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

A NMR method for quantifying the catalytic efficiency and stereospecificity of the exchange of the alpha-protons of glycine is described. It is used to determine how the binding of the alpha-carboxylate group of amino acids contributes to the stereospecificity of exchange reactions catalysed by tryptophan synthase, serine hydroxymethyltransferase and a catalytic antibody utilising pyridoxal-5'-phosphate (PLP) as a cofactor. Using larger substrates, it is shown how the size of the amino acid side chain contributes to the stereospecificity of exchange. Mutants of aspartate aminotransferase are used to determine how substrate binding controls the catalytic efficiency and stereospecificity of the exchange of the alpha-protons of aspartate and glutamate. Evidence is presented which shows that with serine hydroxymethyltransferase, L-norleucine is not bound at the same catalytic site as glycine. Finally the catalytic efficiency and stereospecificity of the alpha-proton exchange reactions catalysed by all the PLP-dependent catalysts examined are compared.
 ...
PMID:Stereospecificity of alpha-proton exchange reactions catalysed by pyridoxal-5'-phosphate-dependent enzymes. 1268 23

Hypercreatinuria is a well-known feature of liver and testicular toxicity and we have recently proposed that hepatotoxin-induced hypercreatinuria would arise as a consequence of increased cysteine synthesis associated with the provision of protective substances (glutathione and/or taurine). Here a direct relationship between hepatotoxin-induced hypercreatinaemia and hypercreatinuria is shown and the possible relationships of hepatotoxin-induced hypercreatinaemia and hypercreatinuria to hepatic damage and to weakened nutritional status are examined. Male Sprague-Dawley rats were dosed with a variety of model hepatotoxins at two dose levels per toxin. Blood plasma samples taken at 24 h post-dosing and urine samples collected from 24-31 h post-dosing were analysed by (1)H NMR spectroscopy. Both hypercreatinaemia and hypercreatinuria were found in rats dosed with allyl formate (75 mg/kg), chlorpromazine (30 and 60 mg/kg), alpha-naphthylisothiocyanate (ANIT, 100 mg/kg) and thioacetamide (200 mg/kg), whilst significant hypercreatinuria, but not hypercreatinaemia, was found after dosing with thioacetamide (50 mg/kg). Neither hypercreatinaemia nor hypercreatinuria were found after dosing with allyl formate (25 mg/kg), ethionine (300 and 1000 mg/kg) or ANIT (30 mg/kg). Reduced feeding is known to cause hypercreatinuria in rats and, of the four hepatotoxins that induced hypercreatinaemia and hypercreatinuria at the given time-points, two, chlorpromazine and ANIT, also affected nutritional status with ketosis being clearly identifiable from the plasma (1)H NMR spectra. Thus, the creatine changes induced by ANIT and chlorpromazine are potentially attributable, in whole or in part, to reduced feeding rather than to liver effects alone and, consequently, the results were examined with and without inclusion of the ANIT and chlorpromazine data. With all of the data included, there were eight out of ten points of correspondence between the incidence of hypercreatinaemia and/or hypercreatinuria and the incidence of increases in plasma alanine aminotransferase (ALT) activity. At the same time there were nine out of ten points of correspondence between the incidence of hypercreatinaemia and/or hypercreatinuria and the incidence of increases in plasma aspartate aminotransferase (AST) activity. However, with the ANIT and chlorpromazine data excluded there was complete (six out of six points) correspondence between the incidence of hypercreatinaemia and/or hypercreatinuria and the incidence of increases in plasma AST and ALT in the remaining data. Likewise, with all of the data included, there was some apparent correlation (correlation coefficient, r=0.80) between the group mean levels of plasma AST and plasma creatine when expressed relative to the mean values for controls sampled at the same time-point. However, with the ANIT and chlorpromazine data excluded, that correlation coefficient was increased to 0.95. The findings of these studies suggest that the ANIT- and chlorpromazine-induced creatine changes may have been caused by reduced feeding rather than by liver toxicity. The allyl formate and thioacetamide data indicate that hepatocellular necrosis is accompanied by increases in plasma and urinary creatine, and suggest the possibility of a quantitative relationship between the increases in plasma AST and the increases in plasma creatine that are associated with hepatocellular necrosis. The ethionine and ANIT data suggest that fatty liver (steatosis) and cholestatic damage may not be associated with hypercreatinaemia and hypercreatinuria.
 ...
PMID:Hepatotoxin-induced hypercreatinaemia and hypercreatinuria: their relationship to one another, to liver damage and to weakened nutritional status. 1452 May 8

One of the most remarkable achievements of in vivo NMR spectroscopy has been the detection of rapid enzyme-catalyzed exchange reactions using phosphorus-31 magnetic resonance spectroscopy-based magnetization transfer experiments. In this paper, we report, for the first time, the in vivo carbon magnetization transfer (CMT) effect and in vivo detection of the CMT effects of the alpha-ketoglutarate <--> glutamate and the oxaloacetate <--> aspartate reactions, both of which are catalyzed by aspartate aminotransferase. By saturating the carbonyl carbon of alpha-ketoglutarate at 206 ppm in alpha-chloralose anesthetized adult rat brain, the unidirectional glutamate --> alpha-ketoglutarate flux was determined to be 78 +/- 9 mumol/g/min (mean +/- SD, n = 11) following i.v. infusion of [1,6-(13)C(2)]D-glucose. Contribution from aspartate aminotransferase-catalyzed partial reactions to the observed CMT effects was emphasized. Because of the large chemical shift separation between the alpha-carbons of the amino acids and the carbonyl carbons of the corresponding cognate keto acids, the spillover of the saturation radiofrequency pulses to the alpha-carbon resonances was negligible. The results indicate that the magnetization transfer effects of aspartate aminotransferase-catalyzed reactions can be used as new biomarkers accessible to non-invasive in vivo magnetic resonance spectroscopy techniques.
 ...
PMID:In vivo carbon-13 magnetization transfer effect. Detection of aspartate aminotransferase reaction. 1627 Mar 28

From the leaves of Viburnum tinus L. (Adoxaceae) two acylated iridoid glucosides (viburtinoside A and B), a coumarin diglucoside scopoletin 7-O-beta-D-sophoroside and a natural occurred dinicotinic acid ester 2,6-di-C-methyl-nicotinic acid 3,5-diethyl ester were isolated. In addition to these, 10 known compounds were isolated, namely two bidesmosidic saponins, a hexamethoxy-flavone and five flavonol glycosides, as well as suspensolide A and oleanolic acid were isolated for the first time in this genus and species, respectively. The structures were determined mainly by spectroscopic methods (UV, IR, ESI-MS, 1H-, 13C NMR and DEPT). Toxicity of the investigated extract was determined (LD50=500 mg/kg). CCl4-induced hepatotoxicity has been evaluated in terms of the determination of alanine aminotransferase (ALT), aspartate aminotransferase (AST), lipid peroxide and nitric oxide levels in serum and compared using adult male rats weighing 150-180 g. Their highly elevated levels were significantly reduced by treatment with the investigated aqueous methanol extract in dose-dependent manner.
 ...
PMID:Phytochemical constituents and hepatoprotective activity of Viburnum tinus. 1630 55

L-serine-O-sulphate is a member of a group of amino acids collectively called gliotoxins and is a substrate for the high affinity sodium-dependent glutamate transporters. Previous studies have shown that it is toxic to primary cultures of astrocytes but the mode of toxicity is unknown. The current study demonstrates that L-serine-O-sulphate, at a sub-toxic concentration (400 microM), causes significant disruption to glucose and alanine metabolism in cultures of rat cortical astrocytes. More specifically, using (13)C NMR spectroscopy a significant reduction in labelled end products from [1-(13)C]glucose and [3-(13)C]alanine was found in the presence of L-serine-O-sulphate. Additionally, using [2-(13)C]glycine a 27% reduction in de novo glutathione synthesis was observed in the presence of the gliotoxin. Incubation of the cells with L-serine-O-sulphate reduced the activity of alanine and aspartate aminotransferase by 53% and 67%, respectively. Collectively these results show that the gliotoxin, L-serine-O-sulphate, causes major disruptions to metabolic pathways in primary cultures of astrocytes.
 ...
PMID:Impact of the gliotoxin L-serine-O-sulphate on cellular metabolism in cultured rat astrocytes. 1645 90

Many enzymes catalyze fast exchange between a small pool and a large pool in vivo. For example, aspartate aminotransferase catalyzes fast exchanges between alpha-ketoglutarate and glutamate and between oxaloacetate and aspartate, which can be detected using in vivo(13)C MRS while saturating alpha-carbons of the keto acids. Unlike in the traditional saturation transfer experiments studied using (31)P MRS, the tricarboxylic acid cycle intermediates alpha-ketoglutarate and oxaloacetate are below the detection limit of in vivo NMR. In this work, a theoretical analysis of the saturation transfer between alpha-ketoglutarate and glutamate catalyzed by aspartate aminotransferase was presented to examine the requirements for complete saturation of the rapidly turning over alpha-ketoglutarate pool without affecting the longitudinal magnetization of glutamate. The fast turnover of the small alpha-ketoglutarate pool also allows a quasi-steady-state approximation of its dynamic longitudinal relaxation. The theoretical analysis provides a useful guide for designing experimental methods to characterize saturation transfer processes associated with fast turning over small pools in vivo.
NMR Biomed 2006 Apr
PMID:Theoretical analysis of carbon-13 magnetization transfer for in vivo exchange between alpha-ketoglutarate and glutamate. 1652 Oct 93

Kava (Piper methysticum), a perennial shrub native to the South Pacific islands, has been used to relieve anxiety. Recently, several cases of severe hepatotoxicity have been reported from the consumption of dietary supplements containing kava. It is unclear whether the kava constituents, kavalactones, are responsible for the associated hepatotoxicity. To investigate the key components responsible for the liver toxicity, bioassay-guided fractionation was carried out in this study. Kava roots, leaves, and stem peelings were extracted with methanol, and the resulting residues were subjected to partition with a different polarity of solvents (hexane, ethyl acetate, n-butanol, and water) for evaluation of their cytotoxicity on HepG2 cells based on the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and lactate dehydrogenase and aspartate aminotransferase enzyme leakage assays. Organic solvent fractions displayed a much stronger cytotoxicity than water fractions for all parts of kava. The hexane fraction of the root exhibited stronger cytotoxic effects than fractions of root extracted with other solvents or extracts from the other parts of kava. Further investigations using bioassay-directed isolation and analysis of the hexane fraction indicated that the compound responsible for the cytotoxicity was flavokavain B. The identity of the compound was confirmed by (1)H and (13) C NMR and MS techniques.
 ...
PMID:In vitro cytotoxicity of nonpolar constituents from different parts of kava plant (Piper methysticum). 1660 46

Three phenolic compounds cosmosiin, caffeic acid, and p-coumaric acid were isolated for the first time from the leaves of Cupressus sempervirens L., together with cupressuflavone, amentoflavone, rutin, quercitrin, quercetin, myricitrin. The isolated compounds were identified using (1)H- and (13)C-NMR spectra. The hepatoprotective activity of the MeOH extract was carried out in liver homogenate of normal and CCl(4)-treated rats; a significant decrease in glutamate oxaloacetate transaminase, glutamate pyruvate transaminase, cholesterol level, and triglycerides, while a significant increase in the total protein level, was observed after the oral administration of MeOH extract. The free radical scavenging activity against stable 2,2-diphenyl-2-picrylhydrazyl (DPPH*) was measured for MeOH extract and some of the isolated phenolic compounds in comparison with alpha-tocopherol and butylated hydroxy toluene as standard antioxidants using ESR technique, showed high antioxidant activity for quercetin, rutin, caffeic acid, and p-coumaric acid.
 ...
PMID:Phytochemical investigation and hepatoprotective activity of Cupressus sempervirens L. leaves growing in Egypt. 1768 Apr 94

Acetaminophen (APAP) is one of the most commonly used drugs for the safe and effective treatment of fever and pain. However, it is a well-established hepatotoxin. The objective of this study was to identify alternation in various genes in liver of mice after administration of low and high doses of APAP. Male C57BL/6J mice received APAP (30 or 300 mg/kg, i.p.). They were sacrificed after 6 hr and 24 hr for assessment of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), total RNA isolation, cDNA microarray analysis and histopathological analysis of liver injury. Low dose of APAP did not cause hepatotoxicity in mice. However, it was toxic at a high dose. Using microarray technology, we selected changed genes more than 1.5 fold. Gene expression changes were recorded even at a low dose treatment with APAP. Six (6) hr after APAP treatment at low dose, 6 genes were up-regulated and 25 genes were down-regulated. However, 24 hr after treatment at low dose 8 genes were up-regulated and 34 genes were down-regulated. 6 hr after of high dose treatment 29 genes were down-regulated and none was up-regulated. A 24 hr treatment with high dose up-regulated 6 genes and down-regulated 18 genes. These expression patterns provide information on high versus low dose mechanisms of APAP toxicity. Gene expression signatures recorded after a nontoxic dose of APAP strongly support the validity of gene expression changes as meaningful markers of hepatotoxicity.
Physiol Chem Phys Med NMR 2006
PMID:Effects of acetaminophen on hepatic gene expression in mice. 1847 68

The toxicological effects of realgar after intragastrical administration (1 g/kg body weight) were investigated over a 21 day period in male Wistar rats using metabonomic analysis of (1)H NMR spectra of urine, serum and liver tissue aqueous extracts. Liver and kidney histopathology examination and serum clinical chemistry analyses were also performed. (1)H NMR spectra and pattern recognition analyses from realgar treated animals showed increased excretion of urinary Kreb's cycle intermediates, increased levels of ketone bodies in urine and serum, and decreased levels of hepatic glucose and glycogen, as well as hypoglycemia and hyperlipoidemia, suggesting the perturbation of energy metabolism. Elevated levels of choline containing metabolites and betaine in serum and liver tissue aqueous extracts and increased serum creatine indicated altered transmethylation. Decreased urinary levels of trimethylamine-N-oxide, phenylacetylglycine and hippurate suggested the effects on the gut microflora environment by realgar. Signs of impairment of amino acid metabolism were supported by increased hepatic glutamate levels, increased methionine and decreased alanine levels in serum, and hypertaurinuria. The observed increase in glutathione in liver tissue aqueous extracts could be a biomarker of realgar induced oxidative injury. Serum clinical chemistry analyses showed increased levels of lactate dehydrogenase, aspartate aminotransferase, and alkaline phosphatase as well as increased levels of blood urea nitrogen and creatinine, indicating slight liver and kidney injury. The time-dependent biochemical variations induced by realgar were achieved using pattern recognition methods. This work illustrated the high reliability of NMR-based metabonomic approach on the study of the biochemical effects induced by traditional Chinese medicine.
 ...
PMID:Metabolic profiling studies on the toxicological effects of realgar in rats by (1)H NMR spectroscopy. 1907 2


<< Previous 1 2 3 4 5 6 7 8 Next >>