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PubMed1989

Structure and properties of malic enzyme from Bacillus stearothermophilus.

The malic enzyme (EC 1.1.1.38) gene of Bacillus stearothermophilus was cloned in Escherichia coli, and the enzyme was purified to homogeneity from the E. coli clone. In addition to the NAD(P)-dependent oxidative decarboxylation of L-malate, the enzyme catalyzes the decarboxylation of oxalacetate. The enzyme is a tetramer of Mr 200,000 consisting of four identical subunits of Mr 50,000. The pH optima for malate oxidation and pyruvate reduction are 8.0 and 6.0, respectively; and the optimum temperature is 55 degrees C. The enzyme strictly requires divalent metal cations for its activity, and the activity is enhanced 5-7 times by NH4+ and K+. Kinetic study shows that the values of the dissociation constant of the enzyme-coenzyme complex are 77 microM for NAD and 1.0 mM for NADP, indicating that the enzyme has a higher affinity for NAD than for NADP. The nucleotide sequence of the gene and its flanking regions was also found. A single open reading frame of 1434 base pairs encoding 478 amino acids was concluded to be that for the malic enzyme gene because the amino acid composition of the enzyme and the sequence of 16 amino acids from the amino terminus of the enzyme agreed well with those deduced from this open reading frame.

Amino Acid Sequence↗

PubMed1986

Effect of dichloroacetic acid on rat hepatic messenger RNA activity profiles.

We have previously suggested that the ability of glucose to induce rat hepatic lipogenic enzymes is mediated by the mitochondrial oxidation of pyruvate. In part, this hypothesis is supported by the finding that an activator of pyruvate dehydrogenase, dichloroacetic acid (DCA), is capable of inducing malic enzyme in hepatocyte cultures. In order to further test this hypothesis, we compared the mRNA responses induced by carbohydrate feeding in vivo and by glucose administration to hepatocytes in culture with those mRNA responses induced in DCA both in vivo and in culture. DCA administration to rats resulted in a significant increase in liver:body weight ratio. It was, in addition, a potent inducer of malic enzyme. Hepatic mRNA activity profiles were examined by two-dimensional gel electrophoretic analysis of in vitro translation products. Six of the seven mRNAs altered by carbohydrate feeding were similarly altered by DCA feeding in vivo. In cultured hepatocytes 10 mmol/L DCA significantly increased four of six glucose-induced mRNAs. The mRNA for malic enzyme was among those mRNA sequences induced both in vivo and in culture. Increasing glucose concentrations in the culture medium resulted in an expected rise in pyruvate levels, whereas DCA caused a significant decrease in the concentration of this intermediate. It is likely, therefore, that augmentation of the flux of pyruvate through pyruvate dehydrogenase rather than alterations in pyruvate levels per se, is a proximal event leading to the induction of multiple mRNAs. The marked overlap in mRNA response to both carbohydrate and DCA indicates that the signal regulating the content of the carbohydrate responsive mRNAs is derived from mitochondrial pyruvate oxidation.

Acetates↗

PubMed1992

Adipogenic cell line TA1: a suitable model to study the effect of beta-adrenergic agonists on lipid metabolism.

The stable adipogenic cell line TA1 was investigated as a potential in vitro system to examine effects of beta-adrenergic agonists on lipid metabolism at the cellular level. Initial experiments were conducted to establish whether dexamethasone, indomethacin, or both in combination induce rapid differentiation of TA1 preadipocytes to adipocytes. Based on activity of fatty acid synthase, dexamethasone and indomethacin, individually and in combination, were observed to induce differentiation in TA1 cells at different rates (dexamethasone/indomethacin greater than indomethacin greater than dexamethasone). Dexamethasone/indomethacin induced complete differentiation in TA1 cells 4 days after confluence, as indicated by increased activity of fatty acid synthase, glycerol-3-phosphate dehydrogenase, and malic enzyme. Finally, mature TA1 adipocytes were treated with various concentrations of isoproterenol and ractopamine to determine the responsiveness of TA1 adipocytes to a beta-adrenergic challenge. Glycerol release was increased and fatty acid synthase activity was decreased in a dose-dependent manner for both isoproterenol and ractopamine. These results indicate that fully differentiated TA1 adipocytes may be useful to study direct cellular effects of lipolytic and lipogenic agents on lipid metabolism.

Adipose Tissue↗

PubMed2003

Effects of dietary carbohydrate and myo-inositol on metabolic changes in rats fed 1,1,1-trichloro-2,2-bis (p-chlorophenyl) ethane (DDT).

This study was conducted to examine the effects of dietary carbohydrate [starch or sucrose (500 g/kg diet)] and myo-inositol (2 g/kg diet) on metabolic changes in rats fed 1,1,1-trichloro-2,2-bis (p-chlorophenyl) ethane (DDT) (0.7 g/kg diet). Dietary DDT enhanced serum and hepatic lipids and hepatic thiobarbituric acid reactive substances (TBA-RS), elevated hepatic activities of lipogenic enzymes such as malic enzyme (ME), glucose-6-phosphate dehydrogenase (G6PD) and fatty acid synthetase (FAS), increased hepatic cytochrome P-450 content and the activities of drug-metabolizing enzymes such as aminopyrine N-demethylase, glutathione S-transferase and 4-nitrophenol-UDP glucuronosyltransferase (4NP-UDPGT) and raised hepatic ascorbic acid and serum copper. Dietary sucrose promoted the increases in hepatic concentrations of total lipids, triglyceride and cholesterol, hepatic activity of ME, hepatic TBA-RS, cytochrome P-450 content and serum copper due to DDT feeding when compared to DDT administered in a starch based diet. Dietary myo-inositol significantly depressed the rises in hepatic concentrations of total lipids, triglyceride and cholesterol and the activities of ME and G6PD due to DDT feeding regardless of dietary carbohydrate quality. Dietary starch supplemented with myo-inositol potentiated the enhancements in hepatic activities of Phase II drug-metabolizing enzymes such as glutathione S-transferase and 4NP-UDPGT due to DDT feeding. These results suggest that dietary starch and myo-inositol can protect DDT fed rats against an accumulation of hepatic lipids, which might be mainly ascribed to the depression of hepatic lipogenesis. In addition, the present study implies that the supplementation of myo-inositol to high starch diet might improve the function of drug-metabolizing enzymes exposed to DDT.

Animals↗

PubMed1984

Effect of changes in litter size at mid-lactation on lactation in rats.

The effect of altering the number of pups per litter from ten to two or two to ten at day 14 of lactation in rats was investigated. Reducing litter size had no effect on the daily live weight gain whereas increasing the litter size resulted in an initial weight loss followed by an impaired weight gain. Maternal food consumption decreased to values appropriate for rats feeding two pups within 2 days after litter reduction, but required at least 5 days after the increase in litter size to increase to values appropriate for rats feeding large litters from parturition. Altering the litter size resulted in maternal serum insulin concentrations that were intermediate between those expected for rats feeding two or ten pups from parturition. Maternal serum prolactin concentrations increased after litter sizes were increased and decreased initially after litter reduction before being restored to normal levels. The activities of the lipogenic enzymes, fatty acid synthase, glucose-6-phosphate dehydrogenase and 'malic' enzyme in the mammary gland all decreased within 72 h of litter reduction to levels appropriate for rats feeding two pups. Although all three enzymes increased in activity after litter size increase, only fatty acid synthase had reached values appropriate for rats feeding ten pups by 72 h.

Animals↗

PubMed1975

Valine, malic, and pyruvic dehydrogenase tests in the differentiation of Bacteroides.

Fifteen isolates of Bacteroides were tested for their ability to dehydrogenate a variety of amino acids and organic acids. A simple and rapid method was developed for detecting dehydrogenase activity using 2,3,5-triphenyl tetrazolium chloride as a hydrogen acceptor and indicator. The results indicate that the tests for valine, malic, and pyruvic acid dehydrogenases have value in differentiating organisms in this genus.

Amino Acid Oxidoreductases↗

PubMed1996

DNA polymorphisms of lipogenesis genes and analysis of linkage with fatness in turkeys.

DNA variability of lipogenesis genes was evaluated by Restriction Fragment Length Polymorphism (RFLP) on four selected lines of turkeys. Thirteen polymorphisms were obtained, four on the acetyl-coenzyme A carboxylase gene, one on the apoprotein AI gene, two on the malic enzyme gene, four on the fatty acid synthase gene, and two on the stearoyl-coenzyme A mesaturase gene. Six of these RFLP were studied in more detail on 64 female turkeys sampled in two lines. Large differences in terms of number of DNA profiles and haplotype frequencies were observed between the two genes, in accordance with the variability of recorded fatness performances. An additive model including the effects of RFLP profiles was used to assess linkage between polymorphisms on lipogenesis genes and fatness measured either in vivo by an ultrasonic instrument or, after slaughter, by the ratio of skin plus subcutaneous fat weight to the whole leg weight. In each line, two polymorphisms suggested a statistical association with fat deposit, one on the malic enzyme gene detected by DNA digestion with HindIII and one on the fatty acid synthase gene detected by MspI. A multiple comparison of means associated with each RFLP profile enabled the identification of two lean profiles in one strain, and a fat profile in the other.

Acetyl-CoA Carboxylase↗

PubMed1993

Inhibition of lipid synthesis and secretion in long-term cultures of adult rat hepatocytes by alpha-asarone.

In this work we studied the effect of alpha-asarone, a hypolipidemic active principle of Guatteria gaumeri Greenman, on hepatic lipid metabolism using adult rat hepatocytes cultured on a feeder layer of 3T3 cells. These cultures synthesize and secrete for at least two weeks various lipids from [14C]-acetic and [14C]-oleic acid. Exposure for one or two weeks to 10 micrograms/ml of alpha-asarone decreased the secretion of various lipids to the culture medium; triacylglycerol secretion was inhibited by 80-97%, phospholipid secretion by 70-87%, cholesterol by 64-70%, and cholesterol esters by 50-92%. The incorporation of [14C]-acetic acid into cellular lipids decreased by 30-81% and that of [14C]-oleic acid into phospholipids by 25-47% whereas the incorporation of [14C]-oleic acid into triglycerides and cholesterol esters increased 3.2 fold and by 28-36%, respectively. Similarly, the activities of glycerol-3-phosphate dehydrogenase and malic enzyme, marker enzymes of glycerolipid and fatty acid synthesis, decreased by 22-50% and 30-76%, respectively. Our results show that the exposure of the 3T3-hepatocyte cultures to micromolar concentrations of alpha-asarone significantly inhibits lipid secretion and probably lipid synthesis. They also suggest that at least part of the hypolipidemic effect could be due to a decrease in the secretion of lipids (i.e., lipoproteins) by the hepatocytes.

3T3 Cells↗

PubMed2001

Characterization of the phosphoenolpyruvate carboxykinase gene from Corynebacterium glutamicum and significance of the enzyme for growth and amino acid production.

Corynebacterium glutamicum possesses phosphoenolpyruvate (PEP) carboxykinase, oxaloacetate decarboxylase and malic enzyme, all three in principle being able to catalyze the first step in gluconeogenesis. To investigate the role of PEP carboxykinase for growth and amino acid production, the respective pck gene was isolated, characterized and used for construction and analysis of mutants and overexpressing strains. Sequence analysis of the pck gene predicts a polypeptide of 610 amino acids showing up to 64% identity with ITP-/GTP-dependent PEP carboxykinases from other organisms. C. glutamicum cells harbouring pck on plasmid showed about tenfold higher specific PEP carboxykinase activities than the wildtype. Inactivation of the chromosomal pck gene led to the absence of PEP carboxykinase activity and the inability to grow on acetate or lactate indicating that the enzyme is essential for growth on these carbon sources and thus, for gluconeogenesis. The growth on glucose was not affected. Examination of glutamate production by the recombinant C. glutamicum strains revealed that the PEP carboxykinase-deficient mutant showed about fourfold higher, the pck-overexpressing strain two- to threefold lower glutamate production than the parental strain. Inactivation and overexpression of pck in a lysine-producer of C. glutamicum led to an only 20% higher and lower lysine accumulation, respectively. The results show that PEP carboxykinase activity in C. glutamicum is counteractive to the production of glutamate and lysine and indicate that the enzyme is an important target in the development of strains producing amino acids derived from citric acid cycle intermediates.

Amino Acid Sequence↗

PubMed1990

Comparative studies on lipogenic enzyme activities in the liver of human and some animal species.

1. The activities of enzymes involved in fatty acid synthesis in the human liver (sample taken during abdominal surgery) and in the livers of some animals were studied. 2. Fatty acid synthase, ATP-citrate lyase and malic enzyme activities were found to be from 4 to 70-fold lower in human liver than in rat or bird livers. 3. The activities of hexose monophosphate shunt dehydrogenases in human liver were from half to almost equal to the corresponding activities in birds, but much lower than in rat liver. 4. The activities of all enzymes listed above in human and beef liver were very similar (except fatty acid synthase which was undetectable in the beef liver). 5. Very high activity of NADP-linked isocitrate dehydrogenase was found in livers of all species tested. 6. These results are discussed in relation to the role of the human liver in lipogenesis. 7. The activities of the enzymes generating NADPH in human liver taken during abdominal surgery were similar to the activities observed in the tissue obtained post mortem. 8. This suggested that post mortem tissue may be used as a reliable human material for some enzyme assays. 9. Thus we also examined the activity of malic enzyme in post mortem human kidney cortex, heart, skeletal muscle and brain. 10. Relatively high activity of NADP-linked malic enzyme has been observed in human brain.

Adolescent↗

PubMed1991

Involvement of diminution of glutathione, produced by deficiency of methionine in the diet, in the elevation of malic enzyme level in rat liver.

Rats fed on a low protein diet show an increase in the specific activity of malic enzyme and a concomitant decrease of glutathione concentration. We have studied the effect on malic enzyme activity of supplementing of low protein diet with essential amino acids. Only when methionine was excluded from the diet did the specific activity of malic enzyme increase to the same extent as found in rats fed with low protein diet. Immunoprecipitation of malic enzyme indicated that specific activity changes are the result of changes in the amounts of enzyme. Under all dietary conditions studied, the increase in malic enzyme activity is associated with a decrease in the concentration of GSH. To evaluate the possible causative role of GSH in malic enzyme induction, the specific activity of malic enzyme was measured in rats treated with BSO, an inhibitor of GSH biosynthesis. The results show that in BSO-treated rats the decrease of GSH levels is also accompanied by an increase in the activity of malic enzyme.

Amino Acids, Essential↗

PubMed1995

Transforming growth factor beta 1 induces differentiation-specific gene expression in fetal rat brown adipocytes.

Fetal rat brown adipocytes show a low number of transforming growth factor beta 1 (TGF-beta 1) binding sites of high affinity, revealing the presence of type I, II and III TGF-beta 1 receptors and a minor-labeled species of approximately 140 kDa. The culture of cells in the presence of TGF-beta 1 induced the expression of the tissue-specific gene uncoupling protein in a dose- and time-dependent manner. In addition, TGF-beta 1 up-regulates the expression of genes involved in adipogenesis such as fatty acid synthase, glycerol 3-phosphate dehydrogenase, malic enzyme and glucose 6-phosphate dehydrogenase, as well as induces the expression of fibronectin (specific target gene for TGF-beta 1). Our results suggest that TGF-beta 1 is a major signal involved in initiating and/or maintaining the thermogenic and adipogenic differentiation of rat fetal brown adipocytes.

Adipose Tissue, Brown↗

PubMed1979

Isoelectric focusing of some enzymes from Echinococcus granulosus (horse and sheep strains) and E. multilocularis.

Extracts of the horse and sheep strains of Echinococcus granulosus and E. multilocularis were compared on the basis of their isoenzyme patterns for 10 enzymes by means of isoelectric focusing in polyacrylamide gels. The enzymes examined were: acid phosphatase, lactate dehydrogenase, malate dehydrogenase, malic enzyme, phosphoglucoseisomerase, isocitrate dehydrogenase, adenylate kinase, aldolase and alpha-glycerophosphate dehydrogenase. Interspecific and intraspecific differences are apparent in the isoenzyme profiles of all the enzymes except adenylate kinase; the pattern and activity of adenylate kinase are identical for both strains of E. granulosus but this enzyme clearly distinguishes these forms from E. multilocularis. The absence of electromorphic variation in any of the enzymes from either form of E. granulosus may be a result of the self-fertilizing hermaphraditism of these organisms.

Adenylate Kinase↗

PubMed2005

Leishmania major and Leishmania tropica: II. Effect of an immunomodulator, S(2) complex on the enzymes of the parasites.

S(2) complex has been reported to have a direct antileishmanial effect. The possibility that the direct antileishmanial effect may be due to inhibition of key enzymes involved in glucose metabolism and/ or enzymes associated with virulence was investigated. Cell pellets were prepared from cultures of both axenic amastigotes and promastigotes of Leishmania major (MHOM/IQ/93/MRC6) and L. tropica (MHOM/IQ/93/MRC2). S(2) complex, at various concentrations, was added to the enzyme extracts prepared from the pellets. Results show that in the Embden-Meyerhof pathway, both hexokinase and glucose-phosphate isomerase but not fructophosphokinase were dose dependently inhibited. In the hexose-monophosphate shunt both glucose-6-phosphate dehydrogenase and ribose-5-phosphate isomerase were dose dependently inhibited. Malic dehydrogenase and malic enzyme from the citric-acid cycle were both dose dependently inhibited but succinate dehydrogenase from the same pathway was not inhibited. Both enzymes associated with virulence (protease and acid phosphatase), showed activation rather than inhibition at higher doses of S(2) complex. Thus, the direct antileishmanial effect of S(2) complex may result, partially or entirely, from the inhibition of enzymes that are necessary for the parasites' carbohydrate metabolism.

Acid Phosphatase↗

PubMed1995

Direct evidence for a role of the "spot 14" protein in the regulation of lipid synthesis.

"Spot 14" is a nuclear protein that is rapidly induced by thyroid hormone (T3) and dietary carbohydrate in liver. We used an antisense oligonucleotide to inhibit induction of spot 14 protein by T3 and glucose in primary cultures of rat hepatocytes to test the hypothesis that the protein could function in the regulation of lipid synthesis. Spot 14 protein was undetectable in hepatocytes maintained in 5.5 mM glucose without T3, and was induced within 4 h after addition of 27.5 mM glucose and 50 nM T3 to the culture medium, reaching a maximal level within 24 h. Accumulation of spot 14 protein was markedly inhibited in hepatocytes transfected with a spot 14 antisense oligonucleotide, but not in those treated with a control oligonucleotide. Transfection of the antisense, but not control, oligonucleotide also abrogated the increase in lipogenesis induced by T3 and glucose. Reduced triglyceride formation accounted for the diminished net lipid synthesis. In contrast to lipogenesis, glucose uptake was not significantly affected by the transfections. Antisense transfection inhibited the induction of both ATP-citrate lyase and fatty acid synthase immunoreactivities, as well as malic enzyme activity, indicating that the observed reduction in lipogenesis could be explained by diminished cellular content of lipogenic enzymes. Reduced malic enzyme activity in antisense-transfected hepatocytes was accompanied by lowered relative abundance of malic enzyme mRNA, suggesting that the antisense effects on lipogenic enzymes were mediated at the pretranslational level. The oligonucleotides did not significantly affect lipogenesis in a rat hepatoma cell line that does not express detectable spot 14 mRNA or protein. These data directly implicate the spot 14 protein in the transduction of hormonal and dietary signals for increased lipid metabolism in hepatocytes.

Animals↗

PubMed1977

Light versus Dark Carbon Metabolism in Cherry Tomato Fruits: II. Relationship Between Malate Metabolism and Photosynthetic Activity.

The possible relationship between malate metabolism and photosynthetic activity in green tomato fruit tissues (Lycopersicum esculentum var. cerasiforme Dun A. Gray) was investigated. Initial experiments consisted of vacuum-infiltrating (14)C-3 or (14)C-4-malate into isolated tissues in darkness and then incubating the tissues under photosynthetic conditions. Other experiments involved a short pulse with (14)C-bicarbonate in darkness to label the malate pool(s), followed by a chase in the light in the presence of nonradioactive bicarbonate. Both series of experiments were followed by the separation and identification of labeled metabolic intermediates.Label initially in carbon atoms 3 and 4 of malate, corresponding also to C-3 of pyruvate and CO(2) after malate decarboxylation, was recovered as citrate + isocitrate, sugars and starch following incubations of tissues in the light. These data demonstrate that the reductive pentose phosphate cycle utilizes CO(2) furnished by malate metabolism due to the operation of the citric acid cycle and perhaps also to malic enzyme activity. Some synthesis of sugars and starch from C-3 of malate was observed in darkness or in the light 3-(3,4-dichlorophenyl)-1,1-dimethyl which could be due to gluconeogenesis. Pulse-chase experiments indicated a rapidly turning over malate pool.

Journal Article↗

PubMed1995

Effect of dietary soybean phospholipid and fats differing in the degree of unsaturation on fatty acid synthesis and oxidation in rat liver.

The activities of enzymes in fatty acid oxidation and synthesis in the liver of rats fed soybean phospholipids and soybean oil corresponding to the dietary levels of 3% fatty acid added to the diets containing a saturated fat (coconut oil) and a polyunsaturated fat (safflower oil) at the amounts corresponding to 12% fatty acid levels were compared. Soybean phospholipid compared with soybean oil added to both coconut and safflower oil diets significantly reduced the activities of enzymes in fatty acid synthesis (fatty and synthetase, glucose-6-phosphate dehydrogenase and malic enzyme). However, there were no significant differences in the activities of enzymes in fatty acid oxidation (carnitine palmitoyltransferase, acyl-CoA dehydrogenase and acyl-CoA oxidase) between the groups of rats fed soybean phospholipid and soybean oil added to coconut and safflower oil diets except for one occasion. Soybean phospholipid compared with soybean oil added to coconut oil diet significantly decreased the concentrations of triacylglycerol, cholesterol and phospholipid in the serum and of triacylglycerol and cholesterol in the liver. However, the dietary phospholipid added to safflower oil diet failed to alter these values. These results suggested that the alteration in the rate of fatty acid synthesis, but not oxidation, in the liver is responsible for the lipid-lowering effect of dietary soybean phospholipid added to a saturated fat diet.

Animals↗

PubMed1981

Effects of dietary fat on feed efficiency, reproductive performance, and in vitro lipogenesis by the turkey hen.

Two 16-week feeding trials were conducted with Large White turkey hens to determine the effect of graded energy levels (as fat-6, 18, 30, and 42% substituted isocalorically for corn meal) on energy efficiency, reproductive performance, lipogenic enzyme activity, and in vitro lipogenesis. A constant calorie: gram-protein ratio (17:1) was maintained for all dietary treatments. Also, other components of the diets were adjusted to maintain constant energy-to-nutrient ratios. Additional fat increased (P less than .05) energy utilization but had no effect on reproductive performance. Additional fat calories decreased (P less than .05) malic enzyme, isocitrate dehydrogenase, and fatty acid synthetase activities; however, fatty acid synthetase activity was the most responsive of the three enzymes to 42% metabolizable energy as fat. Liver lipid content was also decreased (P less than .05) by additional fat calories. In vitro lipogenesis (fatty synthesis from 10 mM (1-14C) sodium acetate) was also decreased (P less than .01) by additional dietary fat.

Animal Feed↗