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)

Nitric oxide (NO) and prostaglandins (PG) both possess the ability to induce vasodilatation and prevent the aggregation of platelets. The synthesis of these substances is increased following in vivo lipopolysaccharide (LPS) infusion, but their function during sepsis is incompletely understood. We studied the role of NO and PG in a murine model of chronic hepatic inflammation (Corynebacterium parvum injection), which is known to progress to sudden hepatic necrosis after LPS injection. NO synthesis, which is induced in hepatocytes by C. parvum treatment and in nonparenchymal cells by LPS treatment, was inhibited using NG-monomethyl-L-arginine (L-NMMA). High-dose aspirin (ASA) was used to block PG synthesis. Treatment with L-NMMA or ASA alone, in the absence of LPS, resulted in no increase in hepatic injury. C. parvum-treated mice that received both L-NMMA and ASA without LPS developed marked hepatic damage as reflected by increased hepatocellular enzyme release (aspartate aminotransferase and L-ornithine carbamoyl-transferase). Marked hepatic damage was seen after LPS administration, and ASA pretreatment alone had no effect on the LPS-induced hepatic injury, whereas L-NMMA markedly increased the hepatic damage. The combination of L-NMMA and ASA after LPS resulted in the greatest hepatocellular enzyme release, characterized histologically by intravascular thrombosis with diffuse infarction and necrosis. Simultaneous treatment with either PGI2 or L-arginine partially prevented this injury. These data demonstrate that NO and PG function synergistically to maintain hepatocellular integrity; thus increased synthesis of these mediators protects the liver from the pathophysiological effects of LPS in this model.
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PMID:Nitric oxide and prostaglandins interact to prevent hepatic damage during murine endotoxemia. 802 33

Earlier studies showed that hepatotoxicant-treated experimental animals were more susceptible than controls to the lethal effects of bacterial endotoxin. The exact mechanisms of this effect were not understood. In this paper we showed that nitric oxide (.NO) was produced in whole blood and in liver tissues of rats that had been treated with a nonlethal dose of CCl4 (1.3 g/kg) followed by a low dose of lipopolysaccharide (LPS) (100 micrograms/kg). EPR spectroscopy was used in this study to detect nitrosyl-protein complexes. Hemoglobin-nitrosyl complexes were detected in both whole blood and liver. By performing analyses of EPR spectra obtained from hepatocytes exposed to .NO, we were able to identify EPR signals attributable to nitrosyl-cytochrome P420 in rat liver. We found that nitrosyl complex formation in red blood cells and liver was inhibited by treatment with NG-mono-methyl-L-arginine, suggesting enzymatic biosynthesis of .NO. A small but significant inhibition of nitrosyl complex formation by gadolinium trichloride pretreatment was found in the liver, suggesting that Kupffer cells were also involved in .NO biosynthesis, because this treatment decreased Kupffer cells. There was a synergistic effect of CCl4 and LPS on the serum levels of the hepatic enzymes aspartate aminotransferase, alanine amino-transferase, lactate dehydrogenase, and sorbitol dehydrogenase, which are indices of parenchymal cell damage. NG-Mono-methyl-L-arginine treatment increased these hepatic enzyme activities, suggesting a protective role for .NO. EPR resonances at g approximately 2.48, 2.29, and 1.91, due to low-spin cytochromes P450/P420 (FE3+), were decreased in the livers of LPS-induced rats that had been previously treated with CCl4, indicating cytochrome P450/P420 destruction or at least a change in the valence state of the cytochrome P450/P420 heme groups to Fe2+ in the presence of .NO. Because nitrosyl-cytochrome P450 is not stable, the concomitant detection of nitrosyl-cytochrome P420 (Fe2+) could account, at least in part, for the decrease of the ferric low-spin heme groups. Our novel observations of hepatic nitrosyl species suggest that .NO plays an important role during hepatic injury caused by CCl4 in hosts exposed to endotoxin.
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PMID:Nitric oxide production during endotoxic shock in carbon tetrachloride-treated rats. 807 2

Serum amino acid (AA) profiles are altered in epilepsy. It is not clear whether this is due to the disease process itself or to other variables such as seizure type, seizure frequency, duration of illness, medication, or altered liver function. We investigated serum AA profiles and liver enzymes in 73 epileptic patients and 90 healthy subjects and evaluated the data by analysis of variance to discriminate between age, sex, seizure type, duration of illness, seizure frequency, antiepileptic drug (AED) and increased serum liver enzyme levels, and their putative interaction with the serum AA profile. There was no correlation between the changes in the AA profile and age, duration of illness, seizure frequency, and seizure type. Seventy-two percent of the AED-treated patients and 33% of the unmedicated patients showed an increase in one or several serum liver enzymes [alanine aminotransferase (ALT), aspartate aminotransferase (AST), and/or gamma-glutamyl transferase (gamma-GT)]; particularly gamma-GT. We observed a significant increase in serum concentrations of glutamine and glycine and decreased levels of taurine, threonine, serine, valine, methionine, isoleucine, leucine, phenylalanine, histidine, tryptophan, and arginine in AED-treated patients but not in unmedicated patients. These results show that the changes in the serum AA profiles of epileptic patients treated with AEDs occur in patients with alteration of serum liver enzymes; whether this implies a causal relation is still uncertain.
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PMID:Serum amino acids, liver status, and antiepileptic drug therapy in epilepsy. 809 92

A total of 150 amino acid sequences of vitamin B6-dependent enzymes are known to date, the largest contingent being furnished by the aminotransferases with 51 sequences of 14 different enzymes. All aminotransferase sequences were aligned by using algorithms for sequence comparison, hydropathy patterns and secondary structure predictions. The aminotransferases could be divided into four subgroups on the basis of their mutual structural relatedness. Subgroup I comprises aspartate, alanine, tyrosine, histidinol-phosphate, and phenylalanine aminotransferases; subgroup II acetylornithine, ornithine, omega-amino acid, 4-aminobutyrate and diaminopelargonate aminotransferases; subgroup III D-alanine and branched-chain amino acid aminotransferases, and subgroup IV serine and phosphoserine aminotransferases. (N-1) Profile analysis, a more stringent application of profile analysis [Gribskov, M., McLachlan, A. D. and Eisenberg, D. (1987) Proc. Natl Acad. Sci. USA 84, 4355-4358], established the homology among the enzymes of each subgroup as well as among all subgroups except subgroup III. However, similarity of active-site segments and the hydropathy patterns around invariant residues suggest that subgroup III, though most distantly related, might also be homologous with the other aminotransferases. On the basis of the comprehensive alignment, a new numbering of amino acid residues applicable to aminotransferases (AT) in general is proposed. In the multiply aligned sequences, only four out of a total of about 400 amino acid residues proved invariant in all 51 sequences, i.e. Gly(314AT)197, Asp/Glu(340AT)222, Lys(385AT)258 and Arg(562AT)386, the number not in parentheses corresponding to the structure of porcine cytosolic aspartate aminotransferase. Apparently, the aminotransferases constitute a group of homologous proteins which diverged into subgroups and, with some exceptions, into substrate-specific individual enzymes already in the universal ancestor cell.
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PMID:Aminotransferases: demonstration of homology and division into evolutionary subgroups. 851 4

The physiological role of GH secretion on growth retardation remains to be elucidated especially in patients with beta-thalassemia. In the present study, we investigated IGF-1 circulating levels as well as GH release following GHRH alone or combined with some inhibitors of somatostatin: pyridostigmine and arginine. In thalassemic patients lower IGF-1 circulating levels appear to be negatively correlated with both aspartate aminotransferase and alanine aminotransferase as well as with ferritin circulating levels indicating a probable role of hepatic hemosiderosis in IGF-1 production. The authors however suggest that reduced IGF-1 secretion is not the main cause of growth retardation since this would have elicited an enhanced response of GHRH in the presence of a normal hypothalamic pituitary axis. In contrast, they noticed that GH response to GHRH when expressed as area under the curve was lower in thalassemic patients compared to controls. The combination of GHRH with either pyridostigmine or arginine induced a GH secretion in thalassemics which was comparable to that of controls. The results of this study lead to conclude that the alteration of GH secretion is due, in such patients, to an increased somatostatin activity.
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PMID:GH secretion in thalassemia patients with short stature. 852 76

Acute liver failure is accompanied by a high rate of bacterial and septic complications. Arginine has a potent effect on the immune system and modulates bacterial clearance in septic models. We studied the effect of oral arginine supplementation on the extent of liver injury and the associated bacterial translocation in an acute liver injury model in rats. Sprague-Dawley rats were divided into normal, liver injury, and arginine supplemented groups. In the arginine group, 2% arginine was supplemented daily through a nasogastric tube for 8 d. Acute liver injury was induced on the eighth day by intraperitoneal injection of D-galactosamine (1.1 g/kg body wt). Samples were collected 24 h after the liver injury. In the arginine-supplemented group, alkaline phosphatase, bilirubin, and aspartate aminotransferase were reduced significantly compared with the acute liver injury control group. The results of bacterial translocation in the arginine-supplemented group showed a significantly reduced number of translocated bacteria to the liver and mesenteric lymph nodes than occurred in the acute liver injury group. The histological study of the liver in arginine-supplemented group showed scattered areas of hepatocellular necrosis and inflammatory cell infiltration, and in the acute liver injury group there were more and widespread hepatocellular necrosis and inflammatory cell infiltration. Oral supplementation of arginine in an acute liver injury model improves significantly the state of the liver injury and reduces bacterial translocation to the liver and mesenteric lymph nodes.
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PMID:Oral arginine supplementation in acute liver injury. 887 48

The aspartate aminotransferase gene (AspAT, EC 2.6.1.1) of an extremely thermophilic bacterium, Thermus thermophilus HB8, was cloned and sequenced, and its gene product was overproduced. The purified T. thermophilus AspAT was stable up to about 80 degrees C at neutral pH. T. thermophilus AspAT was strictly specific for acidic amino acid substrates, such as aspartate, glutamate, and the respective keto acids. The gene coding for T. thermophilus AspAT showed that it comprised 1,155 bp with a high G+C content (70 mol%), and encoded a 385-residue protein with a molecular weight of 42,050. The amino acid sequence of T. thermophilus AspAT deduced from its gene showed about 15, 46, and 29% homology with those from Escherichia coli, Bacillus sp. YM-2, and Sulfolobus solfataricus, respectively. When the amino acid sequence of T. thermophilus AspAT was compared with that of E. coli AspAT, the number of Cys was found to have decreased from 5 to 1, that of Asn from 23 to 9, that of Gln from 16 to 8, and that of Asp from 20 to 13, all of which are known to be relatively labile at high temperatures. Conversely, the number of Pro was increased from 15 to 25, Arg from 22 to 32, and Glu 27 to 37. As shown by the E. coli AspAT structure, there was a marked tendency for the extra prolyl residues to be located around the surface of the molecule. This was quite different from that in the case of RecA protein, which shows an increased number of prolyl residues in the interior of its molecule. Different strategies of different proteins as to prolyl contribution to thermostability have been suggested. Despite the high degree of conservation of active-site residues, Arg292 in E. coli AspAT, which interacts with the distal carboxylate of the substrate, was not found in T. thermophilus AspAT. Arg89 may complement the function of Arg292.
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PMID:An aspartate aminotransferase from an extremely thermophilic bacterium, Thermus thermophilus HB8. 890 87

The physiological features of the mildiomycin production by Streptoverticillium rimofaciens were examined in iron-sufficient and -deficient media. Activities of NADP-linked glutamate dehydrogenase (GDH) and aspartate aminotransferase (AAT) were markedly enhanced by the addition of 10 micrograms/ml of ferrous ion into culture. Ammonium nitrogen assimilation increased with the increase in mildiomycin production. These indicate that ferrous ion contributes the supply of amino acids as a precursor of mildiomycin production. In the iron-sufficient medium, glutamate, aspartate, serine and arginine in cells were 2 to 10-fold to those in the iron-deficient medium. The major amino acid excreted from cells was arginine in the iron-sufficient culture, while in the iron-deficient culture, valine. Change in the amino acid profile by addition of ferrous ion was useful for mildiomycin biosynthesis, in which ferrous ion played a leading role in amino acid metabolism.
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PMID:Effect of ferrous ion on amino acid metabolism in mildiomycin production by Streptoverticillium rimofaciens. 912 91

The three-dimensional structure of glutamate-1-semialdehyde aminomutase (EC 5.4.3.8), an alpha2-dimeric enzyme from Synechococcus, has been determined by x-ray crystallography using heavy atom derivative phasing. The structure, refined at 2.4-A resolution to an R-factor of 18.7% and good stereochemistry, explains many of the enzyme's unusual specificity and functional properties. The overall fold is that of aspartate aminotransferase and related B6 enzymes, but it also has specific features. The structure of the complex with gabaculine, a substrate analogue, shows unexpectedly that the substrate binding site involves residues from the N-terminal domain of the molecule, notably Arg-32. Glu-406 is suitably positioned to repel alpha-carboxylic acids, thereby suggesting a basis for the enzyme's reaction specificity. The subunits show asymmetry in cofactor binding and in the mobilities of the residues 153-181. In the unliganded enzyme, one subunit has the cofactor bound as an aldimine of pyridoxal phosphate with Lys-273 and, in this subunit, residues 153-181 are disordered. In the other subunit in which the cofactor is not covalently bound, residues 153-181 are well defined. Consistent with the crystallographically demonstrated asymmetry, a form of the enzyme in which both subunits have pyridoxal phosphate bound to Lys-273 through a Schiff base showed biphasic reduction by borohydride in solution. Analysis of absorption spectra during reduction provided evidence of communication between the subunits. The crystal structure of the reduced form of the enzyme shows that, despite identical cofactor binding in each monomer, the structural asymmetry at residues 153-181 remains.
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PMID:Crystal structure of glutamate-1-semialdehyde aminomutase: an alpha2-dimeric vitamin B6-dependent enzyme with asymmetry in structure and active site reactivity. 914 56

Two high resolution crystal structures of cytosolic aspartate aminotransferase from pig heart provide additional insights into the stereochemical mechanism for ligand-induced conformational changes in this enzyme. Structures of the homodimeric native structure and its complex with the substrate analog 2-methylaspartate have been refined, respectively, with 1.74-A x-ray diffraction data to an R value of 0.170, and with 1.6-A data to an R value of 0.173. In the presence of 2-methylaspartate, one of the subunits (subunit 1) shows a ligand-induced conformational change that involves a large movement of the small domain (residues 12-49 and 327-412) to produce a "closed" conformation. No such transition is observed in the other subunit (subunit 2), because crystal lattice contacts lock it in an "open" conformation like that adopted by subunit 1 in the absence of substrate. By comparing the open and closed forms of cAspAT, we propose a stereochemical mechanism for the open-to-closed transition that involves the electrostatic neutralization of two active site arginine residues by the negative charges of the incoming substrate, a large change in the backbone (phi,psi) conformational angles of two key glycine residues, and the entropy-driven burial of a stretch of hydrophobic residues on the N-terminal helix. The calculated free energy for the burial of this "hydrophobic plug" appears to be sufficient to serve as the driving force for domain closure.
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PMID:Refinement and comparisons of the crystal structures of pig cytosolic aspartate aminotransferase and its complex with 2-methylaspartate. 921 66


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