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PubMed1995

Relationship of aminotransferases to liver histological status in chronic hepatitis C.

OBJECTIVES: Serum aminotransferase levels characteristically fluctuate in chronic hepatitis C, but their relationship to grade (i.e., inflammatory activity) and stage (i.e., degree of fibrosis) of liver disease is uncertain. We therefore correlated aminotransferase levels and liver biopsy findings in 90 patients with serologically confirmed chronic hepatitis C. METHODS: Mode of transmission; disease duration; symptoms and signs of liver disease; alcohol intake; autoantibody, HIV, and hepatitis B virus status; and liver biochemistries were obtained from records. Liver biopsies were 1) given a morphological diagnosis, 2) evaluated for features of chronic hepatitis C, and 3) scored with a histological activity index. RESULTS: Individual aminotransferase levels were not related to clinical or laboratory variables, nor were they reliably predictive of morphological diagnosis. No histological characteristics were associated with a particular range of aminotransferase values, except aminotransferases > 350 U/L, which were associated with piecemeal necrosis. Although mean values of aminotransferases were significantly lower among patients with chronic persistent hepatitis (CPH) (i.e., with minimal activity) compared with chronic active hepatitis (CAH) (mild to moderate activity) (ALT 110 U/L +/- 71 SD vs 256 +/- 211; AST 57 U/L +/- 34 vs 123 +/- 88) and in the absence of piecemeal necrosis compared with in its presence (ALT 133 +/- 84 vs 207 +/- 149; AST 73 +/- 47 vs 120 +/- 83), overlap of values was considerable between different histological groups. CONCLUSION: Aminotransferases do not predict liver histological status in chronic hepatitis C, although > or = 10-fold elevations suggest that piecemeal necrosis is present.

Adult↗

PubMed1998

[Macroaspartate aminotransferase. Study of 5 cases and review of the literature].

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.

Adult↗

PubMed1992

Immunocytochemical localization of kynurenine aminotransferase in the rat striatum: a light and electron microscopic study.

Kynurenine aminotransferase is the biosynthetic enzyme for kynurenic acid, an antagonist of excitatory amino acid receptors. Because of the possible role of kynurenic acid in basal ganglia diseases, the distribution of kynurenine aminotransferase immunoreactivity was examined in the adult rat striatum at the light and electron microscopic levels. Kynurenine aminotransferase immunoreactivity was detected in glial cells and in neurons. The preadsorption control vastly reduced or eliminated specific staining at both the light and electron microscopic levels. Kynurenine aminotransferase positive glial cells were abundant and contained a robust and homogeneous distribution of reaction product in both the nucleus and cytoplasm. The majority of neurons, both medium and large, were immunostained and exhibited granular kynurenine aminotransferase immunoreactivity in the cytoplasm of somata and proximal dendrites. At the ultrastructural level, kynurenine aminotransferase immunoreactive astrocytic processes were apparent throughout the neuropil where they often encircled capillaries and surrounded axospinous synapses. Reaction product was associated with the cytoplasmic matrix, filaments, rough endoplasmic reticulum, and the nucleus. In neurons, the majority of label occurred in round membrane-bound cytoplasmic organelles located adjacent to the Golgi apparatus, rough endoplasmic reticulum, and the cell or nuclear membranes. Cisternae and vesicles were identifiable in some of the labeled profiles. Polyribosomes and rough endoplasmic reticulum were also labeled. These data provide an anatomical basis for biochemical studies that have suggested the presence of striatal kynurenine aminotransferase in both astrocytes and neurons.

Animals↗

PubMed2005

Chronological development of elevated aminotransferases in a nonalcoholic population.

The incidence and risk factors of nonalcoholic fatty liver disease (NAFLD) have never been prospectively determined. To determine the frequency and risk factors of NAFLD and chronological ordering between NAFLD, weight gain, and features of insulin resistance, a historical cohort study was conducted in a Japanese workplace. A cohort free of previous liver injury, alcohol consumption of more than 140 g/wk, and hepatitis B or C infection (529 of 1537 subjects), and a subcohort of 287 subjects free of insulin resistance-related features were identified. Elevated aminotransferases in nonalcoholics were used as a surrogate for NAFLD. High aminotransferases together with weight gain of more than 2 kg and insulin resistance-related features in the subcohort were sought for up to 5 years. The incidence of high aminotransferases was 31 per 1000 person-years (71 events). A significant interaction occurred between age and sex in the development of high aminotransferases. In subjects younger than age 40 years, male sex (hazard ratio [HR]: 4.6), elevated body mass index (HR: 2.1), hypertension (HR: 2.6), and low high-density lipoprotein cholesterol (HR: 2.8) increased the risk of high aminotransferases, whereas age (HR: 0.6 for each 5 years) decreased the risk. In subjects older than age 40 years, glucose intolerance (HR: 5.3) was the only significant risk factor. In the subcohort, weight gain preceded high aminotransferases and other insulin resistance-related features, which appeared sequentially in order of low high-density lipoprotein cholesterol, hypertriglyceridemia/hypertransaminasemia/hypertension, and glucose intolerance. In conclusion, this cohort study clearly showed chronological ordering and an association between development of elevated aminotransferases and risk factors of NAFLD.

Adult↗

PubMed1996

Cloning and expression of a rat kidney cytosolic glutamine transaminase K that has strong sequence homology to kynurenine pyruvate aminotransferase.

An alpha-keto acid-dependent cysteine S-conjugate beta-lyase of rat kidney was identified as cytosolic glutamine transaminase K by Stevens et al. (J. Biol. Chem. 261, 15529-15537, 1986). Subsequently, a rat kidney protein with both glutamine transaminase K- and cysteine S-conjugate beta-lyase activities was cloned and sequenced by Perry et al. (Mol. Pharmacol. 43, 660-665, 1993). This protein was later shown to be identical with kynurenine pyruvate aminotransferase (Mosca et al., FEBS Lett. 353, 21-24, 1994). Thus, kynurenine pyruvate aminotransferase possesses both glutamine transaminase K- and cysteine S-conjugate beta-lyase-type activities. We have also cloned a cytosolic glutamine transaminase K from a rat kidney cDNA library and expressed the full-length clone in COS1 cells. The transfected cells exhibit marked increases in activities of both glutamine transaminase K and cysteine S-conjugate beta-lyase. The enzyme cloned in the present work is a homodimer. Each subunit has a molecular mass of 45.8 kDa and contains 426 amino acid residues. The sequence of cytosolic glutamine transaminase K obtained in the present work has strong similarities to other aminotransferases, including >90% identity with kynurenine pyruvate aminotransferase. Our preparation of purified rat kidney cytosolic glutamine transaminase K possesses some kynurenine pyruvate aminotransferase activity. Thus, rat kidney cytosol possesses at least two distinct enzymes that catalyze glutamine transaminase K/cysteine S-conjugate beta-lyase/kynurenine pyruvate aminotransferase reactions. The present work underscores the difficulties associated with characterizing aminotransferases with overlapping specificities.

Amino Acid Sequence↗

PubMed2001

Analysis of conformationally restricted alpha-ketoglutarate analogues as substrates of dehydrogenases and aminotransferases.

Five synthetic, conformationally restricted alpha-ketoglutarate analogues were tested as substrates of a variety of dehydrogenases and aminotransferases. The compounds were found not to be detectable substrates of glutamate dehydrogenase, L-leucine dehydrogenase, L-phenylalanine dehydrogenase, lactate dehydrogenase, malate dehydrogenase, glutamine transaminase K, aspartate aminotransferase, alanine aminotransferase, and alpha-ketoglutarate dehydrogenase complex. However, two thermostable aminotransferases were identified that catalyze transamination between several L-amino acids (e.g., phenylalanine, glutamate) and the alpha-ketoglutarate analogues of interest. Transamination between L-glutamate (or L-phenylalanine) and the alpha-ketoglutarate analogues was found to be 0.13 to 1.08 micromol/h/mg at 45 degrees C. The products resulting from transamination between L-phenylalanine and the alpha-ketoglutarate analogues were separated by reverse-phase HPLC, and the newly formed amino acid analogues were analyzed by LC-MS in an ion selective mode. In each case, the ions obtained were consistent with the expected product and a representative example is provided. The possibility existed that although the alpha-ketoglutarate analogues are not substrates of the dehydrogenases and most of the aminotransferases investigated, they might be good inhibitors. Weak inhibition of aminotransferases and glutamate dehydrogenase was found with some of the alpha-ketoglutarate analogues. The newly available thermostable aminotransferases may have general utility in the synthesis of bulky L-amino acids from the corresponding alpha-keto acids.

Animals↗

PubMed1994

Hepatitis B surface antigen, hepatitis C virus antibody, body mass index, and alcohol drinking among workers with elevated serum alanine aminotransferase.

METHODS: We conducted a case-control study on liver diseases among Japanese workers to examine associations between elevated serum alanine aminotransferase (alanine aminotransferase value > or = 50 IU/liter) and selected factors such as hepatitis B surface antigen positive, hepatitis C virus antibody positive, body mass index, and alcohol drinking. Out of 3,738 workers (1,477 males and 2,261 females) in a supermarket chain, 91 workers with an elevated serum alanine aminotransferase value (> or = 50 IU/liter) were classified as cases and 182 workers with normal serum alanine aminotransferase value and without an episode of blood transfusion were randomly selected as controls. RESULTS: Prevalence rates of hepatitis B surface antigen positive and hepatitis C virus antibody positive were 4.4 and 23.1% among the overall cases, 2.9 and 11.8% among the cases with 100 > alanine aminotransferase value > or = 50, and 8.7 and 56.5% among the cases with alanine aminotransferase value > or = 100. A logistic regression analysis was conducted. Odds ratios were 4.94 for hepatitis B surface antigen positive (P < 0.05) and 77.19 for hepatitis C virus antibody positive (P < 0.001). Odds ratios for body mass index increased with increasing body mass index values; 3.32 for 26 > body mass index > or = 24 (P < 0.01) and 5.03 for body mass index > or = 26 (P < 0.001). No increased risk was observed among regular drinkers of less than 27 g/day of ethanol (odds ratio is 0.23) or of 27-53 g/day of ethanol (odds ratio is 0.47). A slightly increased odds ratio of 1.35 was observed among regular drinkers of 54-81 g/day of ethanol, but this was not statistically significant. CONCLUSIONS: Our results suggest that hepatitis C virus and high body mass index are predominant factors in elevated serum alanine aminotransferase levels among Japanese workers, while alcohol drinking is a minor factor.

Adult↗

PubMed1985

Novel features of prephenate aminotransferase from cell cultures of Nicotiana silvestris.

A prephenate aminotransferase enzyme that produces L-arogenate was demonstrated in extracts from cultured-cell populations of Nicotiana silvestris. The enzyme was very active with low concentrations of prephenate, but required high concentrations of phenylpyruvate or 4-hydroxyphenylpyruvate to produce activity levels that were detectable. It is the most specific prephenate aminotransferase described to date from any source. Only L-glutamate and L-aspartate were effective amino-donor substrates. Prephenate concentrations greater than 1 mM produced substrate inhibition, an effect antagonized by increasing concentrations of L-glutamate cosubstrate. The enzyme was stable to storage for at least a month in the presence of pyridoxal 5'-phosphate, EDTA, and glycerol, and exhibited an unusually high temperature optimum of 70 degrees C. The identity of L-arogenate formed during catalysis was verified by high-performance liquid chromatography. DEAE-cellulose chromatography revealed two aromatic aminotransferase activities that were distinct from prephenate aminotransferase and which did not require the three protectants for stability. The aromatic aminotransferases were active with phenylpyruvate or 4-hydroxyphenylpyruvate as substrates, but not with prephenate. Both of the latter enzymes were similar in substrate specificity, and each exhibited a temperature optimum of 50 degrees C for catalysis. The primary in vivo function of the two aromatic aminotransferases is probably to transaminate between the aspartate/2-ketoglutarate and glutamate/oxaloacetate couples, since activities with the latter substrate combinations were an order of magnitude greater than with aromatic substrates. The demonstrated existence of a specific prephenate aminotransferase in N. silvestris meshes with other evidence supporting an important role for L-arogenate in tyrosine and phenylalanine biosynthesis in higher plants.

Chromatography, DEAE-Cellulose↗

PubMed1988

Protection of tyrosine aminotransferase against proteolytic digestion by nucleotide derivatives.

The abilities of several nucleotides to protect tyrosine aminotransferase (L-tyrosine: 2-oxoglutarate aminotransferase, EC 2.6.1.5) against proteolytic inactivation in vitro have been examined as part of an ongoing investigation of the role of cyclic GMP in the intracellular degradation of the hepatic enzyme. Although neither cyclic GMP nor cyclic AMP was found to exert such a protective effect, certain nucleotide analogs were observed to inhibit the inactivation of tyrosine aminotransferase by trypsin and chymotrypsin. The nucleotides which conferred the strongest protection were the dibutyryl derivatives of cyclic GMP and cyclic AMP. This phenomenon appears to require a purine nucleotide with hydrophobic substituent(s), while the cyclic phosphate is not essential. The nucleotides probably act by direct interaction with tyrosine aminotransferase as indicated by changes in kinetic properties and heat stability of the enzyme and by their failure to inhibit trypsin when other protein substrates, including another aminotransferase, were used. Dibutyryl cyclic AMP was shown to block the appearance of a characteristic 43 kDa tryptic cleavage product of tyrosine aminotransferase but not the conversion of the native 54 kDa form to a size of 50 kDa. Arguments are presented against the involvement of the protective effect in the actions of dibutyryl cyclic nucleotides on tyrosine aminotransferase in cells.

Animals↗

PubMed1983

Regulation of hepatic tyrosine aminotransferase in genetically obese rats.

The activities of hepatic tyrosine aminotransferase, tryptophan oxygenase and serine dehydratase were increased in obese rats shortly after weaning. Immunotitration experiments showed that the increase in tyrosine aminotransferase activity resulted from an increase in enzyme protein in obese rats. No increase in hepatic tyrosine aminotransferase was observed in suckling pre-obese rats. The post-weaning increase in hepatic tyrosine aminotransferase of obese rats was only observed during the light phase of the diurnal cycle, but was prevented by pair-feeding and by starvation. Tryptophan increased hepatic tyrosine aminotransferase of lean rats to obese levels but had no effect in obese rats until tyrosine aminotransferase levels were reduced by starvation or adrenalectomy. Adrenalectomy abolished the increase in hepatic tyrosine aminotransferase activity in obese rats although serum corticosterone was normal in these animals. Hepatic and brain tyrosine concentrations were decreased in obese rats but normalized after adrenalectomy. The results suggest that the corticosteroid-dependent increase in food and tryptophan intake may be the primary cause of the increased hepatic amino acid catabolism of obese rats.

Adrenalectomy↗

PubMed2006

Long-term outcome of HBV carriers with negative HBe antigen and normal aminotransferase.

PURPOSES: To elucidate the incidence of hepatitis activation and hepatocellular carcinogenesis in patients with negative HBe antigen and normal aminotransferase, long-term observation was performed in a retrospective cohort. METHODS: Among 116 consecutive patients with normal aminotransferase and negative HBe antigen at the time of liver biopsy, sequential frozen sera for initial 5 years were available for 95 patients. Hepatitis B virus (HBV) DNA assay (sensitivity >400 copy/mL) and aminotransferase were annually examined in the initial 5 years after biopsy. RESULTS: Liver biopsy showed minimal hepatitis (F0) in 9, F1 in 53, F2 in 21, F3 in 6, and F4 or cirrhosis in 6. Initial HBV DNA concentration was low (less than 10(4) copies/mL) in 33, intermediate (10(4)-10(6)) in 53, and high (10(6) or more) in 9. Hepatitis activation rates with twice as high as normal aminotransferase at the end of the third year were 12.1% in the low DNA group, 43.4% in the intermediate group, and 66.7% in the high DNA group. Initial HBV DNA values were significantly associated with future increase in aminotransferase (P <.0001). Initial DNA, history of aminotransferase elevation, and histological staging independently affected future hepatitis activation. Carcinogenesis rate in patients with and without high DNA of 10(6) copies/mL during the initial 3 years were 6.9% and 0%, respectively, at the end of the 5th year, and 11.5% and 1.8%, respectively, at the 10th year, (P=.021). CONCLUSION: Advanced stages of hepatitis were sometimes found in HBe antigen-negative, aminotransferase-normal HBV carriers. Serial HBV DNA assessment in early 3 years predicted future hepatitis activation and carcinogenesis.

Adult↗

PubMed2005

Joint effects of body weight and alcohol on elevated serum alanine aminotransferase in the United States population.

BACKGROUND & AIMS: Both alcohol and obesity are associated with hepatic steatosis. However, little is known about whether the toxicity of alcohol to the liver is influenced by adiposity. We examined the relationship of alcohol drinking and binge drinking with abnormal serum aminotransferase activity in normal weight, overweight, and obese persons in a national, population-based study. METHODS: Data were analyzed from 13,580 adult participants in the third US National Health and Nutrition Examination Survey, 1988-1994, after excluding participants with hepatitis B or C or iron overload. Abnormal aminotransferase levels were defined by using sex-specific cutoffs for ALT and AST. Analyses were adjusted for other liver injury risk factors. RESULTS: The prevalence of abnormal aminotransferase activity was elevated with consumption of >2 drinks per day or with overweight and obesity. In multivariate analysis, there was no association of alcohol intake with a higher prevalence of elevated aminotransferase levels among normal weight persons. In contrast, among overweight persons, consumption of >2 drinks per day increased the risk of elevated aminotransferase levels, and among the obese, > or = 1 drink per day was associated with a higher risk. Results were similar with elevated ALT alone as the outcome. With elevated AST alone as the outcome, intake of >2 drinks per day increased the risk, even among normal weight persons. Binge drinking was associated with aminotransferase elevation among obese consumers of 1-2 drinks per day. CONCLUSIONS: In this large, national, population-based study, overweight and obesity increased the risk of alcohol-related abnormal aminotransferase activity.

Adult↗

PubMed1972

Inactivation of tyrosine aminotransferase in neutral homogenates and rat liver slices.

Inactivation of tyrosine aminotransferase induced in vivo by triamcinolone was studied in a homogenate incubated at neutral pH values. The integrity and the presence of subcellular particles together with a compartment of acidic pH are necessary for inactivation of tyrosine aminotransferase. It is suggested that tyrosine aminotransferase is inactivated inside lysosomes. The system responsible for inactivation of tyrosine aminotransferase was partially purified and identified with lysosomal cathepsins B and B(1). Inactivation of tyrosine aminotransferase in liver slices is controlled by the amino acid concentration and strongly stimulated by cysteine. 3,3',5-Tri-iodo-l-thyronine reversibly and strongly decreases the rate of inactivation of tyrosine aminotransferase. The effect is not due to an increased rate of tyrosine aminotransferase synthesis.

Adenosine Triphosphate↗

PubMed2006

Molecular cloning, expression and characterization of pyridoxamine-pyruvate aminotransferase.

Pyridoxamine-pyruvate aminotransferase is a PLP (pyridoxal 5'-phosphate) (a coenzyme form of vitamin B6)-independent aminotransferase which catalyses a reversible transamination reaction between pyridoxamine and pyruvate to form pyridoxal and L-alanine. The gene encoding the enzyme has been identified, cloned and overexpressed for the first time. The mlr6806 gene on the chromosome of a symbiotic nitrogen-fixing bacterium, Mesorhizobium loti, encoded the enzyme, which consists of 393 amino acid residues. The primary sequence was identical with those of archaeal aspartate aminotransferase and rat serine-pyruvate aminotransferase, which are PLP-dependent aminotransferases. The results of fold-type analysis and the consensus amino acid residues found around the active-site lysine residue identified in the present study showed that the enzyme could be classified into class V aminotransferases of fold type I or the AT IV subfamily of the alpha family of the PLP-dependent enzymes. Analyses of the absorption and CD spectra of the wild-type and point-mutated enzymes showed that Lys197 was essential for the enzyme activity, and was the active-site lysine residue that corresponded to that found in the PLP-dependent aminotransferases, as had been suggested previously [Hodsdon, Kolb, Snell and Cole (1978) Biochem. J. 169, 429-432]. The K(d) value for pyridoxal determined by means of CD was 100-fold lower than the K(m) value for it, suggesting that Schiff base formation between pyridoxal and the active-site lysine residue is partially rate determining in the catalysis of pyridoxal. The active-site structure and evolutionary aspects of the enzyme are discussed.

Alphaproteobacteria↗

PubMed1988

The induction, desensitization and de-induction of tyrosine aminotransferase by 8-bromo-cyclic AMP in rat hepatoma cells.

Addition of 1-3 mM-8-bromo-cyclic AMP to monolayer cultures of H-4 rat hepatoma cells resulted in a rapid but short-lived increase in tyrosine aminotransferase (EC 2.6.1.5) activity. The transient nature of this induction is due to desensitization to 8-bromo-cyclic AMP. Throughout this time course of induction and desensitization, removal of 8-bromo-cyclic AMP resulted in a rapid and significant decrease in tyrosine aminotransferase activity, a process referred to as 'de-induction' in this study. We showed that the changes in tyrosine aminotransferase activity in its induction, desensitization and de-induction by 8-bromo-cyclic AMP were directly attributable to changes in the synthesis rate of the protein, and the amount of translatable and hybridizable mRNA encoding for tyrosine aminotransferase (mRNATAT). We further showed that this desensitization was specific to cyclic AMP. First, only active analogues of cyclic AMP and agents which increased cellular concentrations of cyclic AMP elicited this desensitization. Second, the desensitized cells were refractory only to the effects of 8-bromo-cyclic AMP; dexamethasone and insulin induced the tyrosine aminotransferase activity in the 8-bromo-cyclic AMP-desensitized cells in a manner similar to that of the controls. Studies on the metabolism of 8-bromo-cyclic AMP suggest that neither its degradation nor the accumulation of its primary metabolite, 8-bromoadenosine, played a significant role in modulating the expression of tyrosine aminotransferase during the time course of action of 8-bromo-cyclic AMP. These results provide evidence for a specific pretranslational mode of action of cyclic AMP in the control of tyrosine aminotransferase expression in its desensitization and de-induction, in addition to the early phase of induction.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1978

Evidence for acceleration of the rate of elongation of tyrosine aminotransferase nascent chains by dibutyryl cyclic AMP.

Analogs of cyclic AMP elevate the synthesis of tyrosine aminotransferase (L-tyrosine:2-oxoglutarate aminotransferase; EC 2.6.1.5) in cultured hepatoma cells and rat liver at a post-transcriptional level but have no discernible effect on total soluble protein synthesis. In order to determine whether cyclic AMP exerts its effect on a step before or after initiation of the synthesis of this enzyme, we have analyzed the ribosomal transit times for both the aminotransferase and total soluble protein in hepatoma cells incubated in the presence or absence of N(6),O(2)'-dibutyryl cyclic AMP. The time required for one ribosome to translate one subunit of the "average" soluble protein (transit time) was about 2 min in cells incubated with or without the cyclic AMP analog. In contrast, the transit time for tyrosine aminotransferase was found to be reduced from 5-8 min under basal conditions to as low as 45 sec after exposure to dibutyryl cyclic AMP. Although the degree of effect varied from experiment to experiment, the relative rate of aminotransferase nascent chain elongation was found to be proportional to the stimulation of its activity. In contrast, dexamethasone did not alter the rate of aminotransferase elongation even though it elevated enzyme activity between 5- and 10-fold. These data are consistent with the hypothesis that induction of tyrosine aminotransferase with cyclic AMP analogs occurs by stimulation of the rate at which ribosomes translate pre-existing mRNA in contrast to adrenal steroids which act by increasing the level of translatable mRNA coding for this enzyme.

Bucladesine↗

PubMed1993

Expression and processing of human ornithine-delta-aminotransferase in Saccharomyces cerevisiae.

Ornithine-delta-aminotransferase catalyzes the conversion of ornithine to glutamate-gamma-semialdehyde. In humans, deficiency of this mitochondrial matrix enzyme results in the progressive blinding disorder, gyrate atrophy of the choroid and retina. To explore yeast as an expression system, we introduced a cDNA encoding human ornithine-delta-aminotransferase into an ornithine aminotransferase-deficient strain of Saccharomyces cerevisiae. The human enzyme was expressed at high levels, with activity 20-fold greater than that of wild-type yeast and 10-fold higher than in human fibroblasts. Although the normal location of ornithine-delta-aminotransferase in S. cerevisiae is cytosolic, human ornithine-delta-aminotransferase expressed in S. cerevisiae was localized to the mitochondrial matrix with correct proteolytic processing of its mitochondrial leader sequence. Despite this anomalous location in yeast, human ornithine-delta-aminotransferase complemented the phenotype of the mutant strain, restoring its ability to utilize ornithine as a sole nitrogen source. We also expressed a vitamin B6-responsive missense allele of ornithine-delta-aminotransferase (V332M) and showed that the biochemical phenotype of this allele is easily demonstrated confirming the usefulness of this system for examining mutations causing gyrate atrophy.

Base Sequence↗

PubMed1988

Subcellular distribution of branched-chain aminotransferase activity in rat tissues.

The activity of branched-chain aminotransferase in mitochondria isolated from rat tissues was examined, and the mitochondrial contribution to total tissue branched-chain aminotransferase activity was calculated using the mitochondrial marker enzyme citrate synthase. Mitochondrial aminotransferase activity was highest in heart followed by skeletal muscle, kidney and brain. In heart muscle all of the aminotransferase activity was accounted for by the mitochondrial fraction. Activity was found to be mitochondrial in skeletal muscle with high red fiber content and also in kidney cortex. Activity was predominantly cytosolic in brain and muscles with high white fiber composition. Thus, the distribution of branched-chain aminotransferase activity in skeletal muscle was dependent on fiber type. No branched-chain aminotransferase activity was detected in liver mitochondria, and in liver tissue activity was too low to be relevant at physiological concentrations of branched-chain amino acids. Within a tissue, regardless of the subcellular distribution of aminotransferase activity, the relative rates of transamination with subsaturating or "saturating" concentrations of KIV or isoleucine were similar. Finally, amino acid preference was also similar within a tissue, but not necessarily between or among different tissues.

Animals↗