Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.1.1.37 (malate dehydrogenase)
4,591 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nitric oxide synthase produces NO, citrulline, water, and NADP at the expense of arginine, NADPH, and dioxygen. While citrulline has been considered to be an inert by-product of the high output inducible isoform of NO synthase (iNOS), we show here that immunostimulants induce a metabolic pathway in vascular smooth muscle cells, which enables them to regenerate arginine from citrulline. Regeneration of arginine from citrulline is accomplished by two urea cycle enzymes: arginino-succinate synthetase (AS) and argininosuccinate lyase (AL). Whereas AL is constitutive to vascular smooth muscle cells, AS mRNA and enzyme activity is markedly induced in cells by treatment with bacterial lipopolysaccharide (LPS). The induction of AS mRNA and activity by LPS follows a time course which mirrors that for iNOS but lags 1-2 h behind. As shown for iNOS, interferon-gamma does not itself induce AS but is synergistic with LPS. AS induction is suppressed by glucocorticoids, actinomycin D, and, to a lesser extent, cycloheximide. On the other hand, AS induction is unaffected by an excess of citrulline or the inhibitor of iNOS, N omega-methyl-L-arginine. Our results show the urea cycle enzymes AS and AL confer cells with the capacity to produce NO without a need for exogenous arginine. In conjunction with NOS, citric acid cycle enzymes that covert fumarate to oxaloacetate (fumarase and malate dehydrogenase) and oxaloacetate to aspartate (aspartate transaminase), AS and AL form a novel arginine-citrulline cycle that enables high output NO production by cells.
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PMID:Argininosuccinate synthetase mRNA and activity are induced by immunostimulants in vascular smooth muscle. Role in the regeneration or arginine for nitric oxide synthesis. 751 85

Three light/dark-modulated chloroplast enzymes, namely NADP-dependent malate dehydrogenase (EC 1.1.1.82), D-fructose 1,6-bisphosphatase (EC 3.1.3.11), and phosphoribulokinase (EC 2.7.1.19) were purified to apparent homogeneity from spinach leaves. Equilibrium constants for the covalent modification of the regulatory disulfide bonds of these enzymes in dithiothreitol (DTT)-redox buffer were determined according to a previously published method in the literature (Clancey and Gilbert (1987) J. Biol. Chem. 262, 13545-13549). The thiol/disulfide-redox potential (Kox) was defined as the ratio of reduced to oxidized dithiothreitol at which 50% of the maximal enzyme activity was observed after equilibrium had been established. All Kox values were very high, comparable to those of extracellular disulfide containing proteins: 0.23 +/- 0.02 for NADP-malate dehydrogenase, 0.59 +/- 0.17 for phosphoribulokinase, and 0.70 +/- 0.16 for D-fructose 1,6-bisphosphatase. The equilibrium constants for the reactions between these enzymes and the redox buffers were also determined in the presence of various concentrations of specific metabolites known to influence the rates of reduction and oxidation. Increasing concentrations of D-fructose 1,6-bisphosphate in the presence of Ca2+ shift the equilibrium constant between D-fructose 1,6-bisphosphatase and the DTT-redox buffer to much lower values. A decreasing NADPH/(NADP + NADPH) ratio increases the Kox of NADP-malate dehydrogenase in the redox buffer to very high values. For PRK, low concentrations of ATP result in a slight decrease of the Kox that is not further affected by higher ATP concentrations. The differences of the equilibrium constants of NADP-malate dehydrogenase and D-fructose 1,6-bisphosphatase as dependent upon the NADPH/(NADP + NADPH) ratio and the concentration of D-fructose 1,6-bisphosphate, respectively, reflect a mechanism of feed-back and feed-forward regulation by the product NADP and the substrate D-fructose 1,6-bisphosphate, respectively. Thus the actual activation state of these two key enzymes of chloroplast metabolism are determined in an independent manner. The relatively small effect of the ATP concentration upon the redox potential of phosphoribulokinase indicates that fine-regulation at this step might be achieved on another level (e.g., catalysis or aggregation state).
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PMID:Redox equilibria between the regulatory thiols of light/dark-modulated chloroplast enzymes and dithiothreitol: fine-tuning by metabolites. 787 83

To evaluate changes in metabolic heterogeneity in rat liver lobules after partial hepatectomy, we measured parameters of carbohydrate and lipid metabolism cytophotometrically in periportal and pericentral zones of livers of mature female and male rats. Glycogen content was shown to be always higher in pericentral zones than in periportal zones. After a rapid depletion of glycogen stores during the first 8 hr after partial hepatectomy, the levels were restored to normal after 24 hr, but a significant depletion was found again at 48 hr after operation. These fluctuations were similar in female and male rat livers. The lipid content in control rat livers was low and was mainly localized in periportal zones. Partial hepatectomy caused a significant increase in lipid content after 24 to 48 hr in periportal zones only, which was distinctly higher in female than in male rat livers. Activity of NADPH-producing glucose-6-phosphate dehydrogenase was heterogeneously distributed in lobules of female control rats with highest activity in pericentral zones, whereas a lower but evenly distributed activity was found in lobules of control male rats. The activity was not affected by partial hepatectomy in male rats, whereas the activity in female rat livers decreased to levels found in male rats at 24 to 48 hr after operation. Another NADPH-producing enzyme, malate dehydrogenase, showed the highest activity pericentrally in female rats, and a low activity was evenly distributed in male rats. The activity did not change significantly after partial hepatectomy. The ketogenic enzyme beta-hydroxybutyrate dehydrogenase showed the highest activity in pericentral zones of control livers. The activity in male rat livers was almost twice as high as in female rat livers in both zones. Partial hepatectomy caused a distinct reduction in activity in both zones and both sexes, but the strongest reduction was found periportally. Alkaline phosphatase activity, which is linked with bile acid secretion by hepatocytes, was low in control male and female rats and was mainly found periportally. The activity was increased dramatically at 24 to 48 hr after partial hepatectomy in both zones and particularly in male rat livers. The index for the Krebs cycle, succinate dehydrogenase activity, was highest in periportal zones. At 24 to 48 hr after partial hepatectomy, this preferential zonation was lost, and the activity was slightly higher in pericentral zones. This reversal of zonation was found in all livers of female and male rats investigated.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Adaptive sex-dependent changes in the zonation of carbohydrate and lipid metabolism in rat liver lobules after partial hepatectomy. 807 28

Various properties of purified chloroplast NADP-malate dehydrogenase were analyzed with respect to the redox state of the light/dark-modulated enzyme. The reduced enzyme is less resistant to heat, but the instability can be overcome by the addition of the coenzyme NADPH. Similarly, instability of the reduced NADP-MDH at high pH is alleviated by NADPH. The kinetics and protection characteristics of the alkylation of accessible thiols of NADP-MDH are used to describe the location of essential thiols relative to the active site, since again the coenzyme protects the active enzyme very effectively from inactivation by alkylation. The increased hydrophobicity of the reduced as opposed to the oxidized enzyme becomes apparent as the loss of activity from solutions due to adsorption to plastic surfaces. The kinetics and the solvent dependency of this process are analyzed and discussed, both from the practical (recovery of the purified enzyme) and the physiological point of view (in vivo protein/protein and protein/membrane interactions). The oxidized NADP-MDH has a lower tendency to bind to solid surfaces. NADP(H) efficiently prevents adsorption of the reduced form. Macromolecular solvents (polyethylene glycol), detergents (Triton X-100), or competing proteins also protect this otherwise very hydrophobic form from irreversible loss due to adsorption. Ribulosebisphosphate carboxylase/oxygenase and polyethylene glycol 10,000, however, used as competing substances only keep the oxidized, not the reduced, NADP-MDH in solution.
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PMID:Analysis of biophysical differences between oxidized and reduced chloroplast NADP-malate dehydrogenase. 843 43

On the basis of the crystal structure of the NAD-dependent cytoplasmic malate dehydrogenase (MDH) and its alignment with NADP-dependent counterparts, the loop region between beta-strand B and alpha-helix C in the dinucleotide-binding fold was predicted as a principal determinant for the coenzyme specificity. Two mutants, EX7 and EX3, of NAD-dependent MDH from Thermus flavus were constructed. In the EX7 mutant, the seven loop amino acids in positions 41-47, Glu-Ile-Pro-Gln-Ala-Met-Lys, were replaced by the corresponding loop residues in the NADP-dependent MDH from chloroplasts, Gly-Ser-Glu-Arg-Ser-Phe-Gln. In the EX3 mutant, Glu-41, Ile-42, and Ala-45 were substituted with the corresponding 3 amino acids in the NADP-dependent chloroplast MDH. In both mutations the coenzyme specificity was altered from NAD to NADP. Especially, the EX7 mutation resulted in a more than 1000-fold improvement in overall catalytic efficiency with NADPH and a 600-fold decrease in the efficiency with NADH as cofactors. Consequently, EX7 mutant was 132 times more efficient with NADPH than NADH without a large decrease in turnover number.
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PMID:Alteration of coenzyme specificity of malate dehydrogenase from Thermus flavus by site-directed mutagenesis. 844 39

Activity of NADP-dependent isocitrate- and malate dehydrogenases and the rate of NADP reduction into NAD+ were studied in various rat brain compartments during the hypoglycemic coma and within various periods after the coma cupping using glucose administration. Severe hypoglycemia was accompanied by distinct decrease in content of NADH x H+ in nervous tissue, while the enzymatic activity studied was not altered and content of NADPH x H+ was not decreased. Within the early restoration period activity of cytoplasmic NADP-malate dehydrogenase and content of NADPH x H+ were increased in brain tissue. Production of NADPH x H+ during hypoglycemic coma and after its cupping was maintained in nervous tissue at the adequately high level and did not affect the restoration-related synthesis.
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PMID:[Activity of NADP-dependent dehydrogenases and level of recovery of pyridine nucleotides in the rat brain in insulin hypoglycemia and in the recuperative period]. 858 73

Rabbit, pigeon and rat liver mitochondria convert exogenous phosphoenolpyruvate and acetylcarnitine to citrate at rates of 14, 74 and 8 nmol/15 min/mg protein. Citrate formation is dependent on exogenous HCO3-, is increased consistently by exogenous nucleotides (GDP, IDP, GTP, ADP, ATP) and inhibited strongly by 3-mercaptopicolinate and 1,2,3-benzenetricarboxylate. Citrate is not made from pyruvate alone or combined with acetylcarnitine. Pigeon and rat liver mitochondria make large amounts of citrate from exogenous succinate, suggesting the presence of an endogenous source of acetyl units or means of converting oxalacetate to acetyl units. Citrate synthesis from succinate by pigeon and rabbit mitochondria is increased significantly by exogenous acetylcarnitine. Pigeon and rat liver contain 80 and 15 times, respectively, more ATP:citrate lyase activity than does rabbit liver. Data suggest that mitochondrial phosphoenolpyruvate carboxykinase in vivo could convert glycolysis-derived phosphoenolpyruvate to oxalacetate that, with acetyl CoA, could form citrate for export to support cytosolic lipogenesis as an activator of acetyl CoA carboxylase, a carbon source via ATP:citrate lyase and NADPH via NADP:malate dehydrogenase or NADP:isocitrate dehydrogenase.
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PMID:Synthesis of citrate from phosphoenolpyruvate and acetylcarnitine by mitochondria from rabbit, pigeon and rat liver: implications for lipogenesis. 884 May 17

The kinetics of activation of NADP-malate dehydrogenase (MDH; EC 1.1.1.82) from soybean and spinach leaves by the chloroplast thioredoxins isolated from the same plants, by the corresponding storage forms of the soybean chloroplast thioredoxins from soybean seeds, and by the bacterial Escherichia coli thioredoxin have been studied. The Hill equation has been applied to evaluate the saturation kinetics. The observed variable thioredoxin saturation characteristics (Vmax 0.37-14.5 mumol NADPH min-1 mg enzyme-1; K0.5 0.15-1.33 microM; Hill coefficient h 0.90-3.04) indicate that the activation of NADP-MDH depends strongly on the individual thioredoxin used. Thus, thioredoxin action is not solely due to simple reductive activation of the NADP-MDH. Specific thioredoxin complex formation between thioredoxin and NADP-MDH must be included into the mechanism of the activation process. To study the regulatory consequences of the specific thioredoxin/NADP-MDH complexes we investigated the saturation kinetics of the substrates NADPH and oxaloacetate in presence of different concentrations of each individual thioredoxin species. The kinetic characteristics of the substrates (S0.5, Vmax, and Hill coefficients h) varied individually in response to the different thioredoxin species substantiating our model of thioredoxin/ NADP-MDH complex formation. Aminopeptidase-K-truncated pea NADP-MDH has been used to demonstrate that the N-terminal 37 amino residues are involved in providing a specific thioredoxin binding site. The fact that the versatile light-dependent regulation of numerous enzyme activities by only two thioredoxin species in chloroplasts cannot be accomplished without the formation of thioredoxin/target enzyme complexes is discussed in detail.
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PMID:Kinetic evidence for protein complexes between thioredoxin and NADP-malate dehydrogenase and presence of a thioredoxin binding site at the N-terminus of the enzyme. 885 84

Thioredoxins are low molecular weight proteins, which participate in a wide spectrum of biochemical reactions. Two thioredoxins from Streptomyces aureofaciens 3239 have been purified to homogeneity by a sequence of chromatography steps including chromatography on Sephacryl S-300, Phenyl Sepharose CL 4B and MonoQ HR 5/5. Thioredoxin activity clearly separates into two protein fractions on MonoQ HR 5/5 chromatography. Molecular weights determined by chromatography on Superose 12 HR 10/30 and sodium dodecyl sulphate polyacrylamide gel electrophoresis revealed M(r) approximately 10,500 for thioredoxin 1 (TR1) and M(r) approximately 11,000 for thioredoxin 2 (TR2). The isoelectric points of the two thioredoxins are different pI = 4.7 for TR1 and 5.6 for TR2, respectively. Both were effectively reduced with NADPH in reaction catalyzed by Streptomyces aureofaciens thioredoxin reductase. The specific activity of viewly for discovered TR2 is about 1/4 of the specific activity of TR1. Both thioredoxins activate spinach NADPH-malate dehydrogenase. Activation of this enzyme by TR2 is only half effective than by TR1. The stability of TR1 is high and similar to thioredoxins from other organisms unlike the activity of TR2 which is decreased during purification. The proteins diversed in their contents in exponentially growing mycelium.
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PMID:Purification and partial characterization of two thioredoxins from Streptomyces aureofaciens. 890 58

The coupled processes of the chloroplast trans-envelope transport of malate and oxaloacetate and their interconversion as catalyzed by the stromal NADP-linked malate dehydrogenase are quantitatively analyzed by means of a steady-state model. The equation for the NADP-malate dehydrogenase reaction is developed. The empirical dependence of enzyme activity on NADPH and NADP+ is used to determine its actual activity. The trans-envelope counter exchange of malate and oxaloacetate is described by a kinetic model of the translocator. Kinetic parameters are derived from known data, except for the Km value and the maximum rate for oxaloacetate transport, which are estimated from oxaloacetate-dependent malate formation in isolated intact chloroplasts. Using the kinetic properties of the system and the known metabolite concentrations, the model demonstrates that photosynthetically generated NADPH can be exported efficiently from the chloroplasts to the cytosol by the malate-valve system. The transfer capacity of the malate valve is estimated not to exceed 20 mumol (mg Chl)-1 h-1 (or 5% of the electron transport) under normal physiological conditions. The possible role of the malate valve in leaf cells under normal conditions and during stress is discussed.
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PMID:Flux control of the malate valve in leaf cells. 944 17


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