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)

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

Three crystal structures of wild type E. coli aspartate aminotransferase (E.C.2.6.1.1) in space group P2(1) have been determined at resolution limits between 2.6 and 2.35 A. The unliganded enzyme and its complexes with the substrate analogues maleate and 2-methylaspartate resulted in different conformations. The unit cell parameters of the unliganded and the inhibited enzyme are a = 87.2, b = 79.9, c = 89.8 A and beta = 119.1 degrees, and a = 85.4, b = 79.8, c = 89.5 A and beta = 118.6 degrees, respectively. The crystallographic symmetry is pseudo-C222(1). The liganded enzyme structures were solved by difference Fourier techniques from that of a Val39-->Leu mutant partially refined to an R-factor of 0.22 at 2.85 A. They have a "closed" conformation like the chicken mAATase:maleate complex. The models were refined to R-factors of 0.19 (maleate complex) and 0.18 (2-methylaspartate complex) by molecular dynamics and restrained least squares methods. The unliganded crystal form was solved by molecular replacement and refined to an R-factor of 0.19 at 2.5 A resolution. The structure is in a "half-open" conformation, with the small domain rotated about 6 degrees from the closed conformation. The cofactor pyridoxal phosphate has a more relaxed conformation than in mAATase. Both maleate and 2-methylaspartate are hydrogen-bonded to the active site as in mAATase. The C alpha-CH3 bond of 2-methylaspartate is oriented at right angles to the cofactor pyridine ring, the most productive orientation for alpha-deprotonation of the substrate L-aspartate. Comparisons with earlier determined eAATase structures in space group C222(1) revealed differences that can probably be attributed to the somewhat lower resolution of the orthorhombic structures and/or mutations in the eAATases used in those studies. The present P2(1) structures confirm the justification of extrapolating properties of active site point mutants to the vertebrate isozymes. They will serve as reference in the interpretation of the properties of further site-directed mutants in continued studies of structure-function relationships of this enzyme.
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PMID:Crystal structures of Escherichia coli aspartate aminotransferase in two conformations. Comparison of an unliganded open and two liganded closed forms. 819 59

To investigate the hepatic abnormalities accompanying experimental protoporphyria due to griseofulvin (GF), liver function test values and porphyrin levels in mice were assayed at days 2, 4, 8, and 16 after starting the administration of 0.5% GF feed. Furthermore, in an attempt to elucidate the harmful effects of GF on liver functions, the above mentioned assay was also performed after the feed was discontinued in mice given 0.5% GF feed for 16 days. The hepatic protoporphyrin (PP) level had already risen by day 2, but the erythrocytic PP level was within normal limits at that time. Hepatic PP levels increased gradually, followed by an increase in erythrocytic PP levels. The variation in liver function test values roughly paralleled the porphyrin levels. Over the time span of the response to GF, the variations in the serum glutamate oxaloacetate transaminase (S-GOT) levels, serum glutamate pyruvate transaminase (S-GPT) levels, and leucine amino peptidase (LAP) levels resembled those in hepatic PP. On the other hand, the changes in alkaline phosphatase (ALP) levels paralleled those of the erythrocytic PP levels. Erythrocytic and fecal protoporphyrin levels decreased to the normal level one month after the discontinuation of GF administration, but the hepatic protoporphyrin level still was 53.6 times higher than the normal level two months after switching to normal feed. The values of liver function tests had returned to within the normal range after one month. By the fourth day after the administration of GF, a brown pigmented material could be observed around the hepatocytes and the Glisson sheath; the amount of this material increased day by day.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Experimental murine protoporphyria induced by griseofulvin (GF): the relationship between hepatic porphyrin levels and liver function test values in mice treated with GF. 822 9

Soluble and membrane-bound aminopeptidase activities in 11 regions of the rat brain were assayed using L-Leucine-2-naphthylamide as a substrate. In addition, two metabolic enzymatic activities were compared: lactate dehydrogenase and aspartate aminotransferase. All enzymatic activities showed significant regional differences when the data were analyzed statistically. Soluble aminopeptidase and aspartate aminotransferase activities were significantly lower in cortical than in subcortical areas. Membrane-bound aminopeptidase activity levels were higher in cortical areas. Lactate dehydrogenase activities did not differ between cortical areas and the rest of the zones studied. However, although no wide regional differences were found for the other enzymatic activities, membrane-bound aminopeptidase varied markedly across brain regions: a fivefold difference was observed between zones such as parietotemporal cortex and medulla. The differential distribution of this enzymatic activity is consistent with the hypothesis that it could be responsible for the enzymatic inactivation of some neuroactive peptides.
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PMID:Regional distribution of soluble and membrane-bound aminopeptidase activities in rat brain. 849 Jul 37

We studied a new proteinase K assay method for human serum mitochondrial aspartate aminotransferase. We found that proteinase K showed no inactivation of human mitochondrial aspartate aminotransferase isoenzyme and complete inactivation of cytosolic aspartate aminotransferase. Previous studies have shown that selective proteolytic measurement for mitochondrial aspartate aminotransferase in serum using the protease 401 cleaved peptide bond at Leu 20 from the amino-terminal bond shows complete inactivation of cytosolic aspartate aminotransferase and slight inactivation of mitochondrial aspartate aminotransferase isoenzyme, depending on protease concentration. In this investigation, we found that the proteinase K method does not depend on protease concentration. The proteinase K enzyme inactivation of cytosolic aspartate aminotransferase is caused by the cleavage of the peptide bond at Ileu 21 from the aminoterminal bond. In studies with various animal cytosolic aspartate aminotransferase isoenzymes, proteinase K almost completely inactivated cytosolic aspartate aminotransferase. Precision and correlation using proteinase K for measurement of serum mitochondrial aspartate aminotransferase in human showed a good coefficient of variation (within-run < 4.45%) and a coefficient of correlation of r = 0.985 (N = 125).
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PMID:Proteinase K inactivation of cytosolic aspartate aminotransferase isoenzyme for measurement of human serum mitochondrial aspartate aminotransferase. 850

Although several high-resolution X-ray crystallographic structures have been determined for Escherichia coli aspartate aminotransferase (eAATase), efforts to crystallize E. coli tyrosine aminotransferase (eTATase) have been unsuccessful. Sequence alignment analyses of eTATase and eAATase show 43% sequence identity and 72% sequence similarity, allowing for conservative substitutions. The high similarity of the two sequences indicates that both enzymes must have similar secondary and tertiary structures. Six active site residues of eAATase were targeted by homology modeling as being important for aromatic amino acid reactivity with eTATase. Two of these positions (Thr 109 and Asn 297) are invariant in all known aspartate aminotransferase enzymes, but differ in eTATase (Ser 109 and Ser 297). The other four positions (Val 39, Lys 41, Thr 47, and Asn 69) line the active site pocket of eAATase and are replaced by amino acids with more hydrophobic side chains in eTATase (Leu 39, Tyr 41, Ile 47, and Leu 69). These six positions in eAATase were mutated by site-directed mutagenesis to the corresponding amino acids found in eTATase in an attempt to redesign the substrate specificity of eAATase to that of eTATase. Five combinations of the individual mutations were obtained from mutagenesis reactions. The redesigned eAATase mutant containing all six mutations (Hex) displays second-order rate constants for the transamination of aspartate and phenylalanine that are within an order of magnitude of those observed for eTATase. Thus, the reactivity of eAATase with phenylalanine was increased by over three orders of magnitude without sacrificing the high transamination activity with aspartate observed for both enzymes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Redesign of the substrate specificity of Escherichia coli aspartate aminotransferase to that of Escherichia coli tyrosine aminotransferase by homology modeling and site-directed mutagenesis. 852 73

Gabapentin is a novel anticonvulsant drug. The anticonvulsant mechanism of gabapentin is not known. Based on the amino acid structure of gabapentin we explored its possible effects on glutamate and gamma-aminobutyric acid (GABA) metabolism in brain as they may relate to its anticonvulsant mechanisms of action. Gabapentin was tested for its effects on seven enzymes in the metabolic pathways of these two neurotransmitters: alanine aminotransferase (AL-T), aspartate aminotransferase (AS-T), GABA aminotransferase (GABA-T), branched-chain amino acid aminotransferase (BCAA-T), glutamine synthetase (Gln-S), glutaminase (GLNase), and glutamate dehydrogenase (GDH). In the presence of 10 mM gabapentin, only GABA-T, BCAA-T, and GDH activities were affected by this drug. Inhibition of GABA-T by gabapentin was weak (33%). The Ki values for inhibition of cytosolic and mitochondrial forms of GABA-T (17-20 mM) were much higher than the Km values for GABA (1.5-1.9 mM). It is, therefore, unlikely that inhibition of GABA-T by gabapentin is clinically relevant. As with leucine, gabapentin stimulated GDH activity. The GDH activity in rat brain synaptosomes was activated 6-fold and 3.4-fold, respectively, at saturating concentrations (10 mM) of leucine and gabapentin. The half-maximal stimulation by gabapentin was observed at approximately 1.5 mM. Gabapentin is not a substrate of BCAA-T, but it exhibited a potent competitive inhibition of both cytosolic and mitochondrial forms of brain BCAA-T. Inhibition of BCAA-T by this drug was reversible. The Ki values (0.8-1.4 mM) for inhibition of transamination by gabapentin were close to the apparent Km values for the branched-chain amino acids (BCAA) L-leucine, L-isoleucine, and L-valine (0.6-1.2 mM), suggesting that gabapentin may significantly reduce synthesis of glutamate from BCAA in brain by acting on BCAA-T.
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PMID:Effects of anticonvulsant drug gabapentin on the enzymes in metabolic pathways of glutamate and GABA. 856 62

Ayurvedic and other 'traditional' medical practitioners in Sri Lanka use the mature leaves of the plant Osbeckia octandra for its hepatoprotective properties. In this study the effects of an aqueous extract of Osbeckia octandra against injury induced by D-galactosamine and tert-butyl hydroperoxide (TBH) were investigated in freshly isolated rat hepatocytes. The plant extract (500 micrograms/ml) significantly reduced the inhibition of protein synthesis (as assessed by the incorporation of 14C-leucine into protein) in hepatocytes incubated for 1 h with 10 mM galactosamine by a mean of 25.6 +/- 3.6% and decreased the release of cellular lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) enzyme activities into the medium by 55.3% and 32.8%, respectively. With TBH, the plant extract decreased lipid peroxidation (estimated from malondialdehyde formation) by a mean of 29.9 +/- 1.1% together with a 46.8% and 54.7% decrease in the release of LDH and AST, respectively into the incubation medium. Significant protection was also obtained when the Osbeckia extract was added to the incubation medium up to 30 min after pre-exposure of the hepatocytes to either galactosamine or, to a lesser extent, TBH. The results support the use of Osbeckia as a hepatoprotective agent.
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PMID:Protective effects of Osbeckia octandra against galactosamine and tert-butyl hydroperoxide induced hepatocyte damage. 884 86

The possibility that postmortem biochemical changes in blood might parallel drug redistribution and thus serve as markers was explored in a detailed case study. Eighteen blood and 14 tissue and fluid samples were taken at autopsy 16 h after the death of a 34-year-old female from amitriptyline overdose. Ranges of drug concentrations in blood were amitriptyline 1.8 to 20.2 micrograms/mL, nortriptyline 0.6 to 7.3 micrograms/mL, levels were lowest in femoral vein and highest in pulmonary vein blood. Corresponding levels of 17 amino acids showed markedly different patterns of site-to-site variability. There was a strong positive correlation between individual amino acid and drug concentrations in pulmonary blood samples (n = 5), particularly for glycine, leucine, methionine, serine, and valine. In blood samples from the great veins and right heart (n = 10), the correlation was less strong (r = 0.6 to 0.7). Methionine showed a strong positive correlation in pulmonary samples (r = 0.93), and negative correlation in great veing samples (r = -0.68). Lactic acid showed a strong negative correlation in pulmonary samples (r = -0.93) but a positive correlation in great vein samples (r = 0.71). Alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, gamma-glutamyl transferase, glucose, and bilirubin had a weak positive correlation with drug levels in great vein samples but not pulmonary samples. The results suggest that hepatic enzymes are relatively poor markers for postmortem hepatic drug shifts but that amino acids, particularly methionine, may be useful markers for pulmonary drug shifts.
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PMID:Possible markers for postmortem drug redistribution. 898 78

Proteases as well as alterations in intracellular calcium have important roles in hepatic preservation-reperfusion injury, and increased calpain activity recently has been demonstrated in liver allografts. Experiments were designed to evaluate (i) hepatic cytosolic calpain activity during different periods of cold ischemia (CI), rewarming, or reperfusion, and (ii) effects of inhibition of calpain on liver graft function using the isolated perfused rat liver and arterialized orthotopic liver transplantation models. Calpain activity was assayed using the fluorogenic substrate Suc-Leu-Leu-Val-Tyr-7-amino-4-methyl coumarin (AMC) and expressed as mean +/- SD pmol AMC released/min per mg of cytosolic protein. Calpain activity rose significantly after 24 hr of CI in University of Wisconsin solution and further increased with longer preservation. Activity also increased within 30 min of rewarming, peaking at 120 min. Increased durations of CI preceding rewarming resulted in significantly higher activity (P < 0.01). Calpain activity increased rapidly upon reperfusion and was significantly enhanced by previous CI (P < 0.01). Calpain inhibition with Cbz-Val-Phe methyl ester significantly decreased aspartate aminotransferase released in the isolated perfused rat liver perfusate (P < 0.05). Duration of survival after orthotopic liver transplantation using livers cold-preserved for 40 hr was also significantly increased (P < 0.05) with calpain inhibitor. In conclusion, calpain proteases are activated during each phase of transplantation and are likely to play an important role in the mechanisms of preservation-reperfusion injury.
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PMID:Calpain is a mediator of preservation-reperfusion injury in rat liver transplantation. 925 86


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