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PubMed1995

Aspartate aminotransferase isozymes in Panicum miliaceum L., an NAD-malic enzyme-type C4 plant: comparison of enzymatic properties primary structures, and expression patterns.

Panicum miliaceum has at least three isozymes of aspartate aminotransferase (AspAT); the cytosolic and mitochondrial isozymes (cAspAT and mAspAT) are major components and the third is a minor isozyme. Fractionation of leaf subcellular components showed that the minor isozyme was localized in plastids (pAspAT). We purified the three isozymes from green leaves of P. miliaceum. Both cAspAT and pAspAT consisted of triple subforms having the same molecular size but different isoelectric points. No substantial difference in enzymatic properties was observed among these isozymes besides the pH profiles. We isolated a full-length cDNA clone for pAspAT. This clone contains an open reading frame that encodes 457 amino acids. The amino-terminal region of the pAspAT precursor shares common features of plastid transit peptides. The amino acid sequence of P. miliaceum pAspAT shows higher similarity with other plant pAspATs than P. miliaceum cAspAT and mAspAT. The mRNA levels of the three isozymes were high in leaves compared with roots and mesocotyls. The three isozymes showed different expression patterns against environmental stimuli such as light and nitrate. The activities and protein levels of cAspAT and mAspAT increased during greening in accordance with those of phosphoenolpyruvate carboxylase and NAD-malic enzyme involved in the C4 pathway, primarily as a consequence of the increase in the levels of their mRNAs. By contrast, pAspAT was constitutively expressed during greening. The activity and protein levels of cAspAT and mAspAT selectively increased during recovery from an nitrogen deficit, primarily as a consequence of increase in the levels of their mRNAs while those of pAspAT remained unchanged.

Amino Acid Sequence↗
PubMed1987

Changes in immunoreactive malic enzyme in liver and brown adipose tissue during development of the rat.

There is a good correlation between changes in malic enzyme activity and immunoreactive protein in both hepatic and brown adipose tissue during postnatal development of the rat. Furthermore, the previously observed premature appearance of hepatic malic enzyme during the suckling period, in response to triiodothyronine, can also be achieved through dichloroacetate administration. A combination of triiodothyronine and dichloroacetate induces malic enzyme activity and immunoreactive protein in a synergistic manner, indicating different sites of action in the control of synthesis of hepatic malic enzyme although neither agent was found to affect the level of malic enzyme in brown adipose tissue. There is evidence to suggest that changes in the ability of the liver to express malic enzyme in response to triiodothyronine administration occur early in postnatal life.

Adipose Tissue, Brown↗
PubMed1991

Regulation of gene expression by insulin and tumor necrosis factor alpha in 3T3-L1 cells. Modulation of the transcription of genes encoding acyl-CoA synthetase and stearoyl-CoA desaturase-1.

Insulin and tumor necrosis factor alpha (TNF alpha) produce potent and opposing physiological signals in adipocytes. However, genes that are co-regulated by the hormone and cytokine during and after adipocyte differentiation have not been characterized. Using 3T3-L1 cells, we have studied the regulation of the expression of genes encoding acyl-CoA synthetase (ACS), and stearoyl CoA desaturase-1 (SCD-1), two enzymes that play key roles in the metabolism of long chain fatty acids. Insulin is required for triggering the transcriptional activation of the ACS and SCD-1 genes at an early stage in adipocyte differentiation. In mature adipocytes insulin elicits a 4-fold increase in the rates of transcription of the two genes. However, when 3T3-L1 adipocytes are treated with TNF alpha the cytokine causes a 75-90% decrease in the levels of ACS and SCD-1 mRNAs. The decline in mRNA content is associated with similar decrements in the rates of transcription of the ACS and SCD-1 genes. Thus, the ACS and SCD-1 genes are subject to stimulation and counter-regulation (at the transcriptional level) by insulin and TNF alpha, respectively. The opposing effects of insulin and TNF alpha are observed in developing and terminally differentiated adipocytes. Unlike the ACS and SCD-1 genes, the genes that encode the lipogenic enzymes lipoprotein lipase and malic enzyme are not subject to counter-regulation by insulin and TNF alpha at the transcriptional level in 3T3-L1 adipocytes. These observations on the control of ACS and SCD-1 expression suggest possible mechanisms by which adipocytes can markedly adjust their capacity for long chain fatty acid metabolism in response to external stimuli.

3T3 Cells↗
PubMed1999

Pathways of glucose catabolism in procyclic Trypanosoma congolense.

Studies of respiration on glucose in procyclic Trypanosoma congolense in the presence of rotenone, antimycin, cyanide, salicylhydroxamic acid and malonate have indicated the presence of NADH dehydrogenase, cytochrome b-c1, cytochrome aa3, trypanosome alternate oxidase and NADH fumarate reductase/succinate dehydrogenase pathway that contributes electrons to coenzyme Q of the respiratory chain. The rotenone sensitive NADH dehydrogenase, the trypanosome alternate oxidase, and cytochrome aa3 accounted for 24.5 +/- 6.5, 36.2 +/- 4.2 and 54.1 +/- 5.5% respectively of the total respiration. Activities of lactate dehydrogenase, NAD(+)-linked malic enzyme and pyruvate kinase were less than 6 nanomoles/min/mg protein suggesting that they play a minor role in energy metabolism of the parasite. Phosphoenolpyruvate carboxykinase, pyruvate dehydrogenase, succinate dehydrogenase, NADP(+)-linked malic enzyme, NADH fumarate reductase, malate dehydrogenase, and alpha-ketoglutarate dehydrogenase and glycerol kinase on the other hand had specific activities greater than 60 nanomoles/min/mg protein. These enzyme activities could account for the production of pyruvate, acetate, succinate and glycerol. The results further show that the amount of glycerol produced was 35-48% of the combined total of pyruvate, acetate and succinate produced. It is apparent that some of the glycerol 3-phosphate produced in glycolysis in the presence of salicylhydroxamic acid is dephosphorylated to form glycerol while the rest is oxidised via cytochrome aa3 to form acetate, succinate and pyruvate.

Animals↗
PubMed1996

Nutritional and hormonal regulation of expression of the gene for malic enzyme.

We have provided a historical and personal description of the analysis of physiological and molecular mechanisms by which diet and hormones regulate the activity of hepatic malic enzyme. For the most part, our analyses have been reductionist in approach, striving for increasingly simpler systems in which we can ask more direct questions about the molecular nature of the signaling pathways that regulate the activity of malic enzyme. The reductionist approaches that were so successful at analyzing molecular mechanisms in cells in culture may now provide the means to analyze more definitively questions about the physiological mechanisms involved in nutritional regulation of gene expression. In addition to physiological questions, however, there are still many aspects of the molecular mechanisms that have not been elucidated. Despite considerable effort from many laboratories, the molecular mechanisms by which T3 regulates transcription are not clear. Similarly, the molecular details for the mechanisms by which glucagon, insulin, glucocorticoids, and fatty acids regulate gene expression remain to be determined. The role of fatty acids is particularly interesting because it may provide a model for mechanisms by which genes are regulated by metabolic intermediates; this is a form of transcriptional regulation widely used by prokaryotic organisms and extensively analyzed in prokaryotic systems, but poorly understood in higher eukaryotes. At any specific time, there is, of course, only one rate of transcription for each copy of the malic-enzyme gene in a cell. Our long-term objective is to understand how signals from all of the relevant regulatory pathways are integrated to bring about that rate.

Animals↗
PubMed1982

The hepato-muscular metabolic axis and gluconeogenesis.

During starvation alanine synthesised de novo by muscle is an important precursor for hepatic gluconeogenesis. The alanine carbon derives in part from branched-chain amino acids such as valine. In vitro incubations of muscle with [1-14 C]- or [U14C]-valine have shown that sufficient valine carbon passes beyond decarboxylation by branched-chain dehydrogenase, but escapes total oxidation, to account for the observed rate of de novo alanine synthesis. Experiments using hydroxymalonate (an inhibitor of malic enzyme) and mercaptopicolinate (an inhibitor of PEP carboxykinase) have shown that muscle alanine synthesis occurs via the latter route. Ketone bodies suppress muscle alanine formation suggesting a role in the conservation of glucogenic precursors in long-term starvation. Conversely alanine diminishes ketogenesis by isolated hepatocytes. It appears that there is an hepato-muscular metabolic axis operating by which liver and muscle metabolism is co-ordinately controlled by alanine and ketone bodies.

Alanine↗
PubMed1999

Purification and characterization of the 16-kDa heat-shock-responsive protein from the thermophilic cyanobacterium Synechococcus vulcanus, which is an alpha-crystallin-related, small heat shock protein.

A 16-kDa protein, one of the major proteins that accumulates upon heat-shock treatment in the thermophilic cyanobacterium Synechococcus vulcanus, was purified to apparent homogeneity. The N-terminal and internal amino acid sequences of the protein exhibited a homology to the alpha-crystallin-related, small heat shock proteins from other organisms. The protein was designated HspA. Size-exclusion chromatography and nondenaturing gel electrophoresis demonstrated that HspA formed a large homo-oligomer consisting of 24 subunits. It prevented the aggregation of porcine malic dehydrogenase at 45 degrees C and 50 degrees C and citrate synthase at 50 degrees C. The activity of the malic dehydrogenase, however, was not protected under these heat-shock conditions or reactivated after a shift in temperature from 45 or 50 degrees C to 21 degrees C. HspA was able to enhance the refolding of chemically denatured rabbit muscle lactate dehydrogenase in an ATP-independent manner. A homologue to the 16-kDa protein was also found to be induced upon heat-shock treatment in the mesophilic cyanobacterium Synechocystis sp. PCC 6803.

Amino Acid Sequence↗
PubMed1990

Fat supplementation to the gestation diet of older sows and its effect on maternal and fetal fat metabolism.

Sows that had had 3 previous litters were fed either a diet with no added fat (low fat) which was rich in linoleic acid (56.7% 18:2n-6), or a high fat diet containing lard, high in total saturates (28.9%) and oleic acid (37.8% 18:1n-9) during gestation. Backfat build-up in the sows on the high fat diet was accelerated compared to the low fat group. On day 110 of gestation, fetuses were removed. The fat content of the diet had no significant effect on sow weight gain during gestation, and the number or body weight of fetuses. Activities of sow liver and adipose and fetal liver malic enzyme, glucose-6-phosphate dehydrogenase (G-6-P) and acetyl-CoA-carboxylase (ACoABx) were measured. Only fetal liver ACoABx and sow adipose G-6-P were significantly affected by the sow's diet.

Acetyl-CoA Carboxylase↗
PubMedDate not supplied

Metabolism of 3-(13)C-malate in primary cultures of mouse astrocytes.

Malate, specifically labeled with carbon 13 on C(3), was synthesized by chemical means and used to study malate metabolism by primary cultures of mouse cortical astrocytes. 3-(13)C-Malate in combination with glucose as well as 3-(13)C-malate alone were used as substrates; the effect of 3-nitropropionic acid, an inhibitor of succinate dehydrogenase and fumarase was also examined. The consumption of malate was only 0.26 micromol/mg of protein, approx. 25-fold lower than the consumption of glucose. Besides lactate, glutamine and fumarate were the two major metabolites released to the medium. Very low and similar levels of isotopic enrichment were detected on C(2) and C(3) of lactate; glutamine was labeled on C(2) and C(3) to a similar extent as well and labeling on C(4) was only detected when glucose was not added. These labeling studies suggest that cytosolic malic enzyme is not active in primary astrocytes and support the occurrence of pyruvate recycling in astrocytes.

Animals↗
PubMed2004

Malic enzymes of Trichomonas vaginalis: two enzyme families, two distinct origins.

The cytosolic malic enzyme of the amitochondriate protist Trichomonas vaginalis was purified to homogeneity and characterized. The corresponding gene was sequenced and compared with its hydrogenosomal homologue from the same organism. The enzymes were found to differ in coenzyme specificity, molecular mass and physiological role. The cytosolic malic enzyme is a dimer consisting of two 42-kDa subunits with strict specificity for nicotinamide adenine dinucleotide phosphate (NADP(+)), and has a presumed function of pyruvate and NADPH production. The hydrogenosomal malic enzyme is a tetramer of 60-kDa subunits that preferentially utilizes nicotinamide adenine dinucleotide (NAD(+)) to NADP(+). The hydrogenosomal enzyme supplies the hydrogenosome with pyruvate for further catabolic processes linked with substrate-level phosphorylation. Phylogenetic analysis of malic enzymes showed the existence of two distinct families of these enzymes in nature, which differ in subunit size. The trichomonad cytosolic malic enzyme belongs to the small subunit-type family that occurs almost exclusively in prokaryotes. In contrast, the hydrogenosomal malic enzyme displays a close relationship with the large subunit-type family of the enzyme, which is found in mitochondria, plastids and the cytosol of eukaryotes. The eubacterial origin of trichomonad cytosolic malic enzyme suggests an occurrence of horizontal gene transfer from a eubacterium to the ancestor of T. vaginalis. The presence of both prokaryotic and eukaryotic type of malic enzyme in different compartments of a single eukaryotic cell appears to be unique in nature.

Amino Acid Sequence↗
PubMed1996

Prostaglandin E2 derivative, enprostil, reduces hepatic triacylglycerol content in Japanese quail.

This study investigated the effect of prostaglandin E2 derivative, enprostil, on the hepatic lipid metabolism of Japanese quail. In experiment 1, the birds received 0.1, 1, 10 or 100 micrograms enprostil/kg body weight intraperitoneally, and they were killed after 10, 30, 60 and 120 min. After 60 min, hepatic triacylglycerol content was reduced most effectively by 10 micrograms enprostil/kg body weight. In experiment 2, effect of enprostil (10 micrograms/kg body weight) on liver enzyme activities associated with lipid metabolism and plasma lipid concentrations was examined. There were no significant differences in malic enzyme and carnitine palmitoyltransferase activities. Peroxisomal beta-oxidation in birds which received enprostil was significantly lower than that in birds receiving the vehicle. Enprostil caused a significant decrease in plasma triacylglycerol and non-esterified fatty acid concentration. We conclude that the administration of enprostil reduces hepatic triacylglycerol content through the decreased influx of non-esterified fatty acid.

Animals↗
PubMed1976

Effects in the rat of environmental temperature, diet dilution, and treadmill running on liver and adipose enzymes and metabolism of 14C-glucose: a multiple regression analysis.

The effects of two environmental temperatures (T; 16 degrees and 31 degrees), five diet dilutions (D; 0%, 12.5%, 25%, 37.5% and 50%), and five daily treadmill running periods (E; 10 minutes, 40 minutes, 70 minutes, 100 minutes, and 130 minutes) upon enzyme activities of liver and adipose tissue of male rats were observed. Liver enzymes studied were glucose-6-phosphatase (G6Pase), 6-P-gluconate dehydrogenase (6PGD), glucose-6-phosphate dehydrogenase (G6PD), fructose diphosphatase (FDPase), NADP-isocitrate dehydrogenase (ICDH), and malic enzyme (ME). Adipose tissue (epididymal fat) enzymes (6PGD, G6PD, and ME) were studied as well as the in vitro incorporation of the 14C of [U-14C] glucose into liberated 14CO2 and into the triglycerides, free fatty acids, and total lipids by adipose tissue slices. Equations describing regression surfaces for these responses (expressed as units/100 g body weight) could contain significant linear coefficients of the independent variables (T, D, and E), their first order interactions, and quadratic coefficients for D and E. Significnat regression coefficients for activities of liver enzymes associated with increased lipogenesis (6PGD, G6PD, and ME) produced response surfaces with conformations generally concave downward. All enzymes possessed positive and negative linear and quadratic coefficients for D which caused response surfaces to be concave downward with respect to that variable. Also, 6PGD and G6PD (positive linear and negative quadratic coefficients for E) exhibited response surfaces concave downward with respect to E. Additionally, 6PGD showed greater activity at 31 degrees than at 16 degrees while G6PD showed no effect of temperature on activity. Liver ICDH, probably important in supplying reducing equivalents for fatty acid synthesis, evidenced response surfaces almost identical to those for 6PGD. Significant regression coefficients for activity of liver enzymes associated with increased gluconeogenesis (FDPase and G6Pase) produced for FDPase a response surface concave downward with respect to both D and E with greater values at 31 degrees than at 16 degrees; but for G6Pase non-concave surfaces with lesser values at 31 degrees than at 16 degrees. Significant regression coefficients for activities of adipose enzymes associated with increased lipogenesis produced for 6PGD a response surface concave upward due to negative linear and positive quadratic coefficients for both D and E. For G6PD and ME regression surfaces were concave upward with respect to E, but these were modified by positive and negative linear coefficients, respectively, for D. Significant regression coefficients for incorporation of the 14C of glucose into triglycerides and free fatty acids of adipose tissue slices and their production of 14CO2 yielded response surfaces concave upward with respect to E (negative linear and positive quadratic coefficients). In addition, the surface for free fatty acids was concave upward with respect to D. The 14CO2 production was greater at 16 degrees than at 31 degrees...

Adipose Tissue↗
PubMed1988

Effect of short-term DHEA administration on liver metabolism of lean and obese rats.

Lean and obese Zucker rats, 7-8 wk of age, were treated with dehydroepiandrosterone (DHEA) for either 3 or 7 days to determine the initial cellular event(s) that might be responsible for the antiobesity activity of DHEA. Epididymal, retroperitoneal, and brown adipose tissue weights were unaltered by either 3 or 7 days of DHEA treatment. Liver weight was not affected by 3 days of treatment but was 13 and 18% higher in 7-day DHEA-treated lean and obese rats, respectively, compared with their corresponding control group. Mitochondrial state 3 respiration rates with glutamate-malate and succinate as substrates were elevated by an average of 35% in 3- and 7-day DHEA-treated obese rats and by 15-20% in 7-day DHEA-treated lean rats compared with rates obtained in the corresponding control groups. State 3 respiration was not affected in 3-day DHEA-treated lean rats compared with control lean rats. The specific activities of long-chain fatty acyl-coenzyme A synthase and hydrolase and the levels of free CoA were increased by severalfold in cellular fractions of both DHEA-treated lean and obese rats compared with their respective control group. Hepatic malic enzyme activity, which was shown earlier to be elevated with long-term DHEA treatment, was unaltered by either 3 or 7 days of DHEA administration. The above results suggest the involvement of mitochondrial respiration and fatty acid deacylation/reacylation in the antiobesity mechanism of action of DHEA.

Adipose Tissue↗
PubMed2004

Acid-inducible transcription of the operon encoding the citrate lyase complex of Lactococcus lactis Biovar diacetylactis CRL264.

Although Lactococcus is one of the most extensively studied lactic acid bacteria and is the paradigm for biochemical studies of citrate metabolism, little information is available on the regulation of the citrate lyase complex. In order to fill this gap, we characterized the genes encoding the subunits of the citrate lyase of Lactococcus lactis CRL264, which are located on an 11.4-kb chromosomal DNA region. Nucleotide sequence analysis revealed a cluster of eight genes in a new type of genetic organization. The citM-citCDEFXG operon (cit operon) is transcribed as a single polycistronic mRNA of 8.6 kb. This operon carries a gene encoding a malic enzyme (CitM, a putative oxaloacetate decarboxylase), the structural genes coding for the citrate lyase subunits (citD, citE, and citF), and the accessory genes required for the synthesis of an active citrate lyase complex (citC, citX, and citG). We have found that the cit operon is induced by natural acidification of the medium during cell growth or by a shift to media buffered at acidic pHs. Between the citM and citC genes is a divergent open reading frame whose expression was also increased at acidic pH, which was designated citI. This inducible response to acid stress takes place at the transcriptional level and correlates with increased activity of citrate lyase. It is suggested that coordinated induction of the citrate transporter, CitP, and citrate lyase by acid stress provides a mechanism to make the cells (more) resistant to the inhibitory effects of the fermentation product (lactate) that accumulates under these conditions.

Adaptation, Physiological↗
PubMed1988

Nuclear triiodothyronine receptor of human adipose tissue.

L-Triiodothyronine induces malic enzyme in explants from human adipose tissue. Consequently, we looked for the presence of receptors for L-triiodothyronine in nuclei isolated from human adipose tissue. The binding of 125I-triiodothyronine by the nuclei was time- and temperature-dependent. At 37 degrees C binding reached a steady state after 60 minutes. Dithiothreitol enhanced total binding and suppressed nonspecific binding. Scatchard analysis showed the presence of a single class of binding sites. The apparent association constant, Ka, was 0.13 +/- 0.03 X 10(10) M-1, the maximal binding capacity 2.20 +/- 0.81 pmol/mg DNA (mean +/- SD, n = 7) and the number of binding sites 8,000/nucleus. L-Triiodothyronine and D-triiodothyronine had equal affinity to the nuclear receptor; triiodothyroacetic acid had three times higher affinity. L- and D-thyroxine had 8% and 12%, respectively, and tetraiodothyroacetic acid had 19% affinity compared to that of L-triiodothyronine. Reverse triiodothyronine was a weak competitor. Digestion of nuclei with micrococcal nuclease abolished specific binding. These results show that nuclei from human white adipose tissue possess high affinity receptors for L-triiodothyronine, which are associated with nuclear chromatin. It is likely that induction of malic enzyme in human adipose tissue by L-triiodothyronine is mediated by the nuclear receptors.

Adipose Tissue↗
PubMed1988

Quantification of carbon fluxes through the tricarboxylic acid cycle in early germinating lettuce embryos.

A method involving labeling to isotopic steady state and modeling of the tricarboxylic acid cycle has been used to identify the respiratory substrates in lettuce embryos during the early steps of germination. We have compared the specific radioactivities of aspartate and glutamate and of glutamate C-1 and C-5 after labeling with different substrates. Labeling with [U-14C]acetate and 14CO2 was used to verify the validity of the model for this study; the relative labeling of aspartate and glutamate was that expected from the normal operation of the tricarboxylic acid cycle. After labeling with 14CO2, the label distribution in the glutamate molecule (95% of the label at glutamate C-1) was consistent with an input of carbon via the phosphoenolpyruvate carboxylase reaction, and the relative specific radioactivities of aspartate and glutamate permitted the quantification of the apparent rate of the fumarase reaction. CO2 and intermediates related to the tricarboxylic acid cycle were labeled with [U-14C]acetate, [1-14C] hexanoate, or [U-14C]palmitic acid. The ratios of specific radioactivities of asparate to glutamate and of glutamate C-1 to C-5 indicated that the fatty acids were degraded to acetyl units, suggesting the operation of beta-oxidation, and that the acety-CoA was incorporated directly into citrate. Short-term labeling with [1-14C]hexanoate showed that citrate and glutamate were labeled earlier than malate and aspartate, showing that this fatty acid was metabolized through the tricarboxylic acid cycle rather than the glyoxylate cycle. This was in agreement with the flux into gluconeogenesis compared to efflux as respiratory CO2. The fraction of labeled substrate incorporated into carbohydrates was only about 5% of that converted to CO2; the carbon flux into gluconeogenesis was determined after labeling with 14CO2 and [1-14C]hexanoate from the specific radioactivity of aspartate C-1 and the amount of label incorporated into the carbohydrate fraction. It was only 7.4% of the efflux of respiratory CO2. The labeling of alanine indicates a low activity of either a malic enzyme or the sequence phosphoenolpyruvate carboxykinase/pyruvate kinase. After labeling with [U-14C]glucose, the ratios of specific radioactivities indicated that the labeled carbohydrates contributed less than 10% to the flux of acetyl-CoA. The model indicated that the glycolytic flux is partitioned one-third to pyruvate and two-thirds to oxalacetate and is therefore mainly anaplerotic. The possible role of fatty acids as the main source of acetyl-CoA for respiration is discussed.

Acetates↗