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PubMed2006

The role of the endocannabinoid system in the control of energy homeostasis.

The endocannabinoid system has recently emerged as an important regulator of energy homeostasis, involved in the control of both appetite and peripheral fat metabolism. We briefly review current understanding of the possible sites of action and cellular mechanisms involved in the central appetitive and peripheral metabolic effects of endocannabinoids. Studies in our laboratory, using leptin-deficient obese rodents and CB1 cannabinoid receptor (CB1)-deficient mice, have indicated that endocannabinoids acting via CB1 are involved in the hunger-induced increase in food intake and are negatively regulated by leptin in brain areas involved in appetite control, including the hypothalamus, limbic forebrain and amygdala. CB1-/- mice are lean and are resistant to diet-induced obesity (DIO) despite similar energy intake to wild-type mice with DIO, suggesting that CB1 regulation of body weight involves additional peripheral targets. Such targets appear to include both adipose tissue and the liver. CB1 expressed in adipocytes has been implicated in the control of adiponectin secretion and lipoprotein lipase activity. Recent findings indicate that both endocannabinoids and CB1 are present in the liver and are upregulated in DIO. CB1 stimulation increases de novo hepatic lipogenesis through activation of the fatty acid biosynthetic pathway. Components of this pathway are also expressed in the hypothalamus where they have been implicated in the regulation of appetite. The fatty acid biosynthetic pathway may thus represent a common molecular target for the central appetitive and peripheral metabolic effects of endocannabinoids.

Animals↗

PubMed2005

Biosynthesis of irregular diterpenes in Anisotome lyallii by head-to-head coupling of geranyl diphosphate.

Anisotomenes, bicyclic irregular diterpenes found in the genus Anisotome(family Apiaceae), are shown to be products of a unique biosynthetic pathway, involving head-to-head coupling of two geranyl diphosphate units. (13)C labelling studies with [1-(13)C]-glucose on plantlets of A. lyallii also revealed that the isoprene subunits were formed via the MEP pathway. The in vitro-cultured plant material also yielded a new irregular, linear diterpene alcohol, that shares the same biosynthetic pathway.

Apiaceae↗

PubMed1984

Metabolism of 4'-phosphopantetheine in Escherichia coli.

Coenzyme A (CoA) and acyl carrier protein (ACP) contain 4'-phosphopantetheine moieties that are metabolically derived from the vitamin pantothenate. The utilization of metabolites in the biosynthetic pathway during growth was investigated by using an Escherichia coli beta-alanine auxotroph to specifically and uniformly label the pathway intermediates. Pantothenate and 4'-phosphopantetheine were the two intermediates detected in the highest concentration, both intracellularly and extracellularly. The specific cellular content of CoA and ACP was not constant during growth of strain SJ16 (panD) on 4 microM beta-[3-3H]alanine, and alterations in the utilization of 4'-phosphopantetheine and pantothenate correlated with the observed fluctuations of the intracellular pool sizes of CoA and ACP. Double-label experiments indicated that extracellular 4'-phosphopantetheine was derived from the degradation of ACP, and the extent that this intermediate was utilized by 4'-phosphopantetheine adenylyltransferase exerted control over the degradative aspect of the pathway. Control over the biosynthetic aspect of the biochemical pathway was exerted at the level of pantothenate utilization by pantothenate kinase. Reduction in the specific cellular content of CoA and ACP by 4'-phosphopantetheine excretion was irreversible since, in contrast to pantothenate, strain SJ16 was unable to assimilate exogenous 4'-phosphopantetheine into CoA or ACP.

Acyl Carrier Protein↗

PubMed1984

A kinetic study of the immediate nucleotide precursor of riboflavin in whole cells of Eremothecium ashbyii at rest.

Acid -soluble nucleotides from the mycelia were clearly separated by column chromatography on Dowex 1 X 2(HCOO-, 200 to 400 mesh). Under the experimental conditions used [2--14C] xanthine and [2--14C] guanine added were not incorporated into adenosine nucleotides but only into the guanosine nucleotides-GMP, GDP, GDP-Man, and GpA. Purines labeled at carbon 2 were effectively transferred to riboflavin but not radioactivity from [8--14C]--hypoxanthine was detected in the produced riboflavin. Comparison of the specific activity/time curves of guanosine nucleotides and riboflavin indicated that the specific activity of newly formed riboflavin coincides perfectly with that of GTP during incubation, and that the specific activity of accumulated riboflavin, at its maximum value, intersects the GTP curve. Thus, the kinetic studies with whole cells of E. ashbyii provide clear evidence that, among various nucleotides, GTP is the immediate precursor of riboflavin, and further attest that the intermediates involved in the biosynthetic pathway of the nucleotide precursor to riboflavin are in a trace amounts but have high turnover rates and, that the biosynthetic pathway has no salvage pathway for the intermediate derivatives, di- and tri-amino pyrimidines.

Adenosine↗

PubMed1996

Coordinate regulation of bile acid biosynthetic and recovery pathways.

Intestinal and hepatic recovery of bile acids is principally mediated by sodium dependent bile acid transporters. Of these, the ileal sodium bile acid transporter (isbt) and the hepatic sodium bile acid cotransporting polypeptide (ntcp) may be most important in determining the efficiency of bile acid recovery within the enterohepatic circulation. We used molecular probes to explore the relationship between the bile acid recovery pathway, at the level of isbt and ntcp, and the biosynthetic pathway, at the level of cholesterol 7 alpha-hydroxylase (cyp7). Taurocholate feeding of mice suppressed ntcp, isbt, and cyp7 mRNA levels as compared to controls. Cholestyramine feeding induced both cyp7 and isbt mRNA gene expression. Cholesterol feeding induced cyp7 mRNA levels but suppressed isbt gene expression. These results suggest that in mice the bile acid recovery and biosynthetic pathways are coordinately regulated, and these pathways may be responsive to the size of the bile acid pool in the enterohepatic circulation.

Animals↗

PubMed2002

The polyphosphate kinase plays a negative role in the control of antibiotic production in Streptomyces lividans.

The polyphosphate kinase gene (ppk) from Streptomyces lividans, which encodes a 774-amino-acid protein (86.4 kDa) showing extensive homology to other bacterial polyphosphate kinases, was cloned by polymerase chain reaction (PCR) using oligonucleotides derived from the putative ppk gene from the closely related species, Streptomyces coelicolor. In vitro, the purified Ppk was shown to be able to synthesize the polyphosphate [poly(P)] from ATP (forward reaction) as well as to regenerate ATP from the poly(P) in the presence of an excess of ADP (reverse reaction). In conditions of poly(P) synthesis, a phosphoenzyme intermediate was detected, indicating an autophosphorylation of the enzyme in the presence of ATP. The ppk gene was shown to be transcribed as a monocistronic mRNA from a unique promoter. Its transcription was only detectable during the late stages of growth in liquid minimal medium. A mutant strain interrupted for ppk was characterized by increased production of the antibiotic actinorhodin on rich R2YE solid medium (0.37 mM KH2PO4 added). This production was enhanced on the same medium with no KH2PO4 added but was completely abolished by the addition of 1.48 mM KH2PO4. In the ppk mutant strain, this increased production correlated with enhanced transcription of actII-ORF4 encoding the specific activator of the actinorhodin pathway. In that strain, the transcription of redD and cdaR, encoding the specific activators of the undecylprodigiosin and calcium-dependent antibiotic biosynthetic pathways, respectively, was also increased but to a lesser extent. The enhanced expression of these regulators did not seem to be related to increased relA-dependent ppGpp synthesis, as no obvious increase in relA expression was observed in the ppk mutant strain. These results suggested that the negative regulatory effect exerted by Ppk on antibiotic biosynthesis was most probably caused by the repression exerted by the endogenous Pi, resulting from the hydrolysis of the poly(P) synthesized by Ppk, on the expression of the specific activators of the antibiotic biosynthetic pathways.

Anti-Bacterial Agents↗

PubMed1992

Antimalarial activity of orotate analogs that inhibit dihydroorotase and dihydroorotate dehydrogenase.

Dihydroorotase and dihydroorotate dehydrogenase, two enzymes of the pyrimidine biosynthetic pathway, were purified from Plasmodium berghei to apparent homogeneity. Orotate and a series of 5-substituted derivatives were found to inhibit competitively the purified enzymes from the malaria parasite. The order of effectiveness as inhibitors on pyrimidine ring cleavage reaction for dihydroorotase was 5-fluoro orotate greater than 5-amino orotate, 5-methyl orotate greater than orotate greater than 5-bromo orotate greater than 5-iodo orotate with Ki values of 65, 142, 166, 860, 2200 and greater than 3500 microM, respectively. 5-Fluoro orotate and orotate were the most effective inhibitors for dihydroorotate dehydrogenase. In vitro, 5-fluoro orotate and 5-amino orotate caused 50% inhibition of the growth of P. falciparum at concentrations of 10 nM and 1 microM, respectively. In mice infected with P. berghei, these two orotate analogs at a dose of 25 mg/kg body weight eliminated parasitemia after a 4-day treatment, an effect comparable to that of the same dose of chloroquine. The infected mice treated with 5-fluoro orotate at a lower dose of 2.5 mg/kg had a 95% reduction in parasitemia. The effects of the more potent compounds tested in combination with inhibitors of other enzymes of this pathway on P. falciparum in vitro and P. berghei in vivo are currently under investigation. These results suggest that the pyrimidine biosynthetic pathway in the malarial parasite may be a target for the design of antimalarial drugs.

Animals↗

PubMed2000

Studies on the biosynthesis of taxol. Synthesis Of taxa-4(20), 11(12)-diene-2alpha,5alpha-diol.

The synthesis of taxa-4(20),11(12)-diene-2alpha,5alpha-diol is described. An improved procedure for the intramolecular Diels-Alder cycloaddition previously reported in our synthesis of taxa-4(5), 11(12)-diene has been utilized to prepare a taxoid with oxygenation in the B and C rings. It has been established previously that taxa-4(20),11(12)-dien-5alpha-ol is the first oxygenated intermediate on the biosynthetic pathway to Taxol. Taxa-4(20), 11(12)-diene-2alpha,5alpha-diol (5), which has been observed in a biosynthetic conversion, is a potential candidate as the second oxygenated intermediate on the Taxol biosynthetic pathway, has been prepared to probe the intermediacy of this substance.

Antineoplastic Agents, Phytogenic↗

PubMed2003

Comparative genomics of the vitamin B12 metabolism and regulation in prokaryotes.

Using comparative analysis of genes, operons, and regulatory elements, we describe the cobalamin (vitamin B12) biosynthetic pathway in available prokaryotic genomes. Here we found a highly conserved RNA secondary structure, the regulatory B12 element, which is widely distributed in the upstream regions of cobalamin biosynthetic/transport genes in eubacteria. In addition, the binding signal (CBL-box) for a hypothetical B12 regulator was identified in some archaea. A search for B12 elements and CBL-boxes and positional analysis identified a large number of new candidate B12-regulated genes in various prokaryotes. Among newly assigned functions associated with the cobalamin biosynthesis, there are several new types of cobalt transporters, ChlI and ChlD subunits of the CobN-dependent cobaltochelatase complex, cobalt reductase BluB, adenosyltransferase PduO, several new proteins linked to the lower ligand assembly pathway, l-threonine kinase PduX, and a large number of other hypothetical proteins. Most missing genes detected within the cobalamin biosynthetic pathways of various bacteria were identified as nonorthologous substitutes. The variable parts of the cobalamin metabolism appear to be the cobalt transport and insertion, the CobG/CbiG- and CobF/CbiD-catalyzed reactions, and the lower ligand synthesis pathway. The most interesting result of analysis of B12 elements is that B12-independent isozymes of the methionine synthase and ribonucleotide reductase are regulated by B12 elements in bacteria that have both B12-dependent and B12-independent isozymes. Moreover, B12 regulons of various bacteria are thought to include enzymes from known B12-dependent or alternative pathways.

Bacterial Physiological Phenomena↗

PubMed2005

Regulation of pyrimidine synthesis in Pseudomonas resinovorans.

AIMS: To investigate the regulation of de novo pyrimidine biosynthesis in the bacterium Pseudomonas resinovorans ATCC 14235. METHODS AND RESULTS: The pyrimidine biosynthetic pathway enzymes were measured in cell extracts from P. resinovorans ATCC 14235 and from an auxotroph lacking orotate phosphoribosyltransferase activity. Pyrimidine biosynthetic pathway enzyme activities in ATCC 14235 were affected by the addition of pyrimidine bases to the culture medium. The de novo enzyme activities of the phosphoribosyltransferase mutant strain increased after pyrimidine starvation indicating possible repression of the pathway by a pyrimidine-related compound. Aspartate transcarbamoylase activity in ATCC 14235 was inhibited in vitro by ATP, UTP and pyrophosphate. CONCLUSIONS: Pyrimidine biosynthesis in P. resinovorans was regulated at the level of enzyme synthesis and at the level of activity for aspartate transcarbamoylase. Its regulation of enzyme synthesis seemed to be similar to what has been observed in the taxonomically related species Pseudomonas oleovorans. SIGNIFICANCE AND IMPACT OF THE STUDY: This study found that pyrimidine biosynthesis is regulated in P. resinovorans. This could prove helpful to future studies investigating polyhydroxyalkanoate production by the bacterium.

Adenosine Triphosphate↗

PubMed1991

Genetic analysis of photosynthesis in Rhodospirillum centenum.

A genetic system has been developed for studying bacterial photosynthesis in the recently described nonsulfur purple photosynthetic bacterium Rhodospirillum centenum. Nonphotosynthetic mutants of R. centenum were obtained by enrichment for spontaneous mutations, by ethyl methanesulfonate mutagenesis coupled to penicillin selection on solid medium, and by Tn5 transposition mutagenesis with an IncP plasmid vector containing a temperature-sensitive origin of replication. In vivo and in vitro characterization of individual strains demonstrated that 38 strains contained mutations that blocked bacteriochlorophyll a biosynthesis at defined steps of the biosynthetic pathway. Collectively, these mutations were shown to block seven of eight steps of the pathway leading from protoporphyrin IX to bacteriochlorophyll a. Three mutants were isolated in which carotenoid biosynthesis was blocked early in the biosynthetic pathway; the mutants also exhibited pleiotropic effects on stability or assembly of the photosynthetic apparatus. Five mutants failed to assemble a functional reaction center complex, and seven mutants contained defects in electron transport as shown by an alteration in cytochromes. In addition, several regulatory mutants were isolated that acquired enhanced repression of bacteriochlorophyll in response to the presence of molecular oxygen. The phenotypes of these mutants are discussed in relation to those of similar mutants of Rhodobacter and other Rhodospirillum species of purple photosynthetic bacteria.

Bacteriochlorophylls↗

PubMed1988

Regulation of 5-aminolevulinate synthase in mouse erythroleukemic cells is different from that in liver.

We have measured the transcriptional gene activity of 5-aminolevulinate synthase, the first enzyme of the heme biosynthetic pathway, together with corresponding mRNA and protein levels in mouse erythroleukemic cells induced to differentiate with dimethyl sulfoxide. When the heme biosynthetic pathway was blocked by succinylacetone there was a large increase in both 5-aminolevulinate synthase activity and protein levels, and this was reversed by the addition of exogenous hemin. Transcriptional activity of the 5-aminolevulinate synthase gene and mRNA levels were both significantly increased during differentiation of cells by dimethyl sulfoxide but were not markedly altered by succinylacetone or hemin treatment. The results demonstrate that levels of 5-aminolevulinate synthase in mouse erythroleukemic cells are regulated by a significant post-transcriptional mechanism possibly at the translational level. Evidence is also presented for a less significant post-transcriptional control by heme of mRNA levels for 5-aminolevulinate synthase. These results indicate that the regulation of 5-aminolevulinate synthase in differentiating erythroid cells is complex but differs from that in liver cells where heme controls the level of 5-aminolevulinate synthase by acting primarily to inhibit gene transcription.

5-Aminolevulinate Synthetase↗

PubMed1976

Sequential induction of heme pathway enzymes during erythroid differentiation of mouse Friend leukemia virus-infected cells.

The process of erythroid differentiation in mouse Friend leukemia virus transformed cells (T3-C1-2) was examined by following changes in several enzyme activities of the heme biosynthetic pathway and in heme concentration while the cells were undergoing erythroid differentiation after treatment with dimethylsulfoxide. Untreated cells on the one hand, have a limited capacity for spontaneous differentiation. On the other hand, dimethylsulfoxide(DMSO)-treated cells showed an increase in the activities of delta-aminolevulinic acid (ALA) synthetase, ALA dehydratase, uroporphyrinogen-I synthetase, ferrochelatase, and heme concentration by days 1, 1.5, 2, and 4, respectively. The increase of the heme pathway enzymes and heme concentration followed the order of these enzymes or products as they are arranged in the heme biosynthetic pathway. These changes induced by DMSO were effectively inhibited by treatment with actinomycin D, suggesting that continued RNA synthesis is required for the differentiation process. 5-bromo-2'-deoxyuridine (BrdU) (10(-5) M) inhibited the DMSO-induced changes of the heme pathway enzymes. BrdU was most effective when it was present during the first 2 days of cell culture. It gradually lost its inhibitory effect when added after the 3rd day or later. The BrdU-mediated inhibition was completely overcome by the addition of thymidine (7 x 10(-5) M), but not by uridine (7 x 10(-5) M). All these data suggest that a sequential induction of the heme pathway enzyme takes place during erythroid differentiation of Friend leukemia cells, and that the sequential induction of the enzymes may be due to a sequential activation of genes coding for these enzyme activities.

5-Aminolevulinate Synthetase↗

PubMed2000

Polyamines and plant alkaloids.

Naturally occurring alkaloids are nitrogenous compounds that constitute the pharmacogenically active basic principles of flowering plants. Alkaloids are classified into several biogenically related groups. Tobacco alkaloids are metabolised from polyamines and diamines putrescine and cadaverine. N-methyl transferase is the first enzyme in alkaloid biosynthetic pathway which drives the flow of nitrogen away from polyamine biosynthesis to alkaloid biosynthesis. Arginine decarboxylase has been suggested to be primarily responsible for providing putrescine for nicotine synthesis. Tryptophan is the precursor of indole alkaloids. However, the biosynthetic pathway of tropane and isoquinoline alkaloids are not clear. Genes for several key biosynthetic enzymes like arginine decarboxylase, ornithine decarboxylase, putrescine N-methyl transferase and spermidine synthase, hyoscyamine 6 beta hydroxylase,tryptophan decarboxylase etc have been cloned from different plant species. These genes are regulated by plant hormones, light, different kinds of stress and elicitors like jasmonates and their strong expression is primarily in the cultured roots. In view of this, the axenic hairy root cultures induced by Agrobacterium rhizogenes have been utilised to synthesise secondary metabolites. The current development in the knowledge of alkaloid biosynthesis, particularly molecular analysis, has been discussed in this review that may help to open up new avenues of investigation for the researchers.

Alkaloids↗

PubMed1995

Regulation of heme biosynthesis in Escherichia coli.

Escherichia coli is an organism that synthesizes 5-aminolevulinate (ALA), the first committed compound of the heme biosynthetic pathway, from glutamate (C-5 pathway) as opposed to glycine and succinyl CoA (C-4 pathway). While regulation of the C-4 pathway is generally acknowledged to occur at the level of formation of ALA, the mode of regulation of the C-5 pathway is currently unclear. Here we have examined one aspect of regulation of heme synthesis in E. coli: the role of the end product, heme, as a feed-back regulator of ALA production. By using plasmid-encoded ALA synthase and/or cytochrome b5 expressed in a wild type E. coli strain, it was possible to determine the role that the proposed regulatory heme pool plays in the regulation of ALA and heme production. Expression of rat-soluble cytochrome b5 results in an increase of cellular heme, indicating that the cell responds to this foreign "heme sink" by producing more heme even though the cytochrome does not participate directly in normal cellular regulation. Accumulation of pathway intermediates does not occur under these conditions. Expression of plasmid-encoded mouse ALA synthase results in increased cellular heme production as well as the accumulation of pathway intermediates either in the presence or absence of plasmid encoded cytochrome b5. These data support a regulatory scheme where the heme biosynthetic pathway in this C-5 organism is regulated at the level of ALA production in part by cellular heme content.

5-Aminolevulinate Synthetase↗

PubMed1983

Participation of transcriptional and post-transcriptional regulatory mechanisms in the control of arginine metabolism in yeast.

In yeast, as in other organisms, amino acid biosynthetic pathways share a common regulatory control. The manifestation of this control is that derepression of the enzymes belonging to several amino acid biosynthetic pathways follows amino acid starvation or tRNA discharging. The arginine anabolic and catabolic pathways are, in addition, regulated specifically by arginine in opposite ways by common regulators. We have measured the mRNA levels for four genes subject to the general amino acid control: HIS4, ARG3, ARG4 and CPAII and compared them to the corresponding enzyme levels. Similarly we have measured the mRNA levels for two genes subject to the arginine specific regulation: ARG3 and CAR1, the former gene belongs to the arginine anabolic pathway and the latter to the arginine catabolic one. HIS4, ARG4 and CPAII enzyme and messenger amounts are perfectly coordinated in all the conditions of general repression or derepression tested. However, arginine does not reduce the level of the ARG3 mRNA enough to explain the reduction of ornithine carbamoyltransferase activity nor does it increase the level of the CAR1 mRNA enough to explain the extent of induction of arginase. Coordination of enzyme and ARG3 mRNA is achieved only when the specific control is eliminated. The half-lives of the ARG3 and CAR1 messengers are enhanced in mutants leading to constitutive expression of ornithine carbamoyltransferase and arginase. These data suggest that the control that coordinates the synthesis of all the amino acids in the yeast cell operates at the level of transcription while the arginine specific regulatory mechanism seems to operate at a post-transcriptional level.

Arginine↗

PubMed2004

Biosynthesis of deoxyaminosugars in antibiotic-producing bacteria.

Deoxyaminosugars comprise an important class of deoxysugars synthesized by a variety of different microorganisms; they can be structural components of lipopolysaccharides, extracellular polysaccharides, and secondary metabolites such as antibiotics. Genes involved in the biosynthesis of the deoxyaminosugars are often clustered and are located in the vicinity of other genes required for the synthesis of the final compound. Most of the gene clusters for aminosugar biosynthesis have common features, as they contain genes encoding dehydratases, isomerases, aminotransferases, methyltransferases, and glycosyltransferases. In the present mini-review, the proposed biosynthetic pathways for deoxyaminosugar components of both macrolide and non-macrolide antibiotics are highlighted. The possibilities for genetic manipulations of the deoxyaminosugar biosynthetic pathways aimed at production of novel secondary metabolites are discussed.

Amino Sugars↗

PubMed2000

Lesions in gshA (Encoding gamma-L-glutamyl-L-cysteine synthetase) prevent aerobic synthesis of thiamine in Salmonella enterica serovar typhimurium LT2.

Thiamine pyrophosphate is an essential cofactor that is synthesized de novo in Salmonella enterica serovar Typhimurium and other bacteria. In addition to genes encoding enzymes in the biosynthetic pathway, mutations in other metabolic loci have been shown to prevent thiamine synthesis. The latter loci identify the integration of the thiamine biosynthetic pathway with other metabolic processes and can be uncovered when thiamine biosynthesis is challenged. Mutations in gshA, encoding gamma-L-glutamyl-L-cysteine synthetase, prevent the synthesis of glutathione, the major free thiol in the cell, and are shown here to result in a thiamine auxotrophy in some of the strains tested, including S. enterica LT2. Phenotypic characterization of the gshA mutants indicated they were similar enough to apbC and apbE mutants to warrant the definition of a class of mutants unified by (i) a requirement for both the hydroxymethyl pyrimidine (HMP) and thiazole (THZ) moiety of thiamine, (ii) the ability of L-tryosine to satisfy the THZ requirement, (iii) suppression of the thiamine requirement by anaerobic growth, and (iv) suppression by a second-site mutation at a single locus. Genetic data indicated that a defective ThiH generates the THZ requirement in these strains, and we suggest this defect is due to a reduced ability to repair a critical [Fe-S] cluster.

Aconitate Hydratase↗