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)

Tyr70 of chicken mitochondrial aspartate aminotransferase was replaced with a histidine residue by oligonucleotide-directed mutagenesis. Aspartate aminotransferase Y70H retained at pH 7.5 13% of the activity toward dicarboxylic amino acids, whereas the activity toward aromatic amino acids was only 0.6% of that of the wild-type enzyme, corresponding to a 22-fold increase in the ratio of the activities toward these two types of substrates. In comparison to that of the wild-type enzyme, the low-pH limb of the pH-activity profile of the mutant enzyme was shifted to higher pH values, very likely reflecting the titration curve of the newly introduced histidine residue with a pKa' of 6.3. Apparently, a positively charged residue at position 70 abolishes enzymic activity. The spectrophotometrically determined pKa' value of the internal aldimine formed between pyridoxal 5'-phosphate and Lys258 in the mutant enzyme was 6.0, similar to that in the wild-type enzyme. The rate constant of the dissociation of pyridoxamine 5'-phosphate from the mutant enzyme was increased only 3 times over that of the wild-type enzyme, in contrast to the 80-fold increase in Escherichia coli aspartate aminotransferase Y70F [Toney, M. D., & Kirsch, J. F. (1987) J. Biol. Chem. 262, 12403-12405], suggesting that His70 can replace Tyr70 in forming a hydrogen bond to the coenzyme.
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PMID:Shift in pH-rate profile and enhanced discrimination between dicarboxylic and aromatic substrates in mitochondrial aspartate aminotransferase Y70H. 813 Jan 87

Aspartate aminotransferase as well as valine dehydrogenase and threonine dehydratase was required for the biosynthesis of tylosin in Streptomyces fradiae NRRL 2702. The biosynthesis of these enzymes and tylosin production were repressed by high concentrations of ammonium ions. The change in specific tylosin production rates in batch cultures with different initial concentrations of ammonium ions showed patterns similar to those of the specific production rates of aspartate aminotransferase, valine dehydrogenase, and threonine dehydratase. Aspartate aminotransferase has been purified by acetone precipitation, DEAE-cellulose, hydroxyapatite, and preparative electrophoresis chromatographies. The purified enzyme (120 kDa) consisted of two subunits identical in molecular mass (54 kDa) and showed homogeneity, giving one band with a pI of 4.2 upon preparative isoelectric focusing. The enzyme was specific for L-aspartate in the forward reaction; the Km values were determined to be 2.7 mM for L-aspartate, 0.7 mM for 2-oxyglutarate, 12.8 mM for L-glutamate, and 0.15 mM for oxaloacetate. The enzyme was somewhat thermostable, having a maximum activity at 55 degrees C, and had a broad pH optimum that ranged from 5.5 to 8.0. The mode of action was a ping-pong-bi-bi mechanism.
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PMID:Aspartate aminotransferase and tylosin biosynthesis in Streptomyces fradiae. 848 Oct 8

Hepatocytes constitute the principal site of listerial replication in the livers of mice infected i.v. CD8+ T lymphocytes play a predominant role in the host defenses to Listeria monocytogenes. In vitro experiments by others undertaken to delineate the functions of CD8+ T lymphocytes have focused primarily on their interaction with Listeria-infected macrophages. Such experiments do not address directly the role of CD8+ T lymphocytes in eliminating the bulk of Listeria replicating within the liver. Here, we report that immune CD8+ T cells at an E:T cell ratio > or = 10:1 lysed Listeria-infected hepatocytes as judged by the following two criteria. Aspartate aminotransferase activity in the culture supernatants, indicative of hepatocyte damage, increased significantly. Conversely, infected hepatocytes cocultured with immune CD8+ T cells exhibited a marked reduction in viable intracellular Listeria assessed by CFUs. Neither immune CD4+ T cells nor nonimmune CD8+ T cells caused a similar increase in aspartate aminotransferase activity released or a decrease in intracellular bacteria. Immune CD8+ T cell-mediated lysis of infected hepatocytes was restricted by classical MHC class I (H-2Kb) molecules and was inhibited by the presence of either brefeldin A or mAb specific for CD8. These results suggest that the predominant role of CD8+ T lymphocytes in host resistance to listerial infections of the liver may be due to their capacity to lyse infected hepatocytes.
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PMID:Immune CD8+ T lymphocytes lyse Listeria monocytogenes-infected hepatocytes by a classical MHC class I-restricted mechanism. 897 1

Aspartate aminotransferase from Sulfolobus solfataricus (SsAspAT) is an extremely thermophilic and thermostable dimeric enzyme which retains its structure and reaches maximal activity at 100 degrees C. The structural stability of this protein was investigated by coupling isothermally and thermally induced denaturation studies to molecular modeling. Gel filtration analysis indicated that SsAspAT unfolds with an N2 reversible 2D mechanism. In the molecular model, a cluster of hydrophobic residues was shown at the interface between the subunits of SsAspAT and suggested this cluster as a structural feature stabilizing the enzyme quaternary structure. At 25 degrees C, SsAspAT is less resistant to guanidinium chloride-induced denaturation than the cytosolic aspartate aminotransferase from pig heart (cpAspAT), which was chosen as a mesophilic counterpart in the thermodynamic analysis since it shares with SsAspAT the two-state unfolding mechanism. Therefore, in the case of aspartate aminotransferases, thermal stability does not correlate with the stability against chemical denaturants. Isothermal denaturation curves at 25 degrees C and melting profiles recorded in the presence of guanidinium chloride showed that the delta G degrees (H2O) at 25 degrees C of SsAspAT exceeds that of cpAspAT by roughly 15 kJ/mol; the parameter delta n, related to the number of binding sites for the denaturant differentially exposed in unfolded and folded states, is higher for SsAspAT than for cpAspAT; and delta Cp is lower for the thermophilic enzyme than for the mesophilic one by 8 kJ/K.mol. These results are indicative of a less hydrophobic core for SsAspAT than cpAspAT. In agreement with this, the molecular model predicts that some charged side chains are buried in SsAspAT and interact to form an H-bond/ion-pair network.
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PMID:Stability of aspartate aminotransferase from Sulfolobus solfataricus. 915 89

Tacrine is an acetylcholinesterase inhibitor approved for the treatment of Alzheimer's disease. Unfortunately, reversible hepatotoxicity in about 30% of patients at therapeutic doses limits clinical use. The purpose of this study was to develop and characterize a model of tacrine hepatotoxicity to begin to understand the mechanisms of injury. Rats were given tacrine (10-50 mg/kg, intragatrically) and killed 24 hr later. An increase in serum aspartate aminotransferase was observed up to 35 mg/kg and histology revealed pericentral necrosis and fatty changes. Aspartate aminotransferase was increased from 12 to 24 hr and returned to control values by 32 hr. Livers were perfused in a nonrecirculating system to measure oxygen uptake and trypan blue was infused at the end of each experiment to evaluate tissue perfusion. Time for trypan blue to distribute evenly throughout the liver 3 hr after tacrine treatment was significantly increased (6.9 +/- 1.3 min) compared to controls (1.0 +/- 0.3 min) reflecting decreased tissue perfusion. Tacrine also significantly increased the binding of a hypoxia marker, pimonidazole, in pericentral regions almost 3-fold, and increased portal pressure in vivo significantly. It is hypothesized that tacrine, by inhibiting acetylcholine breakdown in the celiac ganglion, increases sympathetic activity in the liver leading to vascular constriction, hypoxia and liver injury. To test this hypothesis, the hepatic nerve was severed and animals were allowed to recover before tacrine treatment. This procedure significantly reduced serum aspartate aminotransferase, time of dye distribution, pimonidazole binding and portal pressure. Furthermore, a free radical adduct was detected with spin trapping and electron spin resonance spectroscopy 8 hr after tacrine treatment, providing evidence for reoxygenation. When catechin (100 mg/kg, i.p.), a free radical scavenger, was given before tacrine, injury was decreased by about 45%. Furthermore, feeding 5% arginine in the diet significantly reduced portal pressure and time of dye distribution. These data are consistent with the hypothesis that tacrine hepatotoxicity is a hypoxia-reoxygenation injury mediated through the sympathetic nervous system.
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PMID:Development and characterization of a new model of tacrine-induced hepatotoxicity: role of the sympathetic nervous system and hypoxia-reoxygenation. 931 76

Aspartate aminotransferase can exist as a macroenzyme, which has a higher molecular mass than the corresponding enzyme normally found in serum under physiologic or pathological conditions. This macroenzyme is often an immunoglobulin complexed-enzyme and induces persistently increased serum aspartate aminotransferase activity without any corresponding liver or muscle damage. We report 5 patients with isolated and persistent increased serum aspartate aminotransferase activity in whom a macroenzyme has been detected. Of these 5 cases, four were apparently healthy subjects and the last had chronic active hepatitis. Electrophoresis of aspartate aminotransferase isoenzymes of the subjects' serum showed an abnormal band migrating between mitochondrial and cytosolic aspartate aminotransferase. In 3 cases, the macrocomplex consisted of aspartate aminotransferase and immunoglobulin G, as shown by the immunoprecipitation method. In the patient with chronic active hepatitis, the macroenzyme disappeared after liver transplantation. As macroaspartate aminotransferase and others macroenzymes, may persist for months or even years, it is important for clinicians to be aware of their existence to avoid unnecessary invasive or costly procedures.
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PMID:[Macroaspartate aminotransferase. Study of 5 cases and review of the literature]. 976 95

The interactions between pig heart citrate synthase and mitochondrial malate dehydrogenase or cytosolic malate dehydrogenase were studied using the frontal analysis method of gel filtration and by precipitation in polyethylene glycol. This method showed that an interaction between citrate synthase and mitochondrial malate dehydrogenase occurred but no interaction between citrate synthase and cytosolic malate dehydrogenase. Channeling of oxaloacetate in the malate dehydrogenase and citrate synthase-coupled systems was tested using polyethylene glycol precipitates of citrate synthase and mitochondrial malate dehydrogenase, and citrate synthase and cytosolic malate dehydrogenase. The effectiveness of large amounts of aspartate aminotransferase and oxaloacetate decarboxylase, as competing enzymes for the intermediate oxaloacetate, was examined. Aspartate aminotransferase and oxaloacetate decarboxylase were less effective competitors for oxaloacetate when precipitated citrate synthase and mitochondrial malate dehydrogenase in polyethylene glycol was used at low ionic strength compared with free enzymes in the absence of polyethylene glycol or with a co-precipitate of citrate synthase and cytosolic malate dehydrogenase. Substrate channeling of oxaloacetate with citrate synthase-mitochondrial malate dehydrogenase precipitate was inefficient at high ionic strength. These effects could be explained through electrostatic interactions of mitochondrial but not cytosolic malate dehydrogenase with citrate synthase.
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PMID:Interaction between citrate synthase and malate dehydrogenase. Substrate channeling of oxaloacetate. 979 62

Niacin is a useful lipid-modifying drug because it (1) decreases low-density lipoprotein (LDL) cholesterol, total cholesterol, triglycerides, and lipoprotein(a), and (2) raises high-density lipoprotein (HDL) cholesterol. Its use tends to be limited by side effects and inconvenient dosing regimens. The availability of an extended-release preparation (Niaspan-which has safety and efficacy similar to immediate-release niacin but which can be given once a day) provides an opportunity to increase the use of this effective lipid-modifying agent. To study the safety and efficacy of escalating doses of extended-release niacin, hyperlipidemic patients were randomly assigned to placebo or Niaspan. A forced dose-titration was done with the dosage increasing by 500 mg every 4 weeks to a maximum of 3,000 mg/day. Niaspan showed dose-related changes in total, LDL, and HDL cholesterol levels, triglycerides, cholesterol/HDL ratio, and lipoprotein(a). At a dosage of 2,000 mg/day, total cholesterol decreased by 12.1%, LDL cholesterol by 16.7%, triglycerides by 34.5%, and lipoprotein(a) by 23.6%; HDL cholesterol increased by 25.8%. Flushing was the most commonly reported side effect; flushing episodes tended to decrease with time despite an increasing dose of niacin. Of the reported side effects, only pruritus and rash were significantly different between the 2 groups. Aspartate aminotransferase, lactate dehydrogenase, and uric acid increased in a dose-dependent fashion, but fasting blood sugar increased by about 5% across most dosages. Two subjects had aspartate aminotransferase levels greater than twice the upper limit of normal, but there were no subjects in whom transaminases increased to 3 times the upper limit of normal. Women tended to have a greater LDL cholesterol response to the medication and also experienced more side effects, especially at higher dosages. Thus, the use of lower dosages of niacin may be desirable in women. The results of this dose-escalation study show beneficial effects of Niaspan on the entire lipid profile. At the maximum recommended dosage of 2,000 mg/day, all lipid and lipoprotein levels changed in desirable directions. Side effects (other than flushing) and blood chemistries were comparable to those seen with immediate-release niacin.
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PMID:Clinical trial experience with extended-release niacin (Niaspan): dose-escalation study. 991 61

We analyzed retrospectively the relationship between coagulation profile, and either hepatic function or hemodynamics, in patients who had undergone a Fontan-type procedure, comparing them, first, with a control group of 12 patients without significant hemodynamic abnormality, and, second, with a group of 14 patients who had not undergone a Fontan procedure, but whose mean right atrial pressure exceeded 8 mmHg. Follow-up catheterization had been performed in all 30 patients submitted to the Fontan-type operation. Prothrombin time, and factor XIII, were significantly lower in those who had undergone the Fontan procedure than in the other groups. Those submitted to the Fontan operation also had lower levels of protein C than controls, and their levels of plasminogen were lower than the patients with high right atrial pressure. Both aspartate aminotransferase and alanine aminotransferase were higher in those undergoing the Fontan procedure than in the other groups, while gamma-glutamyltranspeptidase in these patients was higher than in the control group. Mean right atrial pressure was highest in those undergoing the Fontan procedure, while cardiac index was lowest. Prothrombin time was correlated to some extent with aspartate aminotransferase, mean right atrial pressure, and cardiac index. Protein C correlated with both aspartate aminotransferase and mean right atrial pressure, while factor XIII correlated with alanine aminotransferase, mean right atrial pressure, and cardiac index. Aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyltranspeptidase, parameters of hepatic function, correlated significantly with mean right atrial pressure. In those who had undergone the Fontan procedure, decreased synthesis of pro-and anti-coagulant factors is a risk factor for both thrombosis and bleeding. Abnormal hemodynamics, in the absence of a right sided pumping chamber, may predispose to subclinical hepatic dysfunction, leading to selective disturbances of protein synthesis.
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PMID:Coagulation profile, hepatic function, and hemodynamics following Fontan-type operations. 1123 99

Aspartate aminotransferase (AAT, EC 2.6.1.1) catalyses the transamination of L-asparate to oxaloacetate. It has been reported that AAT from different plant sources can catalyse the transamination of other compounds structurally similar to the natural substrates. Specificity and kinetic studies were performed with two aspartate aminotransferase isoenzymes (AAT-1 and AAT-2) from leaves of Lupinus albus L. cv Estoril using different amino donors and acceptors. Both isoenzymes showed residual activity for some of the substrates tested. Competitive inhibition was found with most of the structural analogues which is typical of a ping-pong bi-bi kinetic mechanism. It was found that both isoenzymes can use 2-amino-4-methoxy-4-oxobutanoic acid as amino donor. AAT-2 uses 2-amino-4-methoxy-4-oxobutanoic acid at a similar rate as L-aspartate but AAT-1 uses this substrate at a slower rate. The use of this amino donor by AAT isoenzymes has not been reported previously, and our results indicate structural differences between both isoenzymes.
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PMID:Effects of substrate structural analogues on the enzymatic activities of aspartate aminotransferase isoenzymes. 1169 45


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