brain, skin, and adipose tissue. Kidney, however, proved to be by far the most active tissue site of mevalonate metabolism by the shunt mechanism in that, on an average, renal tissue metabolized (R)-[14C]mevalonate over the non-sterol pathway at a rate that was 21 times that of any other tissue examined. These results indicate that the kidneys are of major importance in the metabolism of mevalonate by each of the known pathways of metabolism of this sterol precursor.

Adipose Tissue↗
PubMed1996

Inhibition of protein prenylation down-regulates signalling by inflammatory mediators in human keratinocytes.

Several inflammatory mediators have been shown to activate phospholipase C in human keratinocytes via GTP-binding protein-coupled receptors. Since GTP-binding proteins are prenylated proteins, we have examined the role of prenylation in signal transduction in HaCaT keratinocytes. Indirect inhibition of prenylation with the HMG CoA reductase inhibitors fluvastatin or compactin decreased bradykinin-stimulated inositol 1,4,5-triphosphate generation. This effect was abolished by mevalonic acid but not by serum, indicating a requirement for a non-sterol metabolite for signal generation. The BK response was also inhibited by zaragozic acids B and C, known inhibitors of prenyl protein transferases. These results suggest that protein prenylation may be a novel therapeutic target in dermatological conditions where an up-regulation of the inositol lipid pathway has been demonstrated.

Adenosine Triphosphate↗
PubMed1990

Isoprenylation of the low molecular mass GTP-binding proteins rac 1 and rac 2: possible role in membrane localization.

Ras proteins can be modified at their COOH-terminal cysteine in the motif Cys-Ali-Ali-Xaa by a farnesyl isoprenoid. This modification is essential for membrane association and biological activity of ras proteins. A similar COOH-terminal amino acid sequence, Cys-Xaa-Ali-Xaa, exists in the ras-related GTP-binding proteins rac 1 and rac 2. To determine whether these proteins were similarly modified, COS cells were transfected with rac 1 and rac 2 cDNA and expressed proteins were labeled with [3H]mevalonic acid. We report here that both rac 1 and rac 2 are post-translationally modified by addition of an isoprenoid group, the likely site of which is the COOH-terminal cysteine. Isoprenylation was found only in racs associated with particulate cell fractions, suggesting that this modification may be associated with membrane localization of the proteins. These data specifically identify mammalian low molecular mass GTP-binding proteins other than ras that undergo post-translational modification and further define the COOH-terminal consensus sequence, Cys-Ali-Ali-Xaa, as an isoprenylation signal. This sequence may identify a larger family of low molecular mass GTP-binding proteins which are isoprenylated.

Amino Acid Sequence↗
PubMed1992

Post-translational modifications of p21rho proteins.

Post-translational modifications of the ras proteins, which are required for plasma membrane localization and biological function of the proteins, have been shown to include prenylation and carboxymethylation at the carboxyl terminal cysteine residue of the cysteine-aliphatic amino acid-aliphatic amino acid-any amino acid (CAAX) box. In addition, p21Ha-ras and p21N-ras, but not p21K-ras (B), are palmitoylated. The three mammalian rho proteins (A, B, and C) are also members of the ras superfamily but have distinct biological activities and different intracellular distributions from p21ras. Analysis showed all three rho proteins are modified by a COOH-terminal carboxymethylation similar to p21ras, whereas p21rhoC labeled with [3H]mevalonic acid in vivo revealed the presence of a C20 prenoid, similar to that already described for p21rhoA. However, in vivo and in vitro studies of p21rhoB showed this protein to be modified by both C15 and C20 prenoids. Mutation of C193 in the CAAX box abolished prenylation, whereas mutation of the adjacent C192 resulted in a significant reduction in the amount of the C20, but not C15 prenoid, recovered from p21rhoB. In vivo labeling studies with [3H]palmitic acid and mutational analysis showed that both cysteine residues at 189 and 192 upstream of the CAAX box in p21rhoB are sites for palmitoylation. We conclude that there are different populations of post-translationally modified p21rhoB in the cell and that the sequence specificity for geranylgeranyl- and farnesyltransferases may be more complicated than previously proposed.

Amino Acid Sequence↗
PubMed1988

Cyclic AMP decreases LDL catabolism and cholesterol synthesis in the human hepatoma cell line HepG2.

A 24h pretreatment of the human hepatoma cell line HepG2 with dibutyryl cyclic AMP in the presence of theophylline induced a dose dependent decrease in low density lipoprotein binding, uptake and degradation. This effect is most likely due to a reduction of the LDL receptor number. Sterol synthesis from sodium acetate is markedly inhibited, either in the presence or absence of LDL, whereas synthesis from mevalonic acid is unchanged. Cyclic AMP also induced a decrease in hydroxy methyl glutaryl coenzyme A reductase activity. These effects of cyclic AMP might be involved in some hormonal regulation of the LDL pathway and cholesterol metabolism in the liver.

Acetates↗
PubMed2002

Inhibitory effect of fluvastatin on lysophosphatidylcholine-induced nonselective cation current in Guinea pig ventricular myocytes.

Using the whole-cell voltage-clamp method, we investigated the effect of fluvastatin, a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor, on lysophosphatidylcholine (LPC)-induced nonselective cation current (I(NSC)) in guinea pig cardiac ventricular myocytes. External LPC (3 to approximately 50 microM) induced I(NSC) in a dose-dependent manner with a lag. With fluvastatin (5 microM) in the external solution, LPC induced I(NSC), which was significantly smaller and with a longer lag compared with that in the absence of fluvastatin. With mevalonic acid (MVA) (100 microM) in the external solution, fluvastatin did not diminish LPC-induced I(NSC). Geranylgeranylpyrophosphate, an MVA metabolite, in the pipette solution prevented fluvastatin from diminishing LPC-induced I(NSC), suggesting that isoprenylated signaling molecules, such as the small G-protein Rho, might be involved in the LPC effect. Botulinum toxin C3, Rho-kinase inhibitor (R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide, 2 HCl (Y-27632), or pertussis toxin in the pipette solution suppressed LPC-induced I(NSC). We conclude that LPC induces I(NSC) via a Gi/Go-coupled receptor and Rho-mediated pathway. The inhibitory effect of fluvastatin on LPC-induced I(NSC) provides a new insight into the signal transduction mechanism and may have important clinical implications.

ADP Ribose Transferases↗
PubMed1989

Sterol-independent regulation of 3-hydroxy-3-methylglutaryl-CoA reductase by mevalonate in Chinese hamster ovary cells. Magnitude and specificity.

In this paper, we assess the relative degree of regulation of the rate-limiting enzyme of isoprenoid biosynthesis, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, by sterol and nonsterol products of mevalonate by utilizing cultured Chinese hamster ovary cells blocked in sterol synthesis. We also examine the two other enzymes of mevalonate biosynthesis, acetoacetyl-CoA thiolase and HMG-CoA synthase, for regulation by mevalonate supplements. These studies indicate that in proliferating fibroblasts, treatment with mevalonic acid can produce a suppression of HMG-CoA reductase activity similar to magnitude to that caused by oxygenated sterols. In contrast, HMG-CoA synthase and acetoacetyl-CoA thiolase are only weakly regulated by mevalonate when compared with 25-hydroxycholesterol. Furthermore, neither HMG-CoA synthase nor acetoacetyl-CoA thiolase exhibits the multivalent control response by sterol and mevalonate supplements in the absence of endogenous mevalonate synthesis which is characteristic of nonsterol regulation of HMG-CoA reductase. These observations suggest that nonsterol regulation of HMG-CoA reductase is specific to that enzyme in contrast to the pleiotropic regulation of enzymes of sterol biosynthesis observed with oxygenated sterols. In Chinese hamster ovary cells supplemented with mevalonate at concentrations that are inhibitory to reductase activity, at least 80% of the inhibition appears to be mediated by nonsterol products of mevalonate. In addition, feed-back regulation of HMG-CoA reductase by endogenously synthesized nonsterol isoprenoids in the absence of exogenous sterol or mevalonate supplements also produces a 70% inhibition of the enzyme activity.

Acetyl-CoA C-Acetyltransferase↗
PubMed1989

Mevalonate kinase in lysates of cultured human fibroblasts and lymphoblasts: kinetic properties, assay conditions, carrier detection and measurement of residual activity in a patient with mevalonic aciduria.

An assay has been developed for the measurement of mevalonate kinase activity in extracts of cultured human fibroblasts and lymphoblasts. Individual elements of the assay were investigated in order to achieve optimum conditions. Apparent Michaelis constants (KMapp) for the substrates mevalonic acid and adenosine-5'-triphosphate were 22 +/- 10 mumol/l and 0.42-0.53 mmol/l, respectively, in lysates of control fibroblast lines. The same values in lysates of a control lymphoblast line were 17 mumol/l and 0.23 mmol/l, respectively. Mevalonate kinase activity in extracts of cultured fibroblasts derived from 6 control individuals was 3.24 +/- (SD) 0.91 nmol/min/mg protein. The activity in extracts of fibroblasts derived from a patient with mevalonic aciduria was 0.15 +/- 0.10 nmol/min/mg protein, approximately 5% of the control mean. The parents and brother of the patient displayed mevalonate kinase activities in fibroblast extracts approximating 38-42% of the control mean. Substantially higher mevalonate kinase activity was documented in extracts of cultured lymphoblasts. When assayed on various occasions, the mean activity of mevalonate kinase in extracts of lymphoblasts derived from the parents, brother and maternal grandmother of the patient ranged from 27 to 32% of the mean activity of 9.8 +/- (SD) 3.4 nmol/min/mg protein measured in a parallel control lymphoblast line, while the mean activity in a maternal and paternal uncle approximated 65-89% of the same control mean. The mean activity in extracts of lymphoblasts derived from the patient approximated 2% of the control mean. The data suggest that the parents, brother and maternal grandmother are carriers of the defective gene responsible for mevalonate kinase deficiency, consistent with an autosomal recessive mode of inheritance.

Cells, Cultured↗
PubMed1996

Acute hyperinsulinaemia decreases cholesterol synthesis less in subjects with non-insulin-dependent diabetes mellitus than in non-diabetic subjects.

To investigate the effect of insulin on cholesterol synthesis in vivo we measured plasma mevalonic acid (MVA) concentrations using gas chromatography-mass spectrometry in six non-obese patients with non-insulin-dependent diabetes mellitus (NIDDM) [four men, two women; age 57.5 +/- 2.2 years (mean +/- SEM); glycated haemoglobin (HbA1) 8.5 +/- 0.5%; total cholesterol (TC) 5.7 +/- 0.5 mmol L-1, triglyceride (TG) 3.8 +/- 0.9 mmol L-1] and six non-diabetic, sex- and age-matched control subjects (age 55.7 +/- 2.8 years; HbA1 6.5 +/- 0.1%; TC 5.4 +/- 0.3 mmol L-1, TG 1.2 +/- 0.1 mmol L-1). Subjects were studied twice: during 13-h hyperinsulinaemic (1 mu kg-1 min-1), euglycaemic (5 mmol L-1) clamp and during a saline infusion. Baseline MVA concentration was significantly higher in diabetic patients than in control subjects (9.8 +/- 0.7 ng mL-1 vs. 5.6 +/- 0.9 ng mL-1, P = 0.004). At the end of each study, MVA concentration, expressed as a percentage of baseline, was significantly lower during the hyperinsulinaemic, euglycaemic clamp than during the saline study in both the diabetic (54.4 +/- 5.3% vs. 69.6 +/- 6.3%, P = 0.036) and control subjects (30.5 +/- 3.4% vs. 61.7 +/- 6.0%, P = 0.01). However, the decrease in MVA during the hyperinsulinaemic clamp study was more marked in the control subjects than in the diabetic subjects (P = 0.03). A significant positive correlation was found between percentage decrease of MVA and non-esterified fatty acids following the insulin clamp in NIDDM (r = 0.83, P = 0.04). We conclude that acute hyperinsulinaemia decreases cholesterol synthesis less in subjects with NIDDM than in non-diabetic subjects and that this phenomenon, together with increased basal cholesterol synthesis in NIDDM, may in part be due to insulin resistance.

Analysis of Variance↗
PubMed1979

Cholesterol metabolism in diabetes: the effect of insulin on the kinetics of plasma squalene.

The turnover of isotopically labeled squalene formed in plasma from [14C]mevalonate has been used to measure cholesterol synthesis in diabetics over a 7-h period. Five patients were studied while in poor diabetic control (mean daytime glycemia, 349 mg/dl) and at a later date once improved control was established by multiple daily insulin injections (mean glycemia, 175 mg/dl). This degree of diabetic control resulted in an increase in the fractional conversion of [14C]mevalonic acid to [14C]squalene from 55.2 +/- 1% to 67.5 +/- 4% (P less than 0.025). These data together with the area under the squalene specific activity curve yeild an estimated rate of cholesterol synthesis based on the likely assumption that mevalonate pool size did not decrease. Insulinization increased this calculated mean rate of cholesterol synthesis from 961 +/- 151 to 1206 +/- 223 mg/day (P less than 0.025). The use of squalene kinetics to evaluate changes in cholesterol synthesis deserves further study, particularly in metabolically unstable states such as diabetes in which conventional methods for measuring cholesterol synthesis are difficult to apply and to interpret.

Adult↗