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PubMed1991

Identity of a second type of allatostatin from cockroach brains: an octadecapeptide amide with a tyrosine-rich address sequence.

An octadecapeptide that inhibits juvenile hormone synthesis has been isolated by HPLC from brain-retrocerebral complexes of the cockroach Diploptera punctata. The primary structure of this allatostatin has been elucidated by tandem mass spectrometry: Ala-Tyr-Ser-Tyr-Val-Ser-Glu-Tyr-Lys-Arg-Leu-Pro-Val-Tyr-Asn-Phe-Gly-Leu- NH2 (ASB2). The amidated three-residue C terminus of this type B allatostatin is identical to that of four known type A allatostatins, and the preceding three residues show close structural homology. ASB2 has over twice the activity of the type A tridecapeptide Ala-Pro-Ser-Gly-Ala-Gln-Arg-Leu-Tyr-Gly-Phe-Gly-Leu-NH2 (ASA1) in inhibiting juvenile hormone biosynthesis in corpora allata from females in early vitellogenesis (day 2), and its efficacy persists during pregnancy, but it is equally effective as ASA1 on glands from day-10 females (IC50 = 0.31 nM). The octadecapeptide is characterized by a potential dibasic cleavage site, Lys9-Arg10, the integrity of which is needed for high potency. The ASB2-(11-18)-octapeptide amide gives a full response at high concentrations at day 10 (IC50 = 48 nM), but the C-truncated (1-9)-, (1-11)-, and (1-17)-amide fragments of ASB2 are inactive. Thus, the endocrine message is located at the C terminus. N alpha-acetylation of the N-truncated (9-18), (10-18), and (11-18) fragments of ASB2 increases activity relative to the nonacetylated peptides. The site of action of type A and type B allatostatins is located before mevalonate kinase in the biosynthetic pathway for juvenile hormone.

Amino Acid Sequence↗
PubMed1998

(+)-Germacrene A biosynthesis . The committed step in the biosynthesis of bitter sesquiterpene lactones in chicory

The leaves and especially the roots of chicory (Cichorium intybus L. ) contain high concentrations of bitter sesquiterpene lactones such as the guianolides lactupicrin, lactucin, and 8-deoxylactucin. Eudesmanolides and germacranolides are present in smaller amounts. Their postulated biosynthesis through the mevalonate-farnesyl diphosphate-germacradiene pathway has now been confirmed by the isolation of a (+)-germacrene A synthase from chicory roots. This sesquiterpene cyclase was purified 200-fold using a combination of anion-exchange and dye-ligand chromatography. It has a Km value of 6. 6 &mgr;M, an estimated molecular mass of 54 kD, and a (broad) pH optimum around 6.7. Germacrene A, the enzymatic product, proved to be much more stable than reported in literature. Its heat-induced Cope rearrangement into (-)-beta-elemene was utilized to determine its absolute configuration on an enantioselective gas chromatography column. To our knowledge, until now in sesquiterpene biosynthesis, germacrene A has only been reported as an (postulated) enzyme-bound intermediate, which, instead of being released, is subjected to additional cyclization(s) by the same enzyme that generated it from farnesyl diphosphate. However, in chicory germacrene A is released from the sesquiterpene cyclase. Apparently, subsequent oxidations and/or glucosylation of the germacrane skeleton, together with a germacrene cyclase, determine whether guaiane- or eudesmane-type sesquiterpene lactones are produced.

Journal Article↗
PubMed2006

AMPK and cell proliferation--AMPK as a therapeutic target for atherosclerosis and cancer.

AMPK is a serine/threonine protein kinase, which serves as an energy sensor in all eukaryotic cell types. Published studies indicate that AMPK activation strongly suppresses cell proliferation in non-malignant cells as well as in tumour cells. These actions of AMPK appear to be mediated through multiple mechanisms including regulation of the cell cycle and inhibition of protein synthesis, de novo fatty acid synthesis, specifically the generation of mevalonate as well as other products downstream of mevalonate in the cholesterol synthesis pathway. Cell cycle regulation by AMPK is mediated by up-regulation of the p53-p21 axis as well as regulation of TSC2-mTOR (mammalian target of rapamycin) pathway. The AMPK signalling network contains a number of tumour suppressor genes including LKB1, p53, TSC1 and TSC2, and overcomes growth factor signalling from a variety of stimuli (via growth factors and by abnormal regulation of cellular proto-oncogenes including PI3K, Akt and ERK). These observations suggest that AMPK activation is a logical therapeutic target for diseases rooted in cellular proliferation, including atherosclerosis and cancer. In this review, we discuss about exciting recent advances indicating that AMPK functions as a suppressor of cell proliferation by controlling a variety of cellular events in normal cells as well as in tumour cells.

AMP-Activated Protein Kinases↗
PubMed2005

Statin-inhibited endothelial permeability could be associated with its effect on PECAM-1 in endothelial cells.

UNLABELLED: The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are known to inhibit leukocyte recruitment to endothelium but the mechanism is less understood. Platelet endothelial cell adhesion molecule-1 (PECAM-1) is an endothelial junction protein involved in leukocyte diapedesis. We hypothesize that in endothelial cells, statins may well recruit PECAM-1 to exert their inhibitory effect on leukocyte trans-endothelial migration (TEM). In lovastatin-treated resting human umbilical vein endothelial cells (HUVECs), increased levels of mRNA and protein of PECAM-1 as well as its bio-synthesis (all approximately 2-fold) were observed by real-time PCR, Western blotting and 35S-labeled methionine incorporation assay, respectively. Moreover, in lovastatin treated resting cells as well as TNF-alpha activated endothelial cells, unanimously decreased Triton X-100 insoluble and soluble PECAM-1 ratio was observed. Such changes were accompanied by decreased TEM of U-937 cells (a promonocyte cell line). All lovastatin's effects were abrogated by mevalonic acid. In resting HUVECs, geranylgeranyl pyrophosphate (GGPP), but not farnesyl pyrophosphate (FPP) (both are isoprenoid intermediates in the cholesterol biosynthesis pathway) compromised the effect of lovastatin on PECAM-1 expression, whereas C3 toxin, an inhibitor of small G proteins, exerted statin-like effect. CONCLUSION: Statin-reduced endothelial permeability could be attributed to altered intracellular distribution of PECAM-1 in endothelial cells. We speculate that lovastatin regulates PECAM-1 expression in HUVECs through the mevalonate-GGPP pathway by inhibiting of Rho small GTPase.

Cells, Cultured↗
PubMed1978

Cholesterol is a critical cellular component for T-lymphocyte cytotoxicity.

Preincubation of cytolytic T lymphocytes (CTLs) generated in secondary C57BL/6 anti-DBA/2 mixed leukocyte cultures with an inhibitor of cellular cholesterol synthesis (25-OH-cholesterol) for 24 hr strongly depressed the cytolytic activity as determined in a 3-hr 51Cr assay. The effect of the inhibitor was reversed by the simultaneous addition of cholesterol or of mevalonic acid during the preincubation period (mevalonate is the product of the regulatory enzyme in the sterol synthesis pathway, 3-hydroxy-3-methylglutaryl-CoA reductase (NADP) [mevalonate:NADP+ oxidoreductase (CoA-acylating), EC 1.1.1.34]). Because, under the same culture conditions, inhibition of DNA synthesis had no effect on CTL activity, the experiments suggest that the effect of 25-OH-cholesterol is related to its inhibitory effect on sterol synthesis, resulting in decreased levels of membrane-bound cholesterol, rather than to inhibition of cellular proliferation.

Animals↗
PubMed2001

Carotenoid biosynthesis and biotechnological application.

A survey is given on the carotenoid biosynthetic pathway leading to beta-carotene and its oxidation products in bacteria and plants. This includes the synthesis of prenyl pyrophosphates via the mevalonate or the 1-deoxyxylulose-5-phosphate pathways as well as the reaction sequences of carotenoid formation and interconversion together with the properties of the enzymes involved. Biotechnological application of this knowledge resulted in the development of heterologous carotenoid production systems using bacteria and fungi with metabolic engineered precursor supply and crop plants with manipulated carotenoid biosynthesis. The recent developments in engineering crops with increased carotenoid contents are covered.

Bacterial Proteins↗
PubMed2002

Role of the cholesterol biosynthetic pathway in osteoblastic differentiation of marrow stromal cells.

Cholesterol is an important molecule that plays a key role in regulating cellular differentiation and function. Although the possible role of lipids has been implicated in regulating osteoblastic cells, the role of cholesterol in that process is not well defined. In this study we have examined the role of the cellular cholesterol biosynthetic pathway on osteoblastic differentiation of marrow stromal cells (MSCs). Treatment of pluripotent mouse MSCs M2-10B4 with inhibitors of the cholesterol biosynthetic pathway mevastatin or mevinolin inhibited the maturation of these cells into functional osteoblastic cells. This was determined by the inhibition of the activity and expression of alkaline phosphatase (ALP), a key enzyme involved in differentiation and mineralization of osteoblastic cell cultures, as well as inhibition of mineralization. Mevastatin treatment did not affect expression of the osteoblast-specific gene osteocalcin (OCN). Furthermore, promoter-reporter studies in MSCs showed that mevastatin inhibited activity of the ALP gene promoter, suggesting regulation by derivatives of the cholesterol biosynthetic pathway. The effects of mevastatin and mevinolin were reversed by mevalonate but not by geranylgeraniol or farnesol, intermediates in the cholesterol biosynthetic pathway. Altogether, these results suggest that products of the cholesterol biosynthetic pathway are important for proper development of MSCs into functional osteoblastic cells capable of forming a mineralized matrix. Identification of those molecules may provide new therapeutic approaches to prevent the decline in osteoblastic activity in osteoporosis and aging.

Alkaline Phosphatase↗
PubMed1999

THE 1-DEOXY-D-XYLULOSE-5-PHOSPHATE PATHWAY OF ISOPRENOID BIOSYNTHESIS IN PLANTS.

In plants the biosynthesis of prenyllipids and isoprenoids proceeds via two independent pathways: (a) the cytosolic classical acetate/mevalonate pathway for the biosynthesis of sterols, sesquiterpenes, triterpenoids; and (b) the alternative, non-mevalonate 1-deoxy-d-xylulose-5-phosphate (DOXP) pathway for the biosynthesis of plastidic isoprenoids, such as carotenoids, phytol (a side-chain of chlorophylls), plastoquinone-9, isoprene, mono-, and diterpenes. Both pathways form the active C5-unit isopentenyl diphosphate (IPP) as the precursor from which all other isoprenoids are formed via head-to-tail addition. This review summarizes current knowledge of the novel 1-deoxy-d-xylulose-5-phosphate (DOXP) pathway for isopentenyl diphosphate biosynthesis, apparently located in plastids. The DOXP pathway of IPP formation starts from D-glyceraldehyde-3-phosphate (GA-3-P) and pyruvate, with DOXP-synthase as the starting enzyme. This pathway provides new insight into the regulation of chloroplast metabolism.

Journal Article↗
PubMed2005

HMG CoA reductase inhibition modulates VEGF-induced endothelial cell hyperpermeability by preventing RhoA activation and myosin regulatory light chain phosphorylation.

The beneficial effects of statins are usually assumed to stem from their ability to reduce cholesterol biosynthesis. However, because statins are potent inhibitors of the mevalonate, which governs diverse cell signaling pathways, inhibition of 3-hydroxy-3-methylglutaryl-coenzyme-A reductase may also result in pleiotropic effects. The present study describes a novel pleiotropic effect of statins on vascular endothelial growth factor (VEGF)-induced glomerular endothelial cell (GEnC) hyperpermeability. Using live cell imaging with green fluorescent protein-tagged myosin regulatory light chain (MLC) and correlative biochemical analyses, we investigated 1) VEGF signaling pathway leading to GEnC hyperpermeability and 2) the modulatory effects of statins on VEGF signaling. Our findings indicate that VEGF stimulation elicits a robust increase in GEnC permeability. The signaling pathway that mediates VEGF-induced GEnC hyperpermeability involves RhoA activation leading to actin cytoskeletal remodeling, MLC diphosphorylation, and enhanced paracellular gap formation. Remarkably, cotreatment of endothelial cells with simvastatin, a hydrophobic statin, reversed VEGF-induced GEnC hyperpermeability by preventing MLC diphosphorylation, and cytoskeletal remodeling. In summary, this study identifies RhoA and MLC phosphorylation as key mediators of VEGF-induced endothelial cell hyperpermeability and demonstrates the modulatory effects of statins on VEGF signaling pathway.

Actins↗
PubMed1985

13C NMR study of the biosynthesis of toxins by Fusarium graminearum.

13C NMR spectroscopic investigations on the biosynthesis of mycotoxins produced by Fusarium graminearum (M69) were carried out through the incorporation of [1-13C]- and [2-13C]acetate precursors. The major secondary metabolites produced by this species in still culture were deoxynivalenol (3,7,15-trihydroxy-12,13-epoxytrichothec-9-en-one), 15-acetyldeoxynivalenol, zearalenone, and butenolide. [1-13C]- and [2-13C]acetate were incorporated in alternate carbon atoms in zearalenone, consistent with the head to tail condensation of nine acetate units. The trichothecenes were enriched in a manner consistent with the condensation of three mevalonate units. 13C/13C couplings, observed between C-5 and C-12, as well as between C-6 and C-15 of 15-acetyldeoxynivalenol, confirms the current hypothesis of formation of the trichothecene ring system by cyclization of farnesyl pyrophosphate. The incorporation pattern in ergosterol is also consistent with a mevalonate origin, while the adjacent incorporation of acetate methyl groups in butenolide suggests a glutamate precursor. The degree of enrichment in the secondary metabolites, which ranged from 3 to 10% at each carbon site, was observed in the 13C NMR spectra of the crude fungal extracts to be dependent on the timing of acetate addition to the culture. The specific toxins produced together with the quantity of each, were also found to be dependent on the timing of acetate addition. Competition between the three biosynthetic pathways of secondary metabolism, i.e. polyketide, mevalonate, and amino acid for the labeled acetate in this organism is a complex function of culture conditions.

Acetates↗
PubMed2005

Muscle coenzyme Q10 level in statin-related myopathy.

BACKGROUND: Statin drugs (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) reduce the level of cholesterol by inhibiting the synthesis of mevalonate, an intermediary in the cholesterol biosynthetic pathway. Use of statin drugs has been associated with a variety of skeletal muscle-related complaints. Coenzyme Q10 (CoQ10), a component of the mitochondrial respiratory chain, is also synthesized from mevalonate, and decreased muscle CoQ10 concentration may have a role in the pathogenesis of statin drug-related myopathy. OBJECTIVES: To measure the CoQ10 concentration and respiratory chain enzyme activities in muscle biopsy specimens from 18 patients with statin drug-related myopathy and to look for evidence of apoptosis using the TUNEL (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling) assay. DESIGN: An open-labeled study of CoQ10 concentration in muscle from patients with increased serum creatine kinase concentrations while receiving standard statin drug therapy. SETTING: Neuromuscular centers at 2 academic tertiary care hospitals. RESULTS: Muscle structure was essentially normal in 14 patients and showed evidence of mitochondrial dysfunction and nonspecific myopathic changes in 2 patients each. Muscle CoQ10 concentration was not statistically different between patients and control subjects, but it was more than 2 SDs below the normal mean in 3 patients and more than 1 SD below normal in 7 patients. There was no TUNEL positivity in any patients. CONCLUSION: These data suggest that statin drug-related myopathy is associated with a mild decrease in muscle CoQ10 concentration, which does not cause histochemical or biochemical evidence of mitochondrial myopathy or morphologic evidence of apoptosis in most patients.

Adult↗
PubMed2003

Molecular characterization of three 3-hydroxy-3-methylglutaryl-CoA reductase genes including pathogen-induced Hmg2 from pepper (Capsicum annuum).

Sesquiterpene phytoalexins, a class of plant defense metabolites, are synthesized from the cytosolic acetate/mevalonate pathway in isoprenoids biosynthetic system of plants. The 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) catalyzes the synthesis of mevalonate, which is the specific precursor of this pathway, as a multi gene family. Three kinds of cDNA clones encoding HMGR were isolated from Korean red pepper (Capsicum annuum L. cv. NocKwang) and the HMGR2 gene (Hmg2) was especially obtained from a cDNA library constructed with Phytophthora capsici-infected pepper root RNAs. The Hmg2 encoding a 604-amino-acid peptide had typical features as an elicitor-induced isoform among HMGRs on its gene structure and had a predicted amino acid sequence homology. In addition, the expression of Hmg2 was rapidly induced within 1 h in response to a fungal pathogen and continuously increased up to 48 h. Together with sesquiterpene cyclase gene that was strongly induced 24 h after pathogen-infection, the Hmg2 and farnesyl pyrophosphate synthase gene were coordinately and sequentially regulated for the biosynthesis of defense-related sesquiterpene phytoalexins in pepper.

Alkyl and Aryl Transferases↗
PubMed1998

Biosynthesis of the diterpene verrucosan-2beta-ol in the phototrophic eubacterium Chloroflexus aurantiacus. A retrobiosynthetic NMR study.

The biosynthesis of verrucosan-2beta-ol in the green phototrophic eubacterium Chloroflexus aurantiacus was investigated by in vivo incorporation of singly or doubly 13C-labeled acetate. The 13C labeling of the isolated diterpene was analyzed by one- and two-dimensional NMR spectroscopy. The 13C-labeling patterns of verrucosan-2beta-ol were compared with the labeling patterns of intermediary metabolites (acetyl-CoA, pyruvate, and glyceraldehyde 3-phosphate) which were deduced from amino acids and nucleosides by retrobiosynthetic analysis. The results show that verrucosan-2beta-ol is synthesized via mevalonate and not via the deoxyxylulose pathway, which was discovered recently in some eubacteria, algae, and plants. A scheme for the formation of the unusual tetracyclic ring system is offered. The cyclization process is initiated by the solvolysis of pyrophosphate from geranyllinaloyl pyrophosphate and the mechanism involves a Wagner-Meerwein rearrangement, a 1,5-hydride shift, and a cyclopropylcarbinyl to cyclopropylcarbinyl rearrangement.

Acetyl Coenzyme A↗
PubMed1990

Effect of chemical carcinogens on cholesterol biosynthetic pathways in the skin of mice.

The metabolism of zymosterol and mevalonic acid was studied in vitro using the skin homogenates of 3-methylcholanthrene (3MC), diazacholesterol-treated and untreated mice. In normal mouse skin only lathosterol was a major metabolite and the other metabolites, cholesta-5,7,24-trien-3 beta-ol, desmosterol, cholesterol and 7-dehydrocholesterol were much less abundant. However, in the skin homogenate of mice treated with 3MC lathosterol production was depressed, while the production of cholesta-5,7,24-trien-3 beta-ol and desmosterol was significantly increased, the cholesterol level being normal or a little higher. In contrast, in the skin homogenate of mice administered diazacholesterol the production of both lathosterol and cholesterol was almost completely blocked with the slightly increased production of cholesta-5,7,24-trien-3 beta-ol and desmosterol. The metabolism in vitro of [2-14C]-mevalonic acid was quite similar to that of zymosterol, and no additional product which might possibly have been produced by the Kandutsch-Russell pathway was observed. Two pathways for cholesterol biosynthesis, therefore, may exist in mouse skin; the first is lanosterol----zymosterol----5 alpha-cholesta-7,24-dien-3 beta-ol----lathosterol----7-dehydrocholesterol----cholesterol, and the second by Bloch: lanosterol----zymosterol----5 alpha-cholesta-7,24-dien-3 beta-ol----cholesta-5,7,24-trien-3 beta-ol----desmosterol----cholesterol. When mouse skin is treated with 3-MC the former pathway is virtually blocked and the latter is stimulated, keeping the level of cholesterol in the tissue constant or a little higher than normal, which seems to be a significant change in the early stage of chemical carcinogenesis.

Animals↗
PubMed2001

Chlorophyta exclusively use the 1-deoxyxylulose 5-phosphate/2-C-methylerythritol 4-phosphate pathway for the biosynthesis of isoprenoids.

The biosynthesis of the C5 building block of isoprenoids, isopentenyl diphosphate (IPP), proceeds in higher plants via two basically different pathways; in the cytosolic compartment sterols are formed via mevalonate (MVA), whereas in the plastids the isoprenoids are formed via the 1-deoxyxylulose 5-phosphate/2-C-methylerythritol 4-phosphate pathway (DOXP/MEP pathway). In the present investigation, we found for the Charophyceae, being close relatives to land plants, and in the original green flagellate Mesostignma virilde the same IPP biosynthesis pattern as in higher plants: sterols are formed via MVA, and the phytol-moiety of chlorophylls via the DOXP/MEP pathway. In contrast, representatives of four classes of the Chlorophyta (Chlorophyceae, Ulvophyceae, Trebouxiophyceae, Prasinophyceae) did not incorporate MVA into sterols or phytol. Instead, they incorporated [1-2H1]-1-deoxy-D-xylulose into phytol and sterols. The results indicate that the entire Chlorophyta lineage, which is well separated from the land plant/Charophyceae lineage, is devoid of the acetate/ MVA pathway and uses the DOXP/MEP pathway not only for plastidic, but also for cytosolic isoprenoid formation.

Carbon Radioisotopes↗
PubMed2001

Sterol regulatory element-binding proteins induce an entire pathway of cholesterol synthesis.

To evaluate the effects of sterol regulatory element-binding proteins (SREBPs) on the expression of the individual enzymes in the cholesterol synthetic pathway, we examined expression of these genes in the livers from wild-type and transgenic mice overexpressing nuclear SREBP-1a or -2. As estimated by a Northern blot analysis, overexpression of nuclear SREBP-1a or -2 caused marked increases in mRNA levels of the whole battery of cholesterogenic genes. This SREBP activation covers not only rate-limiting enzymes such as HMG CoA synthase and reductase that have been well established as SREBP targets, but also all the enzyme genes in the cholesterol synthetic pathway tested here. The activated genes include mevalonate kinase, mevalonate pyrophosphate decarboxylase, isopentenyl phosphate isomerase, geranylgeranyl pyrophosphate synthase, farnesyl pyrophosphate synthase, squalene synthase, squalene epoxidase, lanosterol synthase, lanosterol demethylase, and 7-dehydro-cholesterol reductase. These results demonstrate that SREBPs activate every step of cholesterol synthetic pathway, contributing to an efficient cholesterol synthesis.

Animals↗
PubMed1994

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

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

Animals↗
PubMed1989

Control of DNA replication and cell growth by inhibiting the export of mitochondrially derived citrate.

When citrate export from mitochondria is blocked with 1,2,3-benzenetricarboxylate (BTC) during the G1/S phase of the cell cycle, both DNA synthesis and cell growth are dramatically inhibited in suspension-grown 70Z/3 murine lymphoma cell cultures sustained under otherwise optimal conditions. Synchronized (G0/G1 or G1/S) and unsynchronized cultures are susceptible to this phenomenon. BTC prevents two requirements from being met. (1) It deprives the cytosol of the acetyl CoA necessary for operation of the cholesterogenesis pathway, thereby depleting the supply of mevalonate (MVA) implicated as a requirement for triggering DNA synthesis. (2) It behaves as a nonmetabolizable divalent cation chelator, reducing the availability of Ca2+ and Mg2+, which, in whole cells are both required for DNA synthesis. Such inhibitions are reversible. In whole cells, removal of the inhibitor yields rapid and complete recovery of DNA synthesis. During the prolonged presence of BTC, the addition of MVA plus the Ca2+ ionophore A23187 allows partial recovery of DNA synthesis. In isolated, DNA synthesizing nuclei, on the other hand, the slight inhibition of DNA synthesis by BTC is reversed merely by addition of Mg2+. We conclude that the uninterrupted production of citrate-derived MVA via the mitochondria, at the G1/S boundary of the cell cycle (i.e., subsequent to peak cholesterol synthesis), is mandatory for initiating the duplication of the cell genome. Consequently, by its mitochondrial site of action, BTC can severely limit the otherwise continuous supply of MVA during late G1, which in turn, prevents entry into the S phase, and thereby cell proliferation.

Animals↗