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:2.6.1.1 (aspartate aminotransferase)
21,665 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Effects of norepinephrine on gluconeogenesis and ureogenesis from glutamine by hepatocytes from fasted rats were assessed. Comparisons were made to asparagine metabolism and to the effects of NH4Cl and dibutyryl cyclic AMP. With asparagine as substrate, aspartate content was very high but norepinephrine, dibutyryl cyclic AMP, or NH4Cl had little effect on gluconeogenesis or ureogenesis. Metabolism of asparagine could be greatly enhanced by the combination of oleate, ornithine, and NH4Cl. However, even under these conditions, asparatate content remained high, and norepinephrine and dibutyryl cyclic AMP had little influence on glucose or urea synthesis. With glutamine as substrate, aspartate content was much lower, but was greatly elevated by norepinephrine, dibutyryl cyclic AMP, or NH4Cl. Each of these effectors strongly stimulated glucose and urea formation from glutamine. NH4Cl stimulation was accompanied by an increased glutamate and decreased alpha-ketoglutarate content. This suggests the mechanism for NH4Cl stimulation is a near-equilibrium adjustment to ammonia by glutamate dehydrogenase and aspartate aminotransferase rather than a principal involvement of glutaminase. Although both norepinephrine and dibutyryl cyclic AMP lowered alpha-ketoglutarate to the same extent, norepinephrine more rapidly increased aspartate content and led to a smaller accumulation of glutamate than did dibutyryl cyclic AMP. Moreover, only norepinephrine led to a rapid increase in succinyl-CoA concentration. The catecholamine effect could not be explained by specific changes in cytosolic or mitochondrial redox states. The results suggest that alpha-ketoglutarate dehydrogenase is a site of catecholamine action in rat liver. Since purified alpha-ketoglutarate dehydrogenase is known to be Ca2+ stimulated and Ca2+ flux is involved in catecholamine action, these findings also suggest that mitochondrial Ca2+ is elevated by catecholamines.
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PMID:Glutamine metabolism of isolated rat hepatocytes. Evidence for catecholamine activation of alpha-ketoglutarate dehydrogenase. 609 58

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

13C NMR was used to follow the metabolism of [2- 13C]acetate and [1- 13C]acetate in aerobic suspensions of Saccharomyces cerevisiae. In the experiment with [2- 13C]acetate, the 13C label appeared first in glutamate C4 and subsequently in glutamate C2 and C3. After exhaustion of the acetate, the glutamate signals diminished and the aspartate C2 and C3 peaks increased. During a subsequent chase experiment with unlabeled acetate, the aspartate peaks decreased and the glutamate C2 and C3 peaks increased in intensity. These observations are interpreted in terms of an interplay between the glutamic-oxalacetic transaminase and Krebs cycle activity. This interpretation was confirmed by an experiment with the transaminase inhibitor 2-amino oxyacetate. During all of these experiments, we observed the formation of trehalose. The NMR gives a direct measurement of the label distribution and from that information it followed that the flows through the glyoxylate and the Krebs cycles are comparable. The intermediates citrate, succinate, fumarate, malate, phosphoenolpyruvate, 3-phosphoglycerate, and glucose 6-phosphate were identified in a 13C NMR spectrum of a perchloric acid extract taken during the metabolism of [2- 13C]acetate. Enrichment of the glutamate C5 position shows the existence of a futile cycle in which phosphoenolpyruvate, formed from oxaloacetate, returns to the Krebs cycle through pyruvate and acetyl CoA
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PMID:13C NMR study of transamination during acetate utilization by Saccharomyces cerevisiae. 701 9

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

We have placed two different penicillin structural genes from Aspergillus nidulans, ipnA (encoding isopenicillin N synthetase, IPNS) and acyA (encoding acyl-CoA:6-aminopenicillanic acid acyltransferase, AAT), under the control of the strong alcA promoter [alcA(p)]. Single copies of these transcriptional fusions were targeted to the same chromosomal location and conditions have been worked out which simultaneously allow induction of the alcA(p) and support penicillin biosynthesis. Transcriptional induction of the chimeric genes alcA(p)::ipnA or alcA(p)::acyA(cdna) in the relevant recombinant strains results in 10-fold higher levels of the ipnA or acyA transcripts than those resulting from transcription of the corresponding endogenous genes. This increase causes a 40-fold rise in IPNS activity or a 8-fold rise in AAT activity. Despite this rise in enzyme levels, forced expression of the ipnA gene results in only a modest increase in levels of exported penicillin, whereas forced expression of the acyA gene reduces penicillin production, showing that neither of these enzymes is rate-limiting for penicillin biosynthesis in A. nidulans. A genomic version of the alcA(p)::acyA fusion in which the acyA gene is interrupted by three small introns, is inducible by threonine to a lesser extent (as determined by both acyA mRNA levels and AAT enzyme levels) than the corresponding cDNA version, suggesting that processing of the introns present in the primary transcript may limit acyA expression.
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PMID:Overexpression of two penicillin structural genes in Aspergillus nidulans. 782 6

Pravastatin, lovastatin, and simvastatin, drugs which lower cholesterol by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, have been linked to skeletal myopathies in humans and rats. The myotoxicity of these three drugs was compared, after 48 hr exposure, in cultures of primary neonatal rat skeletal myotubes. Measurements included HMG CoA reductase activity ([14C]acetate incorporation into cholesterol), indicators of membrane damage (CPK, LDH, and AST), cell viability (mitochondrial dehydrogenase metabolism of MTT), protein synthesis ([3H]leucine incorporation), and energy status (ATP). All three drugs inhibited cholesterol synthesis to the same extent in rat hepatocytes (IC50s approximately 0.07 microM). Lovastatin- and simvastatin-induced inhibition of cholesterol synthesis in myotubes was unchanged compared to that of hepatocytes, but pravastatin was 85-fold less potent (IC50 = 5.9 microM). Protein synthesis and ATP levels were the most sensitive indicators of toxicity. Pravastatin (IC50 = 759 microM) was > 100-fold less inhibitory of protein synthesis than lovastatin (IC50 = 5.4 microM) or simvastatin (IC50 = 1.9 microM). Addition of mevalonic acid (the immediate product of the HMG CoA reductase reaction), as 100 microM mevalonic acid lactone, reversed the toxicity of all three drugs. Removal of serum for 24-72 hr did not alter the toxicity of any of the drugs compared to cultures containing 10% serum, suggesting that differences in protein binding did not account for the differences in toxicity of the drugs. These results indicate that pravastatin is less myotoxic than lovastatin or simvastatin in this in vitro system using neonatal rat skeletal muscle cells, and this differential toxicity is correlated with the selective decrease in inhibition of HMG CoA reductase by pravastatin in nonhepatic tissues.
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PMID:In vitro myotoxicity of the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, pravastatin, lovastatin, and simvastatin, using neonatal rat skeletal myocytes. 787 72

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

Many cobalt-deficient sheep develop liver lesions known as ovine "white liver" disease, but the etiology of these changes is controversial. It has been suggested that cofactors are required for development of liver damage in cobalt-deficient sheep. In this study, one group of lambs (n = 5) was fed a diet low in cobalt (4.5 micrograms/kg) while a group of control lambs (n = 4) received the same diet after it had been supplemented with cobalt (1000 micrograms/kg). All cobalt-depleted lambs had reduced growth rate, anorexia, lacrimation, and alopecia, and they eventually became emaciated (mean body weight at end of study: 83% of initial body weight). Plasma concentrations of bilirubin and serum activity of glutamate-oxaloacetate transferase were elevated in these animals, while plasma concentrations of vitamin B12 were reduced (less than 220 pmol/L from day 42). Fatty degeneration of the liver associated with reduced concentrations of vitamin B12 (14.5 pmol/g) was seen in these animals at necropsy at 196 days. Microscopic liver lesions included accumulation of lipid droplets and lipofuscin particles in hepatocytes, dissociation and necrosis of hepatocytes, and sparse infiltration by neutrophils, macrophages, and lymphocytes. Ultrastructural hepatocytic alterations included swelling, condensation and proliferation of mitochondria, hypertrophy of smooth endoplasmic reticulum, vesiculation and loss of arrays of rough endoplasmic reticulum, and accumulation of lipid droplets and lipofuscin granules in cytoplasm of hepatocytes. No liver lesions were seen in control lambs. The results of this study indicate that cofactors are not a prerequisite to development of hepatic damage in cobalt-deficient sheep. Reduced activities of the vitamin B12-dependent enzymes, methylmalonyl CoA mutase and methionine synthase, and lipid peroxidation are of likely pathogenetic importance in the development of the lesions.
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PMID:Histopathologic and ultrastructural alterations of white liver disease in sheep experimentally depleted of cobalt. 939 38

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


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