Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P17174 (aspartate aminotransferase)
 14,872 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The rate of fatty acid synthesis from acetoacetate (AcAc) is 2-3 times greater than from glucose in developing rat lung. To determine the reason for this difference, we investigated the pathways of lipogenesis from [3-14C] AcAc, [3-14C] beta-hydroxybutyrate (beta OHB), [U-14C] glucose or [2-14C] pyruvate in minced lung tissue of 3- to 4-day-old rats. The addition of (-)hydroxycitrate, an inhibitor of ATP-citrate lyase, inhibited fatty acid synthesis from glucose, pyruvate, and beta OHB by 88%, 70% and 60%, respectively, but had no effect on that from AcAc. Benzene 1,2,3-tricarboxylate, an inhibitor of tricarboxylate translocase, inhibited fatty acid synthesis from all substrates by at least 50%. Incubation with aminooxyacetate, an inhibitor of aspartate aminotransferase, had no effect on lipid synthesis from glucose, pyruvate or AcAc, but increased lipid synthesis from beta OHB. Results indicate that for lipid synthesis in the neonatal lung, acetyl CoA from AcAc is derived predominantly from a cytoplasmic pathway involving AcAcCoA synthetase and AcAcCoA thiolase, whereas citrate is the major route of acetyl group transfer from glucose. Lipogenesis from beta OHB involves both the cytoplasmic and citrate pathways.
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PMID:Pathways of acetyl CoA production for lipogenesis from acetoacetate, beta-hydroxybutyrate, pyruvate and glucose in neonatal rat lung. 670 49

Holstein bull calves were used to determine the influence of degradable nitrogen and ration physical form on rumen epithelial transport and enzymic activity. Rations contained 30, 45 and 60% ruminal degradable nitrogen (RDN), each with three forms (ground hay, GR; chopped hay, CH; and all concentrate, CONC). Rumen tissue samples were obtained by biopsy (8 weeks) and at slaughter (20 weeks). Acetate transport across rumen epithelium increased between 8 and 20 weeks in calves fed GR and CH, but not in calves fed CONC. Propionate transport was highest in calves fed GR and lowest in calves fed CONC at both 8 and 20 weeks. Transport of acetate and propionate was incresed with increasing RDN at 20 weeks. There were no differences in ruminal tissue lactate production. Rumen papillae of calves fed CONC were abnormal in morphology and at 20 weeks dry mucosal weights (mg/cm2) were highest. Lactate dehydrogenase and NADP-malic dehydrogenase activities were not different. Propionyl CoA synthetase activity was higher in 20-week calves fed CONC, compared to GR to CH. Glutamate dehydrogenase and aspartate aminotransferase activities were highest in 20-week calves fed 60% RDN rations, regardless of physical form.
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PMID:Influence of ration physical form, ruminal degradable nitrogen and age on rumen epithelial propionate and acetate transport and some enzymatic activities. 744 67

Prolactin is an important regulator of prostate citrate production. In rats this regulatory effect of prolactin is specific for lateral prostate, and has no effect on either ventral or dorsal prostate. The mechanisms by which prolactin regulates prostate citrate production have not been elucidated. Two key regulatory enzymes involved in citrate synthesis by prostate epithelial cells are mitochondrial aspartate aminotransferase (mAAT) which provides oxalacetate, and PDH E1 alpha (pyruvate dehydrogenase) which provides acetyl CoA for citrate synthesis. Our previous studies demonstrated that prolactin regulates mAAT. However, an increase in citrate synthesis would require an increase in both oxalacetate and acetyl CoA. Therefore, we investigated the possibility that prolactin might also regulate PDH E1 alpha in LP epithelial cells. The present studies demonstrate that prolactin administration (1 mg/rat) to rats resulted in an increased level of E1 alpha in LP epithelial cells within 6 hr, but had no effect on the E1 alpha level of VP epithelial cells. In vitro studies demonstrated that exposure of freshly prepared LP epithelial cells to prolactin (0.1-1.0 microgram/ml) resulted in increased levels of E1 alpha. Prolactin had no effect on either VP or DP epithelial cells. The stimulatory effect of prolactin on E1 alpha was inhibited by actinomycin and cycloheximide, thereby indicating that prolactin stimulated the biosynthesis of E1 alpha. The studies reveal that prolactin specifically stimulates E1 alpha levels of LP epithelial cells, whereas testosterone specifically stimulates E1 alpha levels of VP epithelial cells. At this time, we propose that the effects of prolactin and testosterone involve increased expression of the E1 alpha gene of LP and VP epithelial cells, respectively.
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PMID:Prolactin specifically increases pyruvate dehydrogenase E1 alpha in rat lateral prostate epithelial cells. 771 83

Weiss et al. (Circ. Res. 70: 392-408, 1992) proposed a model of the citric acid cycle (CAC) in myocytes and a system of 17 differential equations that can be used to describe the changes over time in enrichment of carbons C-2 and C-4 of glutamate under conditions of metabolic steady state. They also proposed an empirical measure (KT) of flux through the CAC, which has been shown to be correlated to O2 consumption in rat hearts perfused with acetate or a mixture of glucose and acetate. We report a new method for estimation of the absolute rate of the flux through the CAC in heart (vTCA), without the numerical solution of differential equations. Unlike KT, our estimate is equal to the rate of flux catalyzed by the alpha-ketoglutarate dehydrogenase complex (vTCA), not merely correlated with it. We also estimate the rate of flux catalyzed by aspartate aminotransferase (vTA) and by NADP(+)-dependent malic enzyme (an anaplerotic reaction). The formula for vTCA during administration of [2-13C]acetate is as follows: vTCA = M[(C-2ssLC-4)/[C-4ss(LC-4-LC-2)]], where C-2ss and C-4ss represent steady-state fractional enrichment, LC-2 and LC-4 represent dominant rate constants of C-2 and C-4 of glutamate, respectively, and M is the sum of concentrations of aspartate, glutamate, and intermediates of the CAC. The assumptions underlying our formula are as follows: 1) metabolic steady state is maintained, 2) exchange of molecules between cytosolic and mitochondrial compartments is rapid, 3) 13C enters pools of the CAC only from acetyl CoA via citrate synthase, 4) [citrate]/[glutamate] < 1 + (vTCA/vTA), and 5) (m-[glutamate])/M < C-2ss/C-4ss.
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PMID:Estimation of TCA cycle flux, aminotransferase flux, and anaplerosis in heart: validation with syntactic model. 790 Jul 86

5-Aminolevulinate synthase (ALAS) catalyzes the first step in the heme biosynthetic pathway in nonplant eukaryotes and some prokaryotes, which is the condensation of glycine with succinyl-coenzyme A to yield coenzyme A, carbon dioxide, and 5-aminolevulinate. ALAS requires pyridoxal 5'-phosphate as an essential cofactor and functions as a homodimer. D279 in murine erythroid enzyme was found to be conserved in all aminolevulinate synthases and appeared to be homologous to D222 in aspartate aminotransferase, where the side chain of the residue stabilizes the protonated form of the cofactor ring nitrogen, thus enhancing the electron sink function of the cofactor during enzyme catalysis. D279A mutation in ALAS resulted in no detectable enzymatic activity under standard assay conditions, and the conservative D279E mutation reduced the catalytic efficiency for succinyl-CoA 30-fold. The D279A mutation resulted in a 19-fold increase in the dissociation constant for binding of the pyridoxal 5'-phosphate cofactor. UV-visible and CD spectroscopic analyses indicated that the D279A mutant binds the cofactor in a different mode at the active site. In contrast to the wild-type and D279E mutant, the D279A mutant failed to catalyze the formation of a quinonoid intermediate upon binding of 5-aminolevulinate. Importantly, this partial reaction could be rescued in D279A by reconstitution of the mutant with the cofactor analogue N-methyl-PLP. The steady-state kinetic isotope effect when deuteroglycine was substituted for glycine was small for the wild-type enzyme (kH/kD = 1.2 +/- 0.1), but a strong isotope effect was observed with the D279E mutant (kH/kD = 7.7 +/- 0.3). pH titration of the external aldimine formed with ALA indicated the D279E mutation increased the apparent pKa for quinonoid formation from 8.10 to 8.25. The results are consistent with the proposal that D279 plays a crucial role in aminolevulinate synthase catalysis by enhancing the electron sink function of the cofactor.
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PMID:Aspartate-279 in aminolevulinate synthase affects enzyme catalysis through enhancing the function of the pyridoxal 5'-phosphate cofactor. 952 72

Renal and hepatic subacute toxicity induced by the antihyperlipidaemic drugs: Bezalip-Pravastatin and Lopid was investigated in rats using serum biochemical parameters. Toxicological evaluation was performed in serum samples following the administration of the therapeutic dose regimens of the compounds that were previously shown to be effective in inhibition of 3-hydroxy-methylglutaryl coenzyme A (HMG CoA) reductase, the enzyme controlling the rate-limiting step in the synthesis of cholesterol, and acyl-CoA cholesterol acyl transferase (ACAT) which converts intracellular free cholesterol to cholesterol ester. Renal and hepatic subacute toxicity was evaluated by measuring enzyme activity or concentrations of: alanine aminotransferace, alkaline phosphatase, aspartate aminotransferase, gamma-glutamyltransferase, glucose, potassium, sodium, blood urea nitrogen, uric acid and creatinine. The use of the above serum biochemical parameters indicated that the overall toxicity impact of antihyperlipidaemic drugs was Bezalip = Pravastatin < Lopid. We have found that the Pravastatin--in contrast to the above antihyperlipidaemic drugs--only transiently affects the biochemical parameters associated with toxicity, but, it affects some of the biochemical parameters associated with hepatic and renal toxicity, up to a significantly lower extent than the antihyperlipidaemic drugs.
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PMID:Evaluation of kidney and liver subacute toxicity induced by Bezalip-Pravastatin-Lopid antihyperlipidaemic compounds in rats. 1020 89

2-Amino-3-ketobutyrate CoA ligase (KBL, EC 2.3.1.29) is a pyridoxal phosphate (PLP) dependent enzyme, which catalyzes the second reaction step on the main metabolic degradation pathway for threonine. It acts in concert with threonine dehydrogenase and converts 2-amino-3-ketobutyrate, the product of threonine dehydrogenation by the latter enzyme, with the participation of cofactor CoA, to glycine and acetyl-CoA. The enzyme has been well conserved during evolution, with 54% amino acid sequence identity between the Escherichia coli and human enzymes. We present the three-dimensional structure of E. coli KBL determined at 2.0 A resolution. KBL belongs to the alpha family of PLP-dependent enzymes, for which the prototypic member is aspartate aminotransferase. Its closest structural homologue is E. coli 8-amino-7-oxononanoate synthase. Like many other members of the alpha family, the functional form of KBL is a dimer, and one such dimer is found in the asymmetric unit in the crystal. There are two active sites per dimer, located at the dimer interface. Both monomers contribute side chains to each active/substrate binding site. Electron density maps indicated the presence in the crystal of the Schiff base intermediate of 2-amino-3-ketobutyrate and PLP, an external aldimine, which remained bound to KBL throughout the protein purification procedure. The observed interactions between the aldimine and the side chains in the substrate binding site explain the specificity for the substrate and provide the basis for a detailed proposal of the reaction mechanism of KBL. A putative binding site of the CoA cofactor was assigned, and implications for the cooperation with threonine dehydrogenase were considered.
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PMID:Three-dimensional structure of 2-amino-3-ketobutyrate CoA ligase from Escherichia coli complexed with a PLP-substrate intermediate: inferred reaction mechanism. 1131 37

Nutrient secretagogues can increase the production of succinyl-CoA in rat pancreatic islets. When succinate esters are the secretagogue, succinyl-CoA can be generated via the succinate thiokinase reaction. Other secretagogues can increase production of succinyl-CoA secondary to increasing alpha-ketoglutarate production by glutamate dehydrogenase or mitochondrial aspartate aminotransferase followed by the alpha-ketoglutarate dehydrogenase reaction. Although secretagogues can increase the production of succinyl-CoA, they do not increase the level of this metabolite until after they decrease the level of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). This suggests that the generated succinyl-CoA initially reacts with acetoacetate to yield acetoacetyl-CoA plus succinate in the succinyl-CoA-acetoacetate transferase reaction. This would be followed by acetoacetyl-CoA reacting with acetyl-CoA to generate HMG-CoA in the HMG-CoA synthetase reaction. HMG-CoA will then be reduced by NADPH to mevalonate in the HMG-CoA reductase reaction and/or cleaved to acetoacetate plus acetyl-CoA by HMG cleavage enzyme. Succinate derived from either exogenous succinate esters or generated by succinyl-CoA-acetoacetate transferase is metabolized to malate followed by the malic enzyme reaction. Increased production of NADPH by the latter reaction then increases reduction of HMG-CoA and accounts for the decrease in the level of HMG-CoA produced by secretagogues. Pyruvate carboxylation catalyzed by pyruvate carboxylase will supply oxaloacetate to mitochondrial aspartate aminotransferase. This would enable this aminotransferase to supply alpha-ketoglutarate to the alpha-ketoglutarate dehydrogenase complex and would, in part, account for secretagogues increasing the islet level of succinyl-CoA after they decrease the level of HMG-CoA. Mevalonate could be a trigger of insulin release as a result of its ability to alter membrane proteins and/or cytosolic Ca(2+). This is consistent with the fact that insulin secretagogues decrease the level of the mevalonate precursor HMG-CoA. In addition, inhibitors of HMG-CoA reductase interfere with insulin release and this inhibition can be reversed by mevalonate.
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PMID:The succinate mechanism of insulin release. 1219 57

The inhibitory effects of 1,3-diacylglycerol (DAG) on diet-induced lipid accumulation in liver and abdominal adipose tissue of rats were investigated in the present study. Male Sprague-Dawley rats were given free access to diets containing 7 wt% TAG (low TAG), 20 wt% TAG (high TAG), or 20 wt% DAG (high DAG), respectively, for 8 wk. The body weight of rats in the 20% high-TAG group increased significantly, and the weights of their abdominal adipose tissue and liver also showed a significant increase compared with rats in the low-TAG group. However, the high-DAG diet resulted in both a significant reduction in body weight gain (with a decrease of 70.5%) and an increase in the ratio of abdominal fat to body weight (by 127%) compared with the high-TAG diet. As well, the liver TAG and serum TAG levels of the high-DAG group were significantly lower than those of the high-TAG group. These effects were associated with up-regulation of acyl-CoA carnitine acyltransferase (ACAT) and down-regulation of acyl-CoA DAG acyltransferase (DGAT) in the liver. However, no significant difference was observed in the activities of alanine aminotransferase and aspartate aminotransferase among the groups (P > 0.05). The present results indicate that dietary DAG reduced fat accumulation in viscera and body, and these effects may be involved with up-regulation of ACAT and down-regulation of DGAT in the liver.
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PMID:Dietary diacylglycerol prevents high-fat diet-induced lipid accumulation in rat liver and abdominal adipose tissue. 1505 33

The aqueous extract of Desmodium gangeticum (L) DC (Fabaceae) (DG) was studied in isoproterenol induced myocardial infarcted (MI) rats for the hypocholesterolemic and antioxidant effect. After inducing MI by isoproterenol (35 mg/kg b wt. i.p.), the aqueous extract of Desmodium gangeticum root at a dose of 3 ml/100 g b wt. was orally administered daily for a period of 30 days in six rats. On induction of MI, the activities of creatinine phosphokinase (CPK), lactate dehydrogenase (LDH), alkaline phosphatase (ALP) and serum glutamate oxaloacetate transaminase (SGOT) increased in myocardial tissue, hepatic tissue and serum. Pretreatment of DG to MI rats prevented the increase of these enzymes. The hypocholesterolemic effect of DG was assessed by the concentration of total cholesterol, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol and through the activities of 3-hydroxy 3-methyl glutaryl co-enzyme (HMG CoA) reductase and lecithin cholesterol acyl transferase (LCAT) in the myocardial tissue. The significant (P < 0.001) decrease in the concentration of thiobarbituric acid reactive substances (TBARS) and improved activities of glutathione reductase and catalase in the myocardial tissues of rats treated with DG suggest free radical scavenging activity of the extract.
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PMID:Effect of aqueous extract of the Desmodium gangeticum DC root in the severity of myocardial infarction. 1574 Aug 81


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