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PubMed1970

Inhibition of lipid synthesis and glucose-6-phosphate dehydrogenase in rat skin by dehydroepiandrosterone.

Lipid synthesis from acetate-1-(14)C by rat skin was inhibited 44-56% by 2.5 x 10(-4) m dehydroepiandrosterone (DHA) in vitro with or without addition of glucose in the incubation medium. This inhibition affected all the lipid fractions examined (hydrocarbons, sterols, sterol esters, tri-, di- and monoglycerides, fatty acids, and polar lipids) and could be reversed by NADPH. DHA also inhibited lipid synthesis from glucose-U-(14)C and the formation of (14)CO(2) from glucose-1-(14)C, indicating interference with pentose cycle activity. Experiments with the 105,000 g supernatant fluid of rat skin homogenates demonstrated considerable activities of malic enzyme (ME) (12.6 nmoles of NADPH generated per min per mg of protein), of glucose-6-phosphate dehydrogenase (G6PD), and of 6-phosphogluconate dehydrogenase (6PGD) (17.5 nmoles of NADPH generated per min per mg of protein). G6PD was inhibited 98% by 2.5 x 10(-4) m dehydroepiandrosterone, while 6PGD and ME were not affected. It can be estimated from these data that the pentose cycle may contribute 41-57% of the NADPH needed for lipid synthesis in rat skin; the remainder of the necessary NADPH is presumably supplied by malic enzyme.

Acetates↗
PubMed2001

Pyruvate carboxylation in neurons.

Carboxylation of pyruvate in the brain was for many years thought to occur only in glia, an assumption that formed much of the basis for the concept of the glutamine cycle. It was shown recently, however, that carboxylation of pyruvate to malate occurs in neurons and that it supports formation of transmitter glutamate. The role of pyruvate carboxylation in neurons is to ensure tricarboxylic acid cycle activity by compensating for losses of alpha-ketoglutarate that occur through release of transmitter glutamate and GABA; these amino acids are alpha-ketoglutarate derivatives. Available data suggest that neuronal pyruvate carboxylation is quantitatively important. But because there is no net CO(2) fixation in the brain, pyruvate carboxylation must be balanced by decarboxylation of malate or oxaloacetate. Such decarboxylation occurs in both neurons and astrocytes. Several in vitro studies have shown a neuroprotective effect of pyruvate supplementation. Pyruvate carboxylation may be one mechanism through which such treatment is effective, because pyruvate carboxylation through malic enzyme is active during energy deficiency and leads to an increase in the level of dicarboxylates that can be metabolized through the tricarboxylic acid cycle for ATP production.

Animals↗
PubMed2001

The homeodomain proteins PBX and MEIS1 are accessory factors that enhance thyroid hormone regulation of the malic enzyme gene in hepatocytes.

Triiodothyronine (T3) stimulates a robust increase (>40-fold) in transcription of the malic enzyme gene in chick embryo hepatocytes. Previous work has shown that optimal T3 regulation of malic enzyme transcription is dependent on the presence of an accessory element (designated as region E) that immediately flanks a cluster of five T3 response elements in the malic enzyme gene. Here, we have analyzed the binding of nuclear proteins to region E and investigated the mechanism by which region E enhances T3 responsiveness. In nuclear extracts from hepatocytes, region E binds heterodimeric complexes consisting of the homeodomain proteins PBX and MEIS1. Region E contains four consecutive PBX/MEIS1 half-sites. PBX-MEIS1 heterodimers bind the first and second half-sites, the third and fourth half-sites, and the first and fourth half-sites. The configuration conferring the greatest increase in T3 responsiveness consists of the first and fourth half-sites that are separated by 7 nucleotides. Stimulation of T3 response element functions by region E does not require the presence of additional malic enzyme sequences. In pull-down experiments, PBX1a and PBX1b specifically bind the nuclear T3 receptor-alpha, and this interaction is enhanced by the presence of T3. A T3 receptor-alpha region containing the DNA binding domain plus flanking sequences (amino acids 21-157) is necessary and sufficient for binding to PBX1a and PBX1b. These results indicate that PBX-MEIS1 complexes interact with nuclear T3 receptors to enhance T3 regulation of malic enzyme transcription in hepatocytes.

Animals↗
PubMed1964

PURIFICATION AND PROPERTIES OF ENZYMES INVOLVED IN THE PROPIONIC ACID FERMENTATION.

Allen, S. H. G. (Western Reserve University, Cleveland, Ohio), R. W. Kellermeyer, R. L. Stjernholm, and Harland G. Wood. Purification and properties of enzymes involved in the propionic acid fermentation. J. Bacteriol. 87:171-187. 1964.-Chromatographic procedures are described for the separation and purification of phosphotransacetylase, acetyl kinase, malic dehydrogenase and coenzyme A (CoA) transferase. Purity of the enzymes was judged by homogeneity in an ultracentrifuge and by specific activity. Phosphotransacetylase was obtained 85% pure with a specific activity of 27.1. The preparation of acetyl kinase was a homogeneous protein with a specific activity of 531. The malic dehydrogenase likewise was homogeneous with a specific activity of 938. The CoA transferase, which was about 56% pure with a specific activity of 42.6, is the purest preparation of this enzyme yet described. The pH optimum was 6.5 to 7.8, and the K(m) for succinyl-CoA in the transfer of CoA to acetate was found to be 1.3 x 10(-4)m; for acetate, in the same transfer, the K(m) was 7.0 x 10(-3)m; for succinyl-CoA to propionate it was 6.8 x 10(-5)m, and for propionate, in the same reaction, 6.2 x 10(-4)m. Methods are described for the enzymatic production of methyl-malonyl-CoA, malonyl-CoA, propionyl-CoA, acetyl-CoA, and succinyl-CoA. The role of these enzymes in the propionic acid fermentation as well as the possible mechanism responsible for the high yields of adenosine triphosphate from glucose are considered.

Acetates↗
PubMed1982

Biosynthetic Pathways of Vibrio succinogenes growing with fumarate as terminal electron acceptor and sole carbon source.

1. With fumarate as the terminal electron acceptor and either H2 or formate as donor, Vibrio succinogenes could grow anaerobically in a mineral medium using fumarate as the sole carbon source. Both the growth rate and the cell yield were increased when glutamate was also present in the medium. 2. Glutamate was incorporated only into the amino acids of the glutamate family (glutamate, glutamine, proline and arginine) of the protein. The residual cell constituents were synthesized from fumarate. 3. Pyruvate and phosphoenolpyruvate, as the central intermediates of most of the cell constituents, were formed through the action of malic enzyme and phosphoenolpyruvate synthetase. Fructose-1,6-bisphosphate aldolase was present in the bacterium suggesting that this enzyme is involved in carbohydrate synthesis. 4. In the absence of added glutamate the amino acids of the glutamate family were synthesized from fumarate via citrate. The enzymes involved in glutamate synthesis were present. 5. During growth in the presence of glutamate, net reducing equivalents were needed for cell synthesis. Glutamate and not H2 or formate was used as the source of these reducing equivalents. For this purpose part of the glutamate was oxidized to yield succinate and CO2. 6. The alpha-ketoglutarate dehydrogenase involved in this reaction was found to use ferredoxin as the electron acceptor. The ferredoxin of the bacterium was reoxidized by means of a NADP-ferredoxin oxidoreductase. Enzymes catalyzing the reduction of NAD, NADP or ferredoxin by H2 or formate were not detected in the bacterium.

Electron Transport↗
PubMed2006

Theoretical analysis of amino acid-producing Escherichia coli using a stoichiometric model and multivariate linear regression.

This work demonstrates a novel computational approach combining flux balance modeling with statistical methods to identify correlations among fluxes in a metabolic network, providing insight as to how the fluxes should be redirected to achieve maximum product yield. The procedure is demonstrated using the example of amino acid production from an industrial Escherichia coli production strain and a hypothetical engineered strain overexpressing two heterologous genes. Regression analysis based on a random sampling of 5,000 points within the feasible solution space of the E. coli stoichiometric network suggested that increased activity of the glyoxylate cycle or PEP carboxylase and elimination of malic enzyme will improve lysine and arginine synthesis.

Amino Acids↗
PubMed1988

Metabolic alterations induced by topical dimethylacetylenedicarboxylate.

The disposition of topical dimethylacetylenedicarboxylate (DMAD) in tissue and its effect on glucose metabolism were studied in vivo, using skin grafted athymic nude mice, and in vitro, using excised pig skin. [14C]DMAD that penetrated skin grafts was distributed throughout the body. At 24 hr, the liver contained 15.62% of the applied dose. The kidneys, lungs, brain, and the heart contained 12.73, 5.61, 0.36, and 3.24% of the dose, respectively. One hour postapplication, DMAD markedly decreased [U-14C]glucose oxidation and the syntheses of fatty acids and glycogen in the livers and skin grafts. Similar effects were observed in excised pig skin. In addition, the activities of hepatic glucose-6-phosphate dehydrogenase, isocitric and NADP-malic dehydrogenase, and acetyl-CoA carboxylase were significantly reduced in DMAD-treated mice. In contrast, no effect was observed on the activity of glucokinase. The data indicate that DMAD rapidly penetrates the skin and causes aberrations in the activities of the glycogenic, lipogenic, and tricarboxylic acid metabolic pathways.

Acetylene↗
PubMed1994

Characterization of a bean (Phaseolus vulgaris L.) malic-enzyme gene.

We have isolated a genomic clone encoding a plant NADP(+)-dependent malic enzyme (NADP-ME). This clone, isolated from bean (Phaseolus vulgaris L.), covers the entire gene (exons, introns) and 5'-flanking regions. DNA sequencing defines 20 exons spanning approximately 4.5 kb, which range over 48-235 bp in size. All 19 introns are fairly small (79-391). The first intron resides in the 5'-untranslated leader sequence. Introns 10, 11 and 16 are located at positions identical to a rat malic-enzyme gene. In the promoter region, a TATA box (TATATATA) is easily recognized 41 bp upstream of a single transcription-initiation site. Two potential cis-acting elements with homology to elements from plant genes, activated by UV light and fungal elicitors, were identified at positions -153 and -312, respectively. Southern-blot analysis suggests a single gene copy, but also other distantly related genes, in the bean genome. The deduced NADP-ME protein of 589 amino acids exhibits features consistent with a cytoplasmic location. We describe the organization of the NADP-ME protein into functional domains located on separate exons. The evolution of malic-enzyme genes coding for isoforms in different cellular compartments of plants and animals is discussed.

Amino Acid Sequence↗
PubMed1998

Glutamate Biosynthesis in Lactococcus lactis subsp. lactis NCDO 2118

Unlike other lactic acid bacteria, Lactococcus lactis subsp. lactis NCDO 2118 was able to grow in a medium lacking glutamate and the amino acids of the glutamate family. Growth in such a medium proceeded after a lag phase of about 2 days and with a reduced growth rate (0.11 h-1) compared to that in the reference medium containing glutamate (0.16 h-1). The enzymatic studies showed that a phosphoenolpyruvate carboxylase activity was present, while the malic enzyme and the enzymes of the glyoxylic shunt were not detected. As in most anaerobic bacteria, no alpha-ketoglutarate dehydrogenase activity could be detected, and the citric acid cycle was restricted to a reductive pathway leading to succinate formation and an oxidative branch enabling the synthesis of alpha-ketoglutarate. The metabolic bottleneck responsible for the limited growth rate was located in this latter pathway. As regards the synthesis of glutamate from alpha-ketoglutarate, no glutamate dehydrogenase was detected. While the glutamate synthase-glutamine synthetase system was detected at a low level, high transaminase activity was measured. The conversion of alpha-ketoglutarate to glutamate by the transaminase, the reverse of the normal physiological direction, operated with different amino acids as nitrogen donor. All of the enzymes assayed were shown to be constitutive.

Journal Article↗
PubMed1994

Pyruvate metabolism in Halobacterium salinarium studied by intracellular 13C nuclear magnetic resonance spectroscopy.

13C nuclear magnetic resonance spectroscopy was used to study the metabolism of [2-13C]pyruvate in intact cells of Halobacterium salinarium. The spectra of these cells show that pyruvate is reduced to lactic acid and transaminated to alanine. The intensity of C-2 lactate is higher under anaerobic conditions than under aerobic conditions. When cells are grown in the absence of glucose, the level of C-2 lactate intensity is lower. In extracts of these cells, the level of NADH-dependent lactate dehydrogenase activity is lower than that of cells grown in the presence of glucose. A C-5 glutamate resonance suggests the entry of pyruvate into the tricarboxylic acid cycle through acetyl-coenzyme A. In addition, the label is also observed at C-3 and C-4 of glutamate, signifying a pyruvate carboxylase-type reaction and scrambling of label at the fumarate-succinate stage plus malic enzyme operation, respectively. Citrate synthase and malic enzyme activity appear to be controlled by the growth conditions of H. salinarium.

Alanine↗
PubMed2004

Roles of pyruvate kinase and malic enzyme in Corynebacterium glutamicum for growth on carbon sources requiring gluconeogenesis.

In many bacteria, pyruvate kinase serves a well-defined function in glycolysis, catalyzing an ATP-generating reaction. However, its role during growth on carbon sources requiring glucoeneogenesis is less well investigated. We analyzed a defined pyruvate kinase gene (pyk) deletion mutant of Corynebacterium glutamicum, which is unable to grow on ribose as sole carbon source. Unexpectedly, the pyk deletion mutant was also unable to grow on acetate or citrate as sole carbon sources unless low amounts of pyruvate were added to the growth medium. A spontaneous suppressor mutant of the pyk deletion strain that regained the ability to grow on acetate was isolated. DNA microarray experiments revealed increased expression of the malic enzyme gene malE. The point mutation upstream of malE identified in this mutant was responsible for the loss of carbon-source-dependent regulation, as revealed by transcriptional fusion analysis. Overexpression of malE was sufficient to restore growth of the pyk deletion strain on acetate or citrate. The requirement of increased malic enzyme levels to re-route the carbon flux at the interface between glycolysis, gluconeogenesis and the tricarboxylic acid cycle in order to compensate for the absence of pyruvate kinase indicates a metabolic flux bifurcation at the metabolic node phosphoenolpyruvate. Whereas during growth of C. glutamicum on acetate or citrate most of the phosphoenolpyruvate generated from oxaloacetate is metabolized in gluconeogenesis, a fraction is converted by pyruvate kinase in the glycolytic direction to sustain proper pyruvate availability for biomass synthesis.

Acetates↗
PubMed1992

Pyruvate/malate antiporter in rat liver mitochondria.

To gain some insight into the process by which both acetylCoA and NADPH, needed for fatty acid synthesis, are obtained, in the cytosol, from the effluxed intramitochondrial citrate, via citrate lyase and malate dehydrogenase plus malic enzyme respectively, the capability of externally added pyruvate to cause efflux of malate from rat liver mitochondria was tested. The occurrence of a pyruvate/malate translocator is here shown: pyruvate/malate exchange shows saturation features (Km and Vmax values, measured at 20 degrees C and at pH 7.20, were found to be about 0.25 mM and 2.7 nmoles/min x mg mitochondrial protein, respectively) and is inhibited by certain impermeable compounds. This carrier, together with the previously reported tricarboxylate and oxodicarboxylate translocators proved to allow for citrate and oxaloacetate efflux due to externally added pyruvate.

Animals↗
PubMed2003

The role of lipogenesis in the development of uremic hyperlipidemia.

BACKGROUND: It is well documented that hypertriglyceridemia in renal failure mostly is a result of impaired plasma triglyceride (TG) removal. However, the role of TG production in its development is obscure. Therefore, our attention was given to the gene expression of lipogenic enzymes participating in TG biosynthesis. METHODS: We measured some lipogenic enzyme activities, protein abundance (Western blot analysis), and messenger RNA level (Northern blot analysis) in liver and epididymal white adipose tissue (WAT) of rats with surgically induced renal failure (two-stage subtotal nephrectomy). Simultaneously, plasma TG and very low-density lipoprotein (VLDL) concentrations in uremic animals were determined. RESULTS: An increase in plasma TG and VLDL concentrations in rats with renal failure was observed. It was associated with an increase in fatty acid synthase and adenosine triphosphate-citrate lyase (ACL) gene expression in liver and WAT. Moreover, increased activities of malic enzyme, glucose-6-phosphate dehydrogenase, and 6-phosphogluconate dehydrogenase were found. CONCLUSION: Results of the present study provide some evidence that the accumulation of TG-rich lipoproteins in renal insufficiency could be related in part to increased lipogenic enzyme gene expression and, consequently, TG overproduction.

ATP Citrate (pro-S)-Lyase↗
PubMed2001

The disruption of a gene encoding a putative arylesterase impairs pyruvate dehydrogenase complex activity and nitrogen fixation in Sinorhizobium meliloti.

Nitrogen-fixing Sinorhizobium meliloti cells depend upon dicarboxylic acids as carbon and energy sources. The metabolism of these intermediate compounds of the trichloroacetic acid cycle is dependent upon the availability of acetyl-coenzyme A (CoA). In bacteroids, the combined activities of malic enzymes and pyruvate dehydrogenase (PDH) have been proposed to be responsible for the anaplerotic synthesis of acetyl-CoA. We obtained a S. meliloti mutant strain, PD3, in which a Tn5 insertion led to a significant decrease in the overall PDH activity. The genetic characterization of this mutant revealed that the transposon is located at the 3' end of a gene (ada) encoding a putative arylesterase. The mutant PD3 is deficient in nitrogen fixation, which strengthens the physiological importance of PDH activity in the symbiosis of S. meliloti with alfalfa plants.

Acetyl Coenzyme A↗
PubMed1977

Comparative morphological and histochemical aspects of selected arteries in the chicken and rat.

Morphologic and histochemical characteristics of selected portions of normal arteries from two species known to differ in susceptibility to vascular disease were examined. Arteries were classified as predominantly elastic, muscular or complex. Species differences in the structural organization of the abdominal aortic segment were observed. Arterial mucopoly-saccharides were stained more intensely in the tunica intima and media of chicken vessels than within those of the rat, and tended to be most concentrated in proximity of the internal elastic membrane. Histochemical procedures for the demonstration of enzymatic activity revealed inter-and intraspecies variations in vascular metabolism. Pronounced differences in reaction intensity for hydroxybutyrate dehydrogenase and malic enzyme, affecting chicken and rat coronary arteries, were noted. In contrast, theses vessels displayed only minimal activity for acid phosphatase. Marked endothelial deposition of alkaline phosphatase reaction products in the arteries of the chicken was demonstrated, while this enzyme's activity in the vessels of the rat was restricted to the tunica adventitia. The implications of these structural and histochemical factors with regard to vascular susceptibility to disease were discussed.

Acid Phosphatase↗
PubMed1981

Activities of enzymes required for the conversion of 4-carbon TCA cycle compounds to 3-carbon glycolytic compounds in human diploid fibroblasts.

Phosphoenolpyruvate carboxykinase (PEPCK) and pyruvate carboxylase activities were localized in the mitochondrial (particulate) fraction of human diploid fibroblasts (HDF). Malic enzyme, malate dehydrogenase (MDH) and glutamate oxalacetate transaminase (GOT) were distributed between the mitochondrial and cytosolic (soluble) fractions, the latter two enzymes being more equally distributed than malic enzyme, which was largely cytosolic. The specific activities of mitochondrial PEPCK and cytosolic malic enzyme, MDH and GOT increased during cell growth. The results support an active conversion of 4-carbon tricarboxylic acid cycle intermediates to 3-carbon glycolytic intermediates in HDF.

Aspartate Aminotransferases↗
PubMedDate not supplied

Red cell enzyme polymorphisms in Papua New Guinea Eastern Highlands.

Ten red cell enzyme polymorphisms, malic dehydrogenase (MDH1), adenylate kinase (AK), phosphohexose isomerase (PHI), adenosine deaminase (ADA), esterase D (ESD), glutamic pyruvic transaminase (GPT), acid phosphatase (ACP1), phosphoglucomutase 1 and 2 (PGM1, PGM2), phosphogluconate dehydrogenase (PGD) were investigated in the Baruya tribe and several Anga tribes living high in the Wonenara and Marawaka valleys in Papua New Guinea Eastern Highlands (6.5S, 145.5E). Also a non-Anga tribe, the Aziana or Kenaze, was sampled. Variants were observed in ADA, PGM1 and PGM2. AK and PHI were monomorphic, all subjects being AK 1 and PHI 1; MDH1 was also monomorphic in Anga while variants were observed in Aziana. This latter tribe differed markedly in each system from the Anga peoples.

Alleles↗
PubMed1979

Mechanism of insulin resistance in adipocytes of rats fed a high-fat diet.

Insulin's ability to stimulate glucose metabolism is severely diminished in the adipose tissue of rats fed a high-fat diet as compared to that of rats fed a low-fat diet. To elucidate the mechanism for this effect we have measured the binding of insulin, the hormone effect on 2-deoxyglucose uptake and the major pathways of [1-(14)C]glucose metabolism, and the activity of lipogenesis-related enzymes in adipocytes of rats fed a low- or high-fat diet for 7 days. Rats fed high- or low-fat diets bound equal amounts of insulin per adipocyte at all insulin concentrations tested. Basal and maximally insulin-stimulated 2-deoxyglucose uptake per fat cell were reduced in high-fat-fed rats. However, the insulin stimulation over basal was the same in both groups (230%). Submaximal doses of insulin produced equivalent increments of 2-deoxyglucose uptake in both groups, as would be predicted by the binding studies. The effect of both submaximal and maximal insulin concentration on the labeling of CO(2) and fatty acids was markedly decreased by high-fat feeding. The insulin response of the glyceride-glycerol pathway was less severely, though significantly, reduced. Acetyl CoA carboxylase and malic enzyme in adipocytes of high-fat-fed rats were reduced to 13% of the activity in the low-fat-fed rats. Glucose-6-phosphate and 6-phosphogluconate dehydrogenases were decreased to 20% and 34% of their activities in low-fat-fed rats, respectively. These reductions paralleled the changes in insulin-stimulated glucose oxidation and fatty acid synthesis. The data therefore strongly suggest that the blunted response of glucose metabolism to insulin in adipocytes of high-fat-fed rats is a result of a decreased intracellular capacity to utilize glucose for lipogenesis.

Adipose Tissue↗