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PubMed1998

Coffee consumption and decreased serum gamma-glutamyltransferase and aminotransferase activities among male alcohol drinkers.

BACKGROUND: Attention has long been drawn to the potentially harmful effects of coffee on health, however recent epidemiological studies have suggested unexpected, possibly beneficial effects of coffee against the occurrence of alcoholic liver cirrhosis and upon serum liver enzyme levels. METHODS: We examined the potential inverse association between coffee drinking and serum concentrations of gamma-glutamyltransferase (GGT) and aminotransferases, with special reference to interaction with alcohol consumption, in a cross-sectional study involving 12687 health examinees (7398 men and 5289 women) aged 40-69 years from over 1000 workplaces in Nagano prefecture in central Japan. Those who had a history of liver disease and/or serum aminotransferases exceeding the normal range were excluded. Possible confounding effects of alcohol consumption, body mass index, cigarette smoking, and green tea consumption were controlled through multivariate analyses. RESULTS: Increased coffee consumption was strongly and independently associated with decreased GGT activity among males (P trend < 0.0001); the inverse association between coffee and serum GGT was more evident among heavier alcohol consumers (P < 0.0001), and was absent among non-alcohol drinkers. Among females, however, coffee was only weakly related to lower GGT level. Similar inverse associations with coffee and interactions between coffee and alcohol intake were observed for serum aspartate aminotransferase and alanine aminotransferase. Intake of green tea, another popular source of caffeine in Japan, did not materially influence the liver enzyme levels. CONCLUSIONS: Our results suggest that coffee may inhibit the induction of GGT in the liver by alcohol consumption, and may possibly protect against liver cell damage due to alcohol.

Adult↗

PubMed1977

Pyridoxine deficiency and postnatal development of brain aspartate and alanine aminotransferase activities, and cholesterol levels in chicks.

Feeding a pyridoxine deficient diet, for 2 weeks after hatching, had no effect on post-hatching development of chick brain aspartate aminotransferase (L-aspartate:2-oxoglutarate aminotransferase, EC 2.6.1.1) activity or on cholesterol deposition in the brain, but significantly depressed the development of brain alanine aminotransferase (L-alanine:2-oxoglutarate aminotransferase, EC 2.5.1.2) activity. Feeding a pyridoxine deficient diet from 3 to 8 weeks of age had no effect on any of the three parameters studied.

Alanine Transaminase↗

PubMed1988

Abnormal molecules of mitochondrial aspartate aminotransferase in the liver of vitamin B-6--deficient rats may be produced in the mitochondrial matrix.

The distribution of mitochondrial aspartate aminotransferase (AspATm) in liver cells was studied in rats fed pyridoxine-deficient and control diets. Mitochondrial aminotransferase activity was found mainly in the matrix fraction, with smaller amounts in the outer membranes, intermembrane space and cytosol. The precursor of the enzyme was detected in the liver cytosol of both vitamin B-6--deficient and control rats, and its amount was similar in the two groups. When pyridoxal phosphate was added to the assay system, the ratio of enzyme activity to antigenic activity (E/A) of mitochondrial aspartate aminotransferase in the cytosol of both vitamin B-6--deficient and control rats was about 70% of that in the matrix of control rats. On the other hand, the E/A of the matrix enzyme in deficient rats was 53% of that of controls. From these results we concluded that pyridoxal phosphate is not necessary for translocation of mitochondrial aspartate aminotransferase into mitochondrial matrix and that abnormal molecules of the enzyme may be formed in the matrix of vitamin B-6--deficient rat liver.

Animals↗

PubMed1990

Distribution of aspartate aminotransferase activity in yeasts, and purification and characterization of mitochondrial and cytosolic isoenzymes from Rhodotorula minuta [corrected].

The distribution of aspartate aminotransferase activity in yeasts was determined. The number of species of the enzyme in each yeast was determined by zymogram analysis. All the yeasts, except for the genus Saccharomyces, showed two or three activity bands on a zymogram. From among the strains, Rhodotorula minuta [corrected] and Torulopsis candida were selected for examination of the existence of yeast mitochondrial isoenzymes, because these strains showed two clear activity bands on the zymogram and contained a high amount of the enzyme. Only one aspartate aminotransferase was purified from T. candida: the component in the minor band on the zymogram was not an isoenzyme of aspartate aminotransferase. On the other hand, two aspartate aminotransferases were purified to homogeneity from R. minuta [corrected]. The components in the main and minor activity bands on the zymogram were identified as the mitochondrial and cytosolic isoenzymes, respectively, in a cell-fractionation experiment. The enzymatic properties of these isoenzymes were determined. The yeast mitochondrial isoenzyme resembled the animal mitochondrial isoenzymes in molecular weight (subunits and native form), absorption spectrum, and substrate specificity. The amino acid composition was closely similar to that of pig mitochondrial isoenzyme. Rabbit antibody against the yeast mitochondrial isoenzyme, however, did not form a precipitin band with the pig mitochondrial isoenzyme.

Amino Acids↗

PubMed1994

Construction of aminotransferase chimeras and analysis of their substrate specificity.

Escherichia coli aspartate aminotransferase (AspAT) and E. coli aromatic amino acid aminotransferase (AroAT) have almost identical and high activities toward acidic amino acid substrates. AroAT also has high activity toward aromatic amino acid substrates. The two proteins have 44% amino acid sequence homology. In order to study the mechanism responsible for the different substrate specificities of these aminotransferases, chimeric enzymes of AspAT and AroAT were constructed using homologous recombination in E. coli cells. Five chimeric enzymes were obtained, even though the nucleotide sequence homology between the two parent enzymes was as low as about 50%. The yields of the legitimate chimeric genes were related to the lengths of the homologous region between the two parent genes. Homologous recombination occurred in the region where more than eight nucleotides out of ten were identical. The substrate specificity of the chimeric enzymes suggest that not only the amino acid residues in the active site but also those distant from the active site contribute to the substrate specificity of the parental aminotransferases.

Amino Acid Sequence↗

PubMed1989

Regulation of cytosolic aspartate aminotransferase mRNAs in the Fao rat hepatoma cell line by dexamethasone, insulin and cyclic AMP.

Glucocorticoid hormones increase the activity of cytosolic aspartate aminotransferase (cAspAT) in the Fao rat hepatoma cell line. Maximal increase (6-10-fold) was observed 48 h following the addition of the glucocorticoid agonist dexamethasone at a concentration of 0.1 microM. The effect of dexamethasone was specific since it was not mimicked by sex steroids and was inhibited by the glucocorticoid antagonist RU 486. Insulin (0.1 microM) inhibited by more than 50% the induction of cAspAT by glucocorticoids. The cAMP analog, 8-bromoadenosine 3',5'-monophosphate (Br8cAMP, 0.5 mM), potentiated the effect of dexamethasone (2-3-fold) and partially relieved the inhibitory effect of insulin on the induction by dexamethasone. Both insulin and Br8-cAMP had no significant effect on basal activity. The mitochondrial isoenzyme was insensitive to the various hormonal treatments. Northern blot analysis revealed the presence of two major (2.1-kb and 1.8-kb) and one minor (4-kb) mRNA species hybridizing with a rat cAspAT probe. The regulation of these mRNAs by glucocorticoids, insulin and cAMP correlated with the variation of the cAspAT activity, suggesting that these hormones act at the pretranslational level. We compared the regulation of cAspAT mRNAs with those of tyrosine aminotransferase mRNA. Both were similarly increased by dexamethasone but the latter was also increased by cAMP even in the absence of the glucocorticoid agonist. In addition, the increase in tyrosine aminotransferase mRNA was inhibited by cycloheximide whereas the increase in cAspAT mRNAs was not. These results show that there are significant differences in the regulation of cAspAT and tyrosine aminotransferase by glucocorticoids and other hormones, although both enzymes probably contribute to the same metabolic pathway.

Animals↗

PubMed1994

Probing conformational states of spin-labeled aspartate aminotransferase by ESR.

Mitochondrial aspartate aminotransferase was selectively labeled with various maleimide-linked nitroxide spin labels at the conformationally sensitive Cys166. The mobility of the spin group was found to increase with increasing length of the spacer between the nitroxide and maleimide moiety. The label with the ethylcarbamoyl group, a spacer of intermediate length, responded sensitively to conformational changes of aspartate aminotransferase. The modification with this label decreased the enzymic activity to 30% of its initial value and increased the affinity for various substrates and inhibitors 5-10-fold. Identical ESR spectra were obtained for the pyridoxal and pyridoxamine form of the enzyme. These spectra are complex, consisting of an isotropic and at least two anisotropic components. The spectral complexity is attributed to different modes of interaction of the spin label with its local protein environment giving rise to different motional states. The same changes in the ESR spectra have been observed upon formation of the adsorption complex of the pyridoxal form with a competitive inhibitor and on formation of covalent intermediates of the transamination reaction. Essentially, the isotropic component is converted to a new anisotropic one as the local environment changes due to a conformational adaptation of aspartate aminotransferase. The ESR data are consistent with an equilibrium between two conformational states of the enzyme but inconsistent with individual protein conformations of the various intermediates of the transamination reaction. The two conformational states may be assigned to the open and closed conformations as defined by X-ray crystallography. In the adsorption complex of the pyridoxal enzyme, and in the covalent intermediates, the two-state equilibrium appears to be shifted towards the closed conformation in which the spin label is more rigidly bound, as also suggested by molecular dynamic simulations of the label modelled into aspartate aminotransferase. In contrast the formation of adsorption complexes between the pyridoxamine form and aspartate or maleate was not accompanied by the same shift of the conformational equilibrium.

Aspartate Aminotransferases↗

PubMed1984

Aspartate aminotransferase activity in fiber tracts of the rat brain.

Activity of aspartate aminotransferase, an enzyme which catalyzes the interconversion of the excitatory transmitter candidates, glutamate and aspartate, has been measured in fiber tracts of rat, with an emphasis on sensory and motor systems of the brain. Most tracts had significantly higher activities than the cholinergic facial nerve root, consistent with the possibility that a component of aspartate aminotransferase activity might serve as a marker for neurons using glutamate and/or aspartate as neurotransmitter. Highest activity was in the auditory nerve root. On the other hand, a close correlation was found between aspartate aminotransferase and malate dehydrogenase activities in the fiber tracts, raising the question whether aspartate aminotransferase activity may be more closely related to energy metabolism than to transmitter metabolism.

Animals↗

PubMed1999

Usefulness of alanine and aspartate aminotransferases in the diagnosis of microlithiasis in idiopathic acute pancreatitis.

CONCLUSION: Serum increases of aminotransferases, especially alanine aminotransferase (ALT), were suggestive of microlithiasis in idiopathic acute pancreatitis, particularly when assessed early after the onset of abdominal pain. BACKGROUND: It has been shown that biochemical laboratory values only are useful parameters in distinguishing gallstone from nongallstone acute pancreatitis. We assessed the diagnostic usefulness of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) for identification of occult microlithiasis in idiopathic acute pancreatitis. METHODS: Ninety-one patients with idiopathic acute pancreatitis who underwent microscopic examination of stimulated duodenal bile sediments were retrospectively studied. According to earliness of ALT and AST assay after the onset of abdominal pain, patients were divided into two groups: group A, within the first 24 h (n = 56) and group B, between 24 and 72 h (n = 35). RESULTS: ALT and AST values expressed as number of elevations of the upper limits of normal were higher in group A patients with positive biliary drainage than in group B. Median (range) ALT and AST values were 2.5 (0.1-18.1) vs 0.4 (0.1-8.6) and 3 (0.3-17.4) vs 0.5 (0.3-11.9), respectively. In the univariate analysis and receiver operating characteristic (ROC) curves, ALT within the first 24 h showed a sensitivity of 73%, specificity of 86%, and positive predictive value of 92% for a cutoff of 1.2 elevations of the upper limit of normal. These values were slightly higher, although without statistically significant differences, than those of AST (73, 80, and 89%, respectively).

Acute Disease↗

PubMedDate not supplied

Tyrosine biosynthesis in Sorghum bicolor: characteristics of prephenate aminotransferase.

A stable activity which transfers the amino group from glutamate to prephenate was extracted from 4-day old etiolated shoots of sorghum. The activity was retained on DEAE cellulose and eluted as a single peak. Prephenate aminotransferase co-eluted with a very abundant alpha-ketoglutarate: aspartate aminotransferase, but heating at 70 degrees C resulted in loss of alpha-ketoglutarate: aspartate activity with nearly full retention of prephenate: glutamate aminotransferase activity. The heated enzyme displayed high affinity and specificity for prephenate. Among 7 donors tested, only glutamate, and aspartate at less than 20% the rate with glutamate, supported prephenate aminotransferase activity. In the reverse direction, a reaction rate comparable to that in the forward direction was unchanged as the concentration of alpha-ketoglutarate was reduced from 1.0 to 0.09 mM. The apparent Km for arogenate was 0.8 mM. The forward reaction was unaffected by the inclusion of tyrosine, phenylalanine or tryptophan. Together with the discovery of arogenate dehydrogenase in sorghum [3], these data indicate that, in the sorghum plant, tyrosine derives from prephenate by transamination and aromatization, rather than the reverse sequence.

Aspartate Aminotransferases↗

PubMed1976

Aspartate aminotransferase activity and glutamic dehydrogenase in the cerebellar cortex in several species of animals. A histochemical study.

The histochemical study of the consumption of glutamic acid by way of the aspartate aminotransferase and the glutamic dehydrogenase in the cerebellar cortex of several species of animals have demonstrated that in that nerve centre exists some structures in which the mentioned consumption is specially or exclusively realized by means of one way and not for other different one. Is observed, as well, that in the rats, chicken and lizard, the baskets that surround the Purkinje cells are constituted by basket cells axons and by recurrent collaterals of Purkinje axons and that those structures have an intense aspartate aminotransferase activity, but not glutamic dehydrogenase. The aspartate aminotransferase activity was not observed on the other side, in the perikarya of the Purkinje cells of the related animals. However, there exists intense glutamic dehydrogenase activity. On the other hand, in the toad was not observed baskets with aspartate aminotransferase activity but this enzyme was presented on the other side in the perikarya of the Purkinje cells. All these observations have suggested the possibility that this special utilization of the glutamic acid is in some way concerned with the transmission phenomenons of the nerve impulse.

Animals↗

PubMed1975

Multispecific aspartate and aromatic amino acid aminotransferases in Escherichia coli.

Two aminotransferases from Escherichia coli were purified to homogeneity by the criterion of gel electrophoresis. The first (enzyme A) is active on L-aspartic acid, L-tyrosine, L-phenylalanine, and L-tryptophan; the second (enzyme B) is active on the aromatic amiono acids. Enzyme A is identical in substrate specificity with transaminase A and is mainly an aspartate aminotransferase; enzyme B has never been described before and is an aromatic amino acid aminotransferase. The two enzymes are different in the Vmax and Km values with their common substrates and pyridoxal phosphate, in heat stability (enzyme A being heat-stable and enzyme B being heat-labile at 55 degrees) and in pH optima with the amino acid substrates. They are similar in their amino acid composition, each enzyme appears to consist of two subunits, and enzyme B may be converted to enzyme A by controlled proteolysis with subtilsin. The conversion was detected by the generation of new aspartate aminotransferase activity from enzyme B and was further verified by identification by acrylamide gel electrophoresis of the newly formed enzyme A. The two enzymes appear to be products of two genes different in a small, probably terminal, nucleotide sequence.

Amino Acids↗

PubMed1988

Nucleotide sequence and glucocorticoid regulation of the mRNAs for the isoenzymes of rat aspartate aminotransferase.

Cytosolic and mitochondrial aspartate aminotransferase cDNAs were cloned from a lambda gt11 rat liver cDNA library. The complete coding sequence and the 3' non-coding sequence of the cytosolic isozyme mRNA were obtained from two overlapping cDNA clones. Partial sequences of the mitochondrial enzyme cDNAs were found to be identical to the recently published complete sequence (Mattingly, J. R., Jr., Rodriguez-Berrocal, F. J., Gordon, J., Iriarte, A., and Martinez-Carrion, M. (1987) Biochem. Biophys. Res. Commun. 149, 859-865). A single mRNA (2.4 kb (kilobase pair] hybridizing to the mitochondrial cDNA probe was detected by Northern blot analysis, whereas the cytosolic cDNA probe labeled one major (2.1 kb) and two minor (1.8 and 4 kb) mRNAs. The 1.8-kb and the 2.1-kb cytosolic aspartate aminotransferase mRNAs differ in their 3' ends and probably result from the use of either of the two polyadenylation signals present in the 3' noncoding region of the major cytosolic aspartate aminotransferase mRNA. Glucocorticoid hormones increased the activity of cytosolic but not mitochondrial aspartate aminotransferase in both liver and kidney. The increase in the enzyme activity was accompanied by an increase in the amount of the three corresponding mRNAs, while the mitochondrial enzyme mRNA was not significantly modified.

Adrenalectomy↗

PubMed1986

The importance of aspartate aminotransferase for platelet aggregation.

In bovine platelets aspartate aminotransferase has a high activity. The enzyme in vitro is inhibited in a dose dependent manner by aminooxyacetate (IC50 = 10(-4) M), hydroxylamine (IC50 = 10(-4) M), and cycloserine (IC50 = 5 X 10(-3). The inhibitory effect of all the three compounds is strongest at low substrate (aspartate) concentration. Blocking of aspartate aminotransferase activity by these compounds in intact platelets is accompanied by the inhibition of ADP and collagen-induced aggregation. Among the three compounds the strongest inhibitor of platelet aggregation was hydroxylamine, which was also the most effective inhibitor of aspartate aminotransferase. Other metabolic blockers, i.e. dinitrophenol (DNP), rotenone and antimycin also inhibited the aggregation of platelets, and a synergism has been demonstrated between DNP, rotenone and antimycin A action on platelet aggregation and blockade of aspartate aminotransferase activity. The results are interpreted to mean that transamination is of importance in the energy production in the activated platelet, probably through its participation in reducing equivalents transport from the cytosol to the mitosol via the malate: oxaloacetate: aspartate shuttle.

Adenosine Diphosphate↗

PubMed1982

Prognostic and therapeutic implications of extreme serum aminotransferase elevation in chronic active hepatitis.

Extreme elevation of the serum aspartate aminotransferase level typically suggests acute hepatocellular necrosis and may militate against the diagnosis of chronic active hepatitis. However, we found that 26 of 160 patients (16%) with chronic active hepatitis had aminotransferase elevations of more than 1,000 IU/liter. These patients were younger and more often jaundiced than the others, but they exhibited signs of chronic liver disease as often. In only 2 of 26 patients with extreme aminotransferase abnormality were features of chronic disease absent. Patients with extreme enzyme elevation had histologic findings of confluent necrosis (P greater than 0.005) and features associated with acute viral infection (P greater than 0.005) more often than others, but they as often had cirrhosis on biopsy specimens. Virologic markers did not distinguish the patients or correlate with viral features in liver tissue. Corticosteroids improved immediate survival (P greater than 0.005) and the likelihood of remission (P greater than 0.005). Although chronic active hepatitis may present with extreme aminotransferase elevation and histologic features associated with acute viral infection, ancillary features of chronic disease facilitate the correct diagnosis and the initiation of appropriate therapy.

Adult↗

PubMed1994

Modulation of the activity of mitochondrial aspartate aminotransferase H352C by the redox state of the engineered interdomain disulfide bond.

Molecular modeling suggested that the large and small domain of mitochondrial aspartate aminotransferase might be linked by an engineered disulfide bond that could be expected to interfere with ligand-induced and syncatalytic changes in conformation and thus to assist in the elucidation of their significance for the catalytic mechanism. His-352, which is situated in the small domain close to Cys-166 of the large domain, was replaced with a cysteine residue by oligonucleotide-directed mutagenesis. Aspartate aminotransferase H352C, that had not been exposed to reducing conditions, in part contained a disulfide bond between Cys-166 and Cys-352. Exposure to a reducing agent cleaved the crosslink completely and produced an enzyme derivative with 8% of the activity of the wild type enzyme. Cu2+-mediated autoxidation resulted in complete formation of the disulfide bond and a decrease in enzymic activity to 2%. Independently of the redox state of the disulfide bond, the H352C substitution seems to shift the equilibrium from the open toward the closed conformation of the enzyme. This change in conformation was accompanied by an increase in the binding affinity for both the amino and oxo acid substrate by one order of magnitude. Apparently, 1-2 kcal/mol of the binding energy of the substrates are no longer diverted to shift the conformational equilibrium toward the closed conformation. The kcat/Km values were unchanged or even increased in the reduced form of the mutant enzyme and only slightly decreased in its oxidized form. Both the disulfide-independent decrease in enzymic activity, as observed in reduced aspartate aminotransferase H352C and also in two other mutant enzymes (C166H/H352C and H352Q), and the redox-dependent modulation of activity indicate that unhindered domain movements are essential for full catalytic competence of aspartate aminotransferase.

Animals↗

PubMed1994

NMR studies of 1H resonances in the 10-18-ppm range for aspartate aminotransferase from Escherichia coli.

We have recorded 500-MHz 1H NMR spectra in the 10-18-ppm range for aspartate aminotransferase from Escherichia coli and for three specific mutant forms. Histidine 143 has been replaced by either alanine or asparagine. In the third mutant, tryptophan 140 has been replaced by phenylalanine. The NMR spectrum of the native enzyme is very similar to that of porcine cytosolic aspartate aminotransferase in the most downfield region. However, the resonances of the proton on the ring nitrogen of the pyridoxal 5'-phosphate (peak A) and on the His-143 imidazole ring (peak B) of the E. coli enzyme are broader and more readily lost at low pH or higher temperatures than those of the porcine enzyme. The possible role of tautomerism in promoting such broadening is discussed. In the histidine mutant proteins, peak A of the pyridoxal 5'-phosphate form is too broad to see under most conditions but is clearly present in the pyridoxamine phosphate form. Peak B is missing in the 2 histidine mutants. Observation of nuclear Overhauser effects further confirms the identity of B as the resonance of HN epsilon 2 of His-143 and that of peak D at approximately 11.8 ppm as HN epsilon 2 of His-189. The mutant spectra also provide insight into electronic interactions between groups in and near the active site which confirm and supplement conclusions drawn from spectra of porcine cAspAT. While no clear loss of a peak was observed for the Trp-140 mutant in its free form, the spectrum of the succinate complex lacked a strong band at 11.26 ppm. This may represent the Trp-140 indole NH proton which has been shifted downfield by binding to a succinate carboxylate group. While our results confirm the basic similarity of cytosolic aspartate aminotransferase and E. coli aspartate aminotransferase 1H NMR spectra, they also point out differences that may be useful in identifying resonances. A large number of mutant proteins have been prepared for the E. coli enzyme. The present results provide essential information for future study of these mutants and for study of NMR spectra of isotopically labeled enzyme.

Alanine↗

PubMed1996

Relationships between plasma ferritin and aminotransferase profile in haemodialysis patients with hepatitis C virus.

BACKGROUND: HCV infection is a major complication among patients undergoing dialysis therapy throughout the world. In the years prior to the use of human recombinant erythropoietin (rHuEpo), patients undergoing haemodialysis were subjected to an excessive iron load as a consequence of frequent blood transfusions. Recent data in the non-dialysis population have shown a positive correlation between iron deposits and the severity of HCV hepatitis and between iron deposition and an impaired response to interferon therapy. METHODS: One hundred and five haemodialysis patients were studied. Every patient was screened for HCV infection by ELISA II and HCV RNA. Serum biochemistries were analysed by SMAC20. Ferritin was measured by radioimmunoassay. RESULTS: The aminotransferase levels for the HCV positive (n = 39) and negative patients (n = 66) were below the normal levels for the general population. The mean values of aminotransferases and plasma ferritin were, however, higher in the HCV-positive patients than in the HCV-negative patients. A positive correlation between aminotransferases and plasma ferritin was evident in HCV-positive patients, which was absent in the HCV-negative individuals. The histological severity of liver disease (n = 7) was, however, not statistically related with the levels of either ferritin or aminotransferases. CONCLUSION: HCV infection is a relevant variable when estimating iron deposits by measuring plasma ferritin. Accordingly, a misinterpretation of the actual amount of iron deposits may occur in HCV-positive patients, which should be taken into account at the time of planning their iron reposition therapy. On the other hand, the level of iron deposits might have a significant role in the evolution of HCV-related liver disease.

Aged↗