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PubMed1994

Significant improvement to the catalytic properties of aspartate aminotransferase: role of hydrophobic and charged residues in the substrate binding pocket.

The substrate specificity of tyrosine aminotransferase (eTAT) from Escherichia coli has been tested by transferring the critically different residues Leu39, Glu141, and Arg293 into equivalent positions of aspartate aminotransferase (eAAT). These residues are not directly involved in the catalytic process. The single mutant eAAT V39L possesses greater values of kcat/KM not only for tyrosine but also for aspartate and glutamate. In contrast, the double mutant eAAT P141E,A293R and also the triple mutant eAAT V39L,P141E,A293R exhibit smaller changes of kcat/KM. The converse mutants of tyrosine aminotransferase, in which critical residues of eAAT (Val39) and of mitochondrial AAT (Ala39, Val37) were transferred into equivalent positions of eTAT, exhibited generally decreased values of kcat/KM for both dicarboxylic and aromatic substrates. On the basis of the known structures of eAAT and eAAT V39L as well as of a refined model of eTAT, these results indicate that the different substrate specificities of eAAT and eTAT are due to multiple side chain differences and minor rearrangements of the backbone. The generally improved catalytic efficiency of the mutant eAAT V39L appears to be due to an indirect effect, namely, the facilitated closure of the active site upon substrate binding.

Amino Acid Sequence↗

PubMed1994

Shift in pH-rate profile and enhanced discrimination between dicarboxylic and aromatic substrates in mitochondrial aspartate aminotransferase Y70H.

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.

Amino Acid Sequence↗

PubMed2005

Binding of C5-dicarboxylic substrate to aspartate aminotransferase: implications for the conformational change at the transaldimination step.

The mechanism for the reaction of aspartate aminotransferase with the C4 substrate, l-aspartate, has been well established. The binding of the C4 substrate induces conformational change in the enzyme from the open to the closed form, and the entire reaction proceeds in the closed form of the enzyme. On the contrary, little is known about the reaction with the C5 substrate, l-glutamate. In this study, we analyzed the pH-dependent binding of 2-methyl-l-glutamate to the enzyme and showed that the interaction between the amino group of 2-methyl-l-glutamate and the pyridoxal 5'-phosphate aldimine is weak compared to that between 2-methyl-l-aspartate and the aldimine. The structures of the Michaelis complexes of the enzyme with l-aspartate and l-glutamate were modeled on the basis of the maleate and glutarate complex structures of the enzyme. The result showed that l-glutamate binds to the open form of the enzyme in an extended conformation, and its alpha-amino group points in the opposite direction of the aldimine, while that of l-aspartate is close to the aldimine. These models explain the observations for 2-methyl-l-glutamate and 2-methyl-l-aspartate. The crystal structures of the complexes of aspartate aminotransferase with phosphopyridoxyl derivatives of l-glutamate, d-glutamate, and 2-methyl-l-glutamate were solved as the models for the external aldimine and ketimine complexes of l-glutamate. All the structures were in the closed form, and the two carboxylate groups and the arginine residues binding them are superimposable on the external aldimine complex with 2-methyl-l-aspartate. Taking these facts altogether, it was strongly suggested that the binding of l-glutamate to aspartate aminotransferase to form the Michaelis complex does not induce a conformational change in the enzyme, and that the conformational change to the closed form occurs during the transaldimination step. The hydrophobic residues of the entrance of the active site, including Tyr70, are considered to be important for promoting the transaldimination process and hence the recognition of the C5 substrate.

Amines↗

PubMed1979

Some kinetic and other properties of the isoenzymes of aspartate aminotransferase isolated from sheep liver.

A method for the purification of mitochondrial isoenzyme of sheep liver aspartate aminotransferase (EC 2.6.1.1) is described. The final preparation is homogeneous by ultracentrifuge analyses and polyacrylamide-gel electrophoresis and has a high specific activity (182 units/mg). The molecular weight determined by sedimentation equilibrium is 87,100 +/- 680. The amino acid composition is presented; it is similar to that of other mitochondrial isoenzymes, but with a higher content of tyrosine and threonine. Subforms have been detected. On isoelectric focusing a broad band was obtained, with pI 9.14. The properties of the mitochondrial aspartate aminotransferase are compared with those of the cytoplasmic isoenzyme. The Km for L-aspartate and 2-oxoglutarate for the cytoplasmic enzyme were 2.96 +/- 0.20 mM and 0.093 +/- 0.010 mM respectively; the corresponding values for the mitochondrial form were 0.40 +/- 0.12 mM and 0.98 +/- 0.14 mM. Cytoplasmic aspartate aminotransferase showed substrate inhibition by concentrations of 2-oxoglutarate above 0.25 mM in the presence of aspartate up to 2mM. The mitochondrial isoenzyme was not inhibited in this way. Pi at pH 7.4 inhibited cytoplasmic holoenzyme activity by up to about 60% and mitochondrial holoenzyme activity up to 40%. The apparent dissociation constants for pyridoxal 5'-phosphate were 0.23 micrometer (cytoplasmic) and 0.062 micrometer (mitochondrial) and for pyridoxamine 5'-phosphate they were 70 micrometer (cytoplasmic) and 40 micrometer (mitochondrial). Pi competitively inhibited coenzyme binding to the apoenzymes; the inhibition constants at 37 degree C were 32 micrometer for the cytoplasmic isoenzyme and 19.5 micrometer for the mitochondrial form.

Amino Acids↗

PubMed2002

Mitochondrial aspartate aminotransferase catalyses cysteine S-conjugate beta-lyase reactions.

Rat liver mitochondrial aspartate aminotransferase (a homodimer) was shown to catalyse a beta-lyase reaction with three nephrotoxic halogenated cysteine S-conjugates [ S -(1,1,2,2-tetrafluoroethyl)-L-cysteine, S -(1,2-dichlorovinyl)-L-cysteine and S -(2-chloro-1,1,2-trifluoroethyl)-L-cysteine], and less effectively so with a non-toxic cysteine S-conjugate [benzothiazolyl-L-cysteine]. Transamination competes with the beta-lyase reaction, but is not favourable. The ratio of beta elimination to transamination in the presence of S -(1,1,2,2-tetrafluoroethyl)-L-cysteine and 2-oxoglutarate is >100. Syncatalytic inactivation by the halogenated cysteine S-conjugates is also observed. The enzyme turns over approx. 2700 molecules of halogenated cysteine S-conjugate on average for every monomer inactivated. Kidney mitochondria are known to be especially sensitive to toxic halogenated cysteine S-conjugates. Evidence is presented that 15-20% of the cysteine S-conjugate beta-lyase activity towards S -(1,1,2,2-tetrafluoroethyl)-L-cysteine in crude kidney mitochondrial homogenates is due to mitochondrial aspartate aminotransferase. The possible involvement of mitochondrial aspartate aminotransferase in the toxicity of halogenated cysteine S-conjugates is also discussed.

Animals↗

PubMed1982

Uptake of aspartate aminotransferase into mitochondria in vitro depends on the transmembrane pH gradient.

1. The effects of various inhibitors of electron transport and of oxidative phosphorylation and the effects of ionophores on the uptake of native aspartate aminotransferase into mitochondria were investigated. 2. Both antimycin and cyanide completely inhibited the uptake of the enzyme. On the other hand, uptake was stimulated to ATP and by oligomycin; however, the stimulation by ATP is inhibited by oligomycin. 3. The effects of ionophores of the valinomycin type in media containing K+ ions depended on the conditions used. Valinomycin alone stimulated the uptake of the enzyme, but in the presence of phosphate ions uptake was abolished. Nonactin was without effect at a low K+ concentration, but was stimulatory at 100 mM-KCl. Gramicidin also stimulated the uptake process. 4. Nigericin completely abolished uptake of aspartate aminotransferase into mitochondria. 5. The uptake of te enzyme was decreased by 18% in the absence of inhibitors or ionophores when the external pH was increased from 6.9 to 7.6. 6. These results indicate that ATP is not directly involved in the uptake of aspartate aminotransferase into mitochondria, neither is there a requirement for a cation gradient. Rather the uptake depends on the maintenance of a pH gradient across the mitochondrial inner membrane.

Adenosine Triphosphate↗

PubMed1988

Kinetic studies of chicken and turkey liver mitochondrial aspartate aminotransferase.

The kinetic behaviour of chicken liver and turkey liver aspartate aminotransferases (L-aspartate:2-oxoglutarate aminotransferase, EC 2.6.1.1) was studied. Steady-state data were obtained from a wide range of concentrations of substrates and product L-glutamate. The data were fitted by rational functions of degree 1:1, 1:2 and 2:2 with respect to substrates and 0:1, 1:1, 0:2 and 1:2 with regard to product (L-glutamate), by using a non-linear regression program that guarantees the fit. The goodness of fit was improved by the use of a computer program that combines model discrimination parameter refinement and sequential experimental design. It was concluded that aspartate aminotransferase requires a minimum velocity equation of degree 2:2 for L-aspartate, 2:2 for 2-oxoglutarate and 1:2 for L-glutamate. Finally, a plausible kinetic mechanism that justifies these experimental results is proposed.

Animals↗

PubMed1982

Aspartate: 2-oxoglutarate aminotransferase from bakers' yeast: crystallization and characterization.

Aspartate: 2-oxoglutarate aminotransferase [EC 2.6.1.1] was purified and crystallized from bakers' yeast. The crystalline preparation gave a single band on polyacrylamide disc gel electrophoresis in the presence of sodium dodecyl sulfate. However, in the absence of sodium dodecyl sulfate, the preparation gave one major band with two faint bands, all of which showed the same specific activity, molecular weight and serological properties. These faint bands appeared to be modified forms produced from the major band during the purification. The enzyme showed a molecular weight of 90,000 +/- 8,000 and 92,000 +/- 8,000 by gel filtration and sedimentation equilibrium analysis, respectively. The molecular weight of a subunit was estimated to be 45,000 by sodium dodecyl sulfate slab gel electrophoresis. Each subunit bound approximately 1 mol of pyridoxal 5'-phosphate. The bound pyridoxal 5'-phosphate showed an absorption maximum at 360 nm (epsilon M: 11,500) and 430 nm (epsilon M: 8,200) in alkaline and acidic conditions, respectively. Its proteolytic pK was pH 6.3. The enzyme showed an optimum pH of 8.0-9.0, and fairly high amino donor and acceptor specificities; aromatic amino acids and their corresponding 2-oxoacids were catalyzed at rates of 0.2-0.8% of those for aspartate and oxalacetate, respectively. Michaelis constants for various substrate were: L-aspartate (0.11 mM), L-glutamate (20.0 mM), oxalacetate (0.006 mM), and 2-oxoglutarate (0.16 mM). The antiserum against yeast aspartate aminotransferase did not form precipitin bands with homogeneous aspartate aminotransferases from pig heart cytosol, pig heart mitochondria or Escherichia coli B.

Amino Acids↗

PubMed1986

Selective proteolysis of cytosolic aspartate aminotransferase by a new microbial protease.

A protease from Streptomyces violaceochromogenes (Murao, S., Nishino, Y., & Maeda, Y. (1984) Agric. Biol. Chem. 48, 2163-2166) is known to inactivate pig heart aspartate aminotransferase [EC 2.6.1.1]. Chemical analysis of the core proteins and peptide fragments produced upon proteolysis of the aminotransferase revealed that peptide bond cleavage occurred specifically at Leu 20 with concomitant inactivation. Neither inactivation nor peptide bond cleavage was observed with the mitochondrial isoenzyme. The proteolytically produced derivative 21-412 of the cytosolic isoenzyme retained approximately 0.1% enzymic activity for transamination with natural dicarboxylic substrates. The pyridoxal form of the derivative 21-412 was fully converted by cysteinesulfinate or alanine to the pyridoxamine form and conversely the pyridoxamine form of the derivative was also fully converted by 2-oxoglutarate or pyruvate into the pyridoxal form, indicating that the derivative was still catalytically competent. However, the rates of reaction with dicarboxylic substrates were much reduced whereas the rates with monocarboxylic substrates remained at an order of magnitude similar to that observed with the native enzyme. Thus the NH2-terminal segment appears to be an import structural component which determines the substrate specificity of aspartate aminotransferase for dicarboxylic keto and amino acids. A substantial alteration in the molecular structure accompanying the loss of the NH2-terminal 20 residues was also reflected by the decrease in heat stability and in the lowering of the pKa value for His 68, which is involved in the intersubunit interaction of this dimeric enzyme.

Animals↗

PubMed1997

Stability of aspartate aminotransferase from Sulfolobus solfataricus.

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.

Amino Acid Sequence↗

PubMed1976

Large-scale purification and some properties of the mitochondrial aspartate aminotransferase from pig heart.

A method has been developed which allows isolation of 0.3--0.5 g of mitochondrial aspartate aminotransferase in five days starting from 10 pig hearts; the method does not involve initial preparation of mitochondria. Mitochondrial malate dehydrogenase and the cytoplasmic aspartate aminotransferase may conveniently be recovered from side fractions. The product mitochondrial aspartate aminotransferase is homogeneous as judged by various electrophoretic techniques and by N-terminal analysis. Crystals of the enzyme have been obtained both from concentrated, essentially salt-free, solutions and from solutions of ammonium sulphate. The amino acid composition, N and C-terminal amino acid sequences and subunit molecular weight have been determined; these characteristic properties are compared with those of the cytoplasmic isozyme from the same source.

Amino Acid Sequence↗

PubMed1989

Evidence that 31P NMR is a sensitive indicator of small conformational changes in the coenzyme of aspartate aminotransferase.

The pH dependence of 31P-NMR spectra of pig cytosolic aspartate aminotransferase, containing either N-(5'-phosphopyridoxyl)-L-aspartate or pyridoxal 5'-deoxymethylenephosphonate in place of the normal coenzyme pyridoxal 5'-phosphate, has been analysed. The chemical shifts of phosphopyridoxylaspartate and of pyridoxal 5'-deoxymethylenephosphonate model Schiff base in free solution show pK values of 6.3 and 7.4, attributable to the second deprotonation step of phosphate and phosphonate, respectively. However, these compounds behave very differently when bound to apoaspartate aminotransferase. 31P-NMR spectra of these enzyme derivatives indicate that the phosph(on)ate group remains dianionic throughout the pH range 4-8.5. A clear correlation between apparent pK values obtained from spectrophotometric titration of the coenzyme chromophore and those obtained by 31P NMR indicates that the same ionisation is being reported by both methods. The data are interpreted, on the basis of available crystallographic structures of chicken mitochondrial aspartate aminotransferase, to indicate that in each case the alteration in 31P chemical shift results from a conformational change in the coenzyme 5' side chain, in which one of the structures involves a near-eclipsed pair of bonds. Such a stressed conformation produces slight alterations in bond angles around the phosphorus atom, which in turn cause the observed change in 31P chemical shift. The evidence is taken to indicate that in this case 31P NMR is a sensitive reporter of stress in enzyme-bound pyridoxal 5'-phosphate and its derivatives.

Animals↗

PubMed1991

The open/closed conformational equilibrium of aspartate aminotransferase. Studies in the crystalline state and with a fluorescent probe in solution.

Aspartate aminotransferase undergoes major shifts in the conformational equilibrium of the protein matrix during transamination. The present study defines the two conformational states of the enzyme by crystallographic analysis, examines the conditions under which the enzyme crystallizes in each of these conformations, and correlates these conditions with the conformational behaviour of the enzyme in solution, as monitored by a fluorescent reporter group. Cocrystallization of chicken mitochondrial aspartate aminotransferase with inhibitors and covalent coenzymesubstrate adducts yields three different crystal forms. Unliganded enzyme forms triclinic crystals of the open conformation, the structure of which has been solved (space group P1) [Ford, G. C., Eichele, G. & Jansonius, J. N. (1980) Proc. Natl Acad. Sci. USA 77, 2559-2563; Kirsch, J. F., Eichele, G., Ford, G. C., Vincent, M. G., Jansonius, J. N., Gehring, H. & Christen, P. (1984) J. Mol. Biol. 174, 487-525]. Complexes of the enzyme with dicarboxylate ligands form monoclinic or orthorhombic crystals of the closed conformation. The results of structure determinations of the latter two crystal forms at 0.44 nm resolution are described here. In the closed conformation, the small domain has undergone a rigid-body rotation of 12-14 which closes the active-site pocket. Shifts in the conformational equilibrium of aspartate aminotransferase in solution, as induced by substrates, substrate analogues and specific dicarboxylic inhibitors, can be monitored by changes in the relative fluoresence yield of the enzyme labelled at Cys166 with monobromotrimethylammoniobimane. The pyridoxal and pyridoxamine forms of the labelled enzyme show the same fluorescence properties, whereas in the apoenzyme the fluorescence intensity is reduced by 30%. All active-site ligands, if added to the labelled pyridoxal enzyme at saturating concentrations, cause a decrease in the fluorescence intensity by 40-70% and a blue shift of maximally 5 nm. Comparison of the fluorescence properties of the enzyme in various functional states with the crystallographic data shows that both techniques probe the same conformational equilibrium. The conformational change that closes the active site seems to be ligand-induced in the reaction of the pyridoxal form of the enzyme and syncatalytic in the reverse reaction with the pyridoxamine enzyme.

Animals↗

PubMed1992

Mechanism of racemization of amino acids by aspartate aminotransferase.

Aspartate aminotransferase (mitochondrial isoenzyme from chicken) has been found to racemize very slowly dicarboxylic amino acid substrates in the presence of their cognate oxo acids [Kochhar, S. & Christen, P. (1988) Eur. J. Biochem. 175, 433-438]. Tyrosine, phenylalanine and alanine are racemized at the same rate although they undergo the transamination reaction 3-5 orders of magnitude more slowly than the dicarboxylic substrates. Similarly, the truncated enzyme aspartate aminotransferase-(27/32-410) catalyzes the racemization at the same rate as the native enzyme, while its rate of transamination is decreased to 3% of that of the native enzyme. Apparently, the rate-limiting step in racemization is not immediately linked to the transamination cycle. Decreasing the water concentration in the reaction medium by adding methanol at 0 degrees C drastically reduces the rate of racemization without affecting the rate of transamination. On the basis of these and additional kinetic data and the model of the three-dimensional structure of the active site, we conclude that a water molecule is responsible for the protonation of C alpha of the coenzyme-substrate intermediate from the wrong side. The diffusion of the water molecule into the interior of the enzyme appears to be the rate-limiting step in aspartate-aminotransferase-catalyzed racemization.

Amino Acids↗

PubMed1992

Characterization of tryptophan phosphorescence of aspartate aminotransferase from Escherichia coli.

The Trp phosphorescence spectrum, intensity and decay kinetics of apo-aspartate aminotransferase, pyridoxamine-5P-aspartate-aminotransferase and pyridoxal-5P-aspartate aminotransferase were measured over a temperature range 160-273 K. The fine structure of the phosphorescence spectra in low-temperature glasses, with 0-0 vibrational bands centered at 408, 415 and 417 nm, for both apoenzyme and pyridoxamine-5P-enzyme reveals a marked heterogeneity of the chromophore environments. Only for the pyridoxal-5P form of the enzyme is the triplet emission strongly quenched and, in this case, the spectrum displays a unique 0-0 vibrational band centered at 415 nm. Concomitant to quenching, there is Trp-sensitized delayed fluorescence of the Schiff base, an indication that quenching of the excited triplet state is due, at least in part, to a process of triplet singlet energy transfer to the ketoenamine tautomer. All three forms of the enzyme are phosphorescent for temperatures up to 273 K. However, across the glass transition temperature the pyridoxal-5P enzyme shows a decrease in lifetime-normalized phosphorescence intensity, a thermal quenching that reduces even further the number of phosphorescing residues at ambient temperature. In fluid solution, the triplet decay is nonexponential and multiple lifetimes stress the heterogeneity in dynamical structure of the chromophores' sites. For the pyridoxal-5P enzyme, where only one or at most two residues are phosphorescent at 273 K, the nonexponential nature of the decay implies the presence of different conformers of the protein not interconverting in the millisecond time scale.

Apoenzymes↗

PubMed1996

Crystal structures and solution studies of oxime adducts of mitochondrial aspartate aminotransferase.

The interaction of mitochondrial aspartate aminotransferase with hydroxylamine and five derivatives (in which the hydroxyl hydrogen is replaced by the side chain of naturally occurring amino acids) was investigated by X-ray diffraction as well as by kinetic and spectral measurements with the enzyme in solution. The inhibitors react with pyridoxal 5'-phosphate in the enzyme active site, both in solution and in the crystalline state, in a reversible single-step reaction forming spectrally distinct oxime adducts. Dissociation constants determined in solution range from 10(-8) M to 10(-6) M depending on the nature of the side-chain group. The crystal structures of the adducts of mitochondrial aspartate aminotransferase with the monocarboxylic analogue of L-aspartate in the open and closed enzyme conformation were determined at 0.23-nm and 0.25-nm resolution, respectively. This inhibitor binds to both the open and closed crystal forms of the enzyme without disturbing the crystalline order. Small differences in the conformation of the cofactor pyridoxal phosphate were detected between the omega-carboxylate of the inhibitor and Arg292 of the neighbouring subunit is mainly responsible for the attainment of near-coplanarity of the aldimine bond with the pyridine ring in the oxime adducts. Studies with a fluorescent probe aimed to detect shifts in the open/closed conformational equilibrium of the enzyme in oxime complexes showed that the hydroxylamine-derived inhibitors, even those containing a carboxylate group, do not induce the 'domain closure' in solution. This is probably due to the absence of the alpha-carboxylate group in the monocarboxylic hydroxylamine-derived inhibitors, emphasizing that both carboxylates of the substrates L-Asp and L-Glu are essential for stabilizing the closed form of aspartate aminotransferase.

Amino Acid Sequence↗

PubMed1998

Case report: Alanine aminotransferase deficiency detected in a patient with chronic hepatitis C.

We report a case of alanine aminotransferase (ALT) deficiency in a 68-year-old Japanese female with chronic hepatitis C. The serum was positive for antibody to hepatitis C virus (HCV) and HCV-RNA. Liver biopsy showed histological evidence of chronic active hepatitis. The level of serum aspartate aminotransferase (sAST) was elevated, but sALT was extremely low. The patient was followed up for her serum aminotransferase levels for 1.5 years under the treatment with ursodeoxycholic acid. The low sALT level persisted during all the follow-up period. The ALT activity in liver tissue was also decreased. Based on these findings, ALT deficiency was suspected. sALT activity was also found to be low in her two sons. This latter finding suggests the hereditary character of this abnormality.

Adult↗

PubMed2006

Effect of exercise and dietary modification on serum aminotransferase levels in patients with nonalcoholic steatohepatitis.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is commonly associated with overweight and insulin resistance. Aerobic exercise is known to reduce insulin resistance. We studied the effect of regular aerobic exercise on serum aminotransferase levels in patients with NASH. METHODS: Sixty-five (mean age 38.7+/-9.5 years; 46 [78%] males) out of 94 patients diagnosed with NASH participated in the study. Each patient was advised regular aerobic exercise for 30 min duration per day, and trained to achieve a heart rate of 60-70% of his/her maximal heart rate for at least 5 days a week. In addition, those with a high body mass index (BMI) were advised a moderately energy-restricted diet. Patients were followed up monthly for at least 3 months by BMI, waist-hip ratio (WHR), waist circumference (WC), aspartate aminotransferase (AST) and alanine aminotransferase (ALT). RESULTS: Forty-three (72.8%) patients had a high BMI. Central obesity (WHR >or=0.90 cm in men and >or=0.85 cm in women) was present in 58 (98.3%) patients and metabolic syndrome in 12 (20.3%) patients. In the 44 patients who complied regularly with the exercise program, serum ALT normalized in 20 (45%; P<0.05), and mean AST and ALT values declined from 70.5 and 104.0-41.5 (P<0.001) and 63.2 (P<0.001), respectively. Overweight patients lost a mean 3.1 kg (range 0-13 kg) weight and showed a decline in BMI (28.7 vs 27.5; P<0.001) and WC (99.4 cm vs 96.1 cm; P=0.001). Serum ALT did not normalize in any of the 15 patients who failed to comply with the exercise program; their pre- and post-AST (82.8 and 81.2, respectively) and ALT (98.0 and 96.1, respectively) levels, BMI (27.5 and 27.6, respectively) and WHR (0.99 cm and 0.99 cm, respectively) did not show any significant change at 3 months, and also for an extended mean follow-up period of 5.3 months. CONCLUSION: Moderate intensity aerobic exercise helps in normalizing ALT levels in patients with NASH.

Adult↗