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PubMed2005

Amino acids and transaminases activity in ventricular CSF and in brain of normal and Alzheimer patients.

The present study was conducted to determine the concentration of amino acids in the cerebrospinal spinal fluid (CSF) and the activities of two tramsaminases: glutamic oxaloacetate transaminase (GOT) and glutamic pyruvate transaminase (GPT) in human Alzheimer disease (AD) and normal brain. L-glutamic acid, L-glutamine and L-alanine are the most abundant amino acids in the CSF (50-55% of total amino acids). L-glutamine occurs at much higher levels in Alzheimer CSF compared to the normal CSF (229+/-91.8 nmol/ml in AD versus 107+/-47.2 nmol/ml in normal; P=0.0041). In contrast, L-aspartate occurs at significantly lower concentrations in Alzheimer CSF than normal CSF (46.1+/-25.7 nmol/ml in Alzheimer versus 95.2+/-52.6 nmol/ml in normal; P=0.020). In Alzheimer brain (frontal, parietal and occipital cortices) GOT is present at significantly higher activities than in normal brain cortices (about 1.5 times higher; P<0.01). No significant differences for GPT activity occurred between normal and AD brain. Since CSF receives amino acids from brain tissues, and since GOT catalyzes the conversion of L-aspartate to L-glutamate, the higher concentrations of L-glutamine (which is derived from L-glutamate), and the lower concentrations of L-aspartate found in Alzheimer CSF could be considered as a consequence of the higher activity of GOT that occurs in Alzheimer brain.

Aged↗
PubMed1992

Inactivation of dimeric D-amino acid transaminase by a normal substrate through formation of an unproductive coenzyme adduct in one subunit.

D-amino acid transaminase, which contains pyridoxal 5'-phosphate (vitamin B6) as coenzyme, catalyzes the formation of D-alanine and D-glutamate from their corresponding alpha-keto acids; these D-amino acids are required for bacterial cell wall biosynthesis. Under conditions usually used for kinetic assay of enzyme activity, i.e., short incubation times with dilute enzyme concentrations, D-alanine behaves as one of the best substrates. However, the enzyme slowly loses activity over a period of hours when exposed to substrates, intermediates, and products at equilibrium. The rate of inactivation is dependent on enzyme concentration but independent of substrate concentration greater than Km values. Continuous removal of the product pyruvate by enzymic reduction precludes the establishment of equilibrium and prevents inactivation. The formation of small but detectable amounts of a quinonoid intermediate absorbing at 493 nm is proportional to inactivation. Studies with [14C]-D-alanine labeled on different carbon atoms indicate that the alpha-carboxyl group of the substrate is absent in the inactive enzyme; such decarboxylation is not a usual function of this enzyme. The inactive transaminase contains 1.1 mol of [14C]-D-alanine-derived adduct per mole of dimeric enzyme; this finding is consistent with the 50% reduction in the fluorescence intensity at 390 nm (due to the PMP form of the coenzyme) for the inactive enzyme. Thus, inactivation of one subunit of the dimeric enzyme renders the entire molecule inactive. Inactivation may occur when a coenzyme intermediate, perhaps the ketimine, is slowly decarboxylated and then undergoes a conformational change from its catalytically competent location.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine↗
PubMed1977

Mechanism of the irreversible inhibition of gamma-aminobutyric acid-alpha-ketoglutaric acid transaminase by the neutrotoxin gabaculine.

Gabaculine (5-amino-1,3-cyclohexadienylcarboxylic acid), a naturally occurring amino acid isolated from Streptomyces toyacaenis, is an irreversible inhibitor of bacterial pyridoxal phosphate linked gamma-aminobutyric acid-alpha-ketoglutaric acid transaminase with a t 1/2 (25 degrees C) of 9 min at 3 X 10(-7) M. Gabaculine is a substrate for gamma-aminobutyric acid transaminase. The measured KI is 2.86 X 10(-6) M, and the kcat for its turnover is 1.15 X 10(-2) S-1 at 25 degrees C. When gabaculine is transaminated by the enzyme, it is converted to a cyclohexatrienyl system with one exo double bond. Upon spontaneous aromatization, this high energy intermediate is transformed into a stable m-anthranilic acid derivative (m-carboxyphenylpyridoxamine phosphate), which results in the covalent and irreversible modification of the cofactor. This adduct is bound tightly to the active site of the enzyme and can be liberated under denaturing conditions.

4-Aminobutyrate Transaminase↗
PubMed1973

Aromatic amino acid transaminase in rat intestine.

The transamination of aromatic l-amino acids (5-hydroxytryptophan, tryptophan, tyrosine, phenylalanine and kynurenine) was shown to be catalysed by enzyme preparations from rat small intestine. On the basis of the partial purification and characterization of these aromatic amino acid transaminases, it is suggested that rat small intestine contains several kinds of aromatic amino acid transaminases.

5-Hydroxytryptophan↗
PubMed1977

Intramitochondrial localization of the 4-aminobutyrate-2-oxoglutarate transaminase from ox brain.

In order to determne the intramitochondrial location of 4-aminobutyrate transaminase, mitochondria were prepared from ox brain and freed from myelin and synaptosomes by using conventional density-gradient-centrifugation techniques, and the purity was checked electron-microscopically. Inner and outer membranes and matrix were prepared from the mitochondria by large-amplitude swelling and subsequent density-grient centrifugation. The fractions were characterized by using both electron microscopy and different marker enzymes. From the specific activity of the 4-aminobutyrate transaminase in the submitochondrial fractions it was concluded that this enzyme is associated with the innter mitochondrial membrane.

4-Aminobutyrate Transaminase↗
PubMed2000

Change in transaminases in hepatitis C virus- and HIV-coinfected patients after highly active antiretroviral therapy: differences between complete and partial virologic responders?

Patients with HIV and hepatitis C virus (HCV) coinfection have more severe hepatitis-related disease than do patients with HCV infection alone. Highly active antiretroviral therapy (HAART) with protease inhibitor appears to restore pathogen-specific immune responses, especially in patients with persistent undetectable HIV viral load. To evaluate the potent impact of immune restoration induced by HAART on the course of HCV-related disease, HCV viremia and levels of transaminases were compared between two groups of patients: 10 HIV/HCV-coinfected patients with persistently undetectable HIV viremia (group A) and 12 HIV/HCV-coinfected patients with persistent detectable HIV viremia. No difference was detected in HCV viral load in either group. An increase in transaminases was found only in patients with persistent undetectable HIV viral load, which was correlated with the increase in CD8+ T cells. This may suggest that the restoration of CD8+ T cell cytotoxicity could lead to an enhancement of hepatitis C-related disease in HCV/HIV-coinfected patients receiving HAART.

Adult↗
PubMedDate not supplied

Safety of high-dose naltrexone treatment: hepatic transaminase profiles among outpatients.

OBJECTIVES: This study was carried out to test the hypothesis that the hepatic safety profile of prolonged high-dose oral naltrexone (150 mg/d) is acceptable if over-the-counter analgesic use is restricted. METHODS: Data from 41 consecutive outpatients with impulse-control disorder receiving naltrexone therapy were analyzed. RESULTS: The mean treatment duration was 328 days and the mean naltrexone dose was 142 mg/d. Pretherapy/posttherapy mean aspartate transaminase and alanine transaminase levels in the naltrexone-alone group were 21.79/22.54 and 21.74/21.49 U, respectively (all within reference range). CONCLUSIONS: Although limited in scope, these findings support the hypothesis that long-term use of high-dose oral naltrexone is safe in otherwise healthy patients with impulse-control disorders who restrict their intake of acetaminophen, aspirin, or nonaspirin nonsteroidal anti-inflammatory drugs (NSAID). However, confirming studies are needed.

Adolescent↗
PubMed1982

The differential effects of GABA-transaminase inactivation in the chick retina and brain.

The inactivation of gamma-aminobutyrate (GABA)-transaminase by the highly specific and potent neurotoxin gabaculine leads to different neurochemical consequences in the chick brain as opposed to the chick retina. In the brain, GABA levels continually climb, reaching approximately eightfold increases over control values after 24 h. The elevation in GABA levels leads to a time-dependent and coincident fall in glutamate decarboxylase and cysteine-sulfinate decarboxylase activities, to approximately 50% of control values. On the other hand, in the retina GABA levels only increase to a plateau level two- to threefold that of control after inactivation of GABA-transaminase. Furthermore, although the glutamate decarboxylase activity decreases to about 50% of control values, cysteinesulfinate decarboxylase activity is not affected. These studies show that the processing of GABA in the retina differs from that in the brain, and that cysteinesulfinate and glutamate decarboxylase activity probably reside in different enzyme molecules in the retina, although they may reside in the same enzyme in the brain.

4-Aminobutyrate Transaminase↗
PubMed2001

Comparison of the omega-transaminases from different microorganisms and application to production of chiral amines.

Microorganisms that are capable of (S)-enantioselective transamination of chiral amines were isolated from soil samples by selective enrichment using (S)-alpha-methyl-benzylamine ((S)-alpha-MBA) as a sole nitrogen source. Among them, Klebsiella pneumoniae JS2F, Bacillus thuringiensis JS64, and Vibrio fluvialis JS17 showed good omega-transaminase (omega-TA) activities and the properties of the omega-TAs were investigated. The induction level of the enzyme was strongly dependent on the nitrogen source for the strains, except for V. fluvialis JS17. All the omega-TAs showed high enantioselectivity (E>50) toward (S)-alpha-MBA and broad amino donor specificities for arylic and aliphatic chiral amines. Besides pyruvate, aldehydes such as propionaldehyde and butyraldehyde showed good amino acceptor reactivities. All the omega-TAs showed substrate inhibition by (S)-alpha-MBA above 200 mm. Moreover, substrate inhibition by pyruvate above 10 mm was observed for omega-TA from V. fluvialis JS17. In the case of product inhibition, acetophenone showed much greater inhibitions than L-alanine for all omega-TAs. Comparison of the enzyme properties indicates that omega-transaminase from V. fluvialis JS17 is the best one for both kinetic resolution and asymmetric synthesis to produce enantiomerically pure chiral amines. Kinetic resolution of sec-butylamine (20 mM) was done under reduced pressure (150 Torr) to selectively remove an inhibitory product (2-butanone) using the enzyme from V. fluvialis JS17. Enantiomeric excess of (R)-sec-butylamine reached 94.7% after 12 h of reaction.

Amines↗
PubMed1990

Substitution of glutamine for lysine at the pyridoxal phosphate binding site of bacterial D-amino acid transaminase. Effects of exogenous amines on the slow formation of intermediates.

In bacterial D-amino acid transaminase, Lys-145, which binds the coenzyme pyridoxal 5'-phosphate in Schiff base linkage, was changed to Gln-145 by site-directed mutagenesis (K145Q). The mutant enzyme had 0.015% the activity of the wild-type enzyme and was capable of forming a Schiff base with D-alanine; this external aldimine was formed over a period of minutes depending upon the D-alanine concentration. The transformation of the pyridoxal-5'-phosphate form of the enzyme to the pyridoxamine-5'-phosphate form (i.e. the half-reaction of transamination) occurred over a period of hours with this mutant enzyme. Thus, information on these two steps in the reaction and on the factors that influence them can readily be obtained with this mutant enzyme. In contrast, these reactions with the wild-type enzyme occur at much faster rates and are not easily studied separately. The mutant enzyme shows distinct preference for D- over L-alanine as substrates but it does so about 50-fold less effectively than the wild-type enzyme. Thus, Lys-145 probably acts in concert with the coenzyme and other functional side chain(s) to lead to efficient and stereochemically precise transamination in the wild-type enzyme. The addition of exogenous amines, ethanolamine or methyl amine, increased the rate of external aldimine formation with D-alanine and the mutant enzyme but the subsequent transformation to the pyridoxamine-5'-phosphate form of the enzyme was unaffected by exogenous amines. The wild-type enzyme displayed a large negative trough in the circular dichroic spectrum at 420 nm, which was practically absent in the mutant enzyme. However, addition of D-alanine to the mutant enzyme generated this negative Cotton effect (due to formation of the external aldimine with D-alanine). This circular dichroism band gradually collapsed in parallel with the transformation to the pyridoxamine-5'-phosphate enzyme. Further studies on this mutant enzyme, which displays the characteristics of the wild-type enzyme but at attenuated rates, may yield information on the factors controlling the stereochemistry of the reaction as well as on the catalytic steps of the transaminase pathway.

Base Sequence↗
PubMed1979

Changes in primary afferent depolarization after administration of gamma-acetylenic gamma aminobutyric acid (GAG), a gamma-aminobutyric acid (GABA) transaminase inhibitor.

gamma-Acetylenic gamma-aminobutyric acid (GAG), an irreversible inhibitor of GABA transaminase, increased the concentration of GABA in feline spinal cords to 239% of the control value by 225 min after its injection. After administration of GAG to spinally transected cats, the height of the segmentally evoked dorsal root potential (DRP), which is generated at one point via a GABA synapse, was increased to more than twice the control value although the area increased only slightly. However, GAG had no effect on the segmental DRP in the decerebrate cat. In contrast, the DRP evoked in decerebrate cats by electrical stimulation of the brain stem, which is probably mediated by GABA, was decreased by administration of GAG. These effects of GAG were accompanied by the development of spontaneous primary afferent depolarizations which resembled spontaneous DRPs in both spinal and decerebrate cats. The temporal and size correlation between spontaneous DRPs occurring in different spinal roots indicate they are generated by an interneuronal pathway that is released by the action of GAG. The action of GAG on the segmental DRP in the spinal but not decerebrate preparation is also most easily explained by GAG-induced effects on interneuronal pathways. These data suggest GABA transaminase inhibition does not affect the axoaxonic GABA synapse mediating the DRP.

4-Aminobutyrate Transaminase↗
PubMed1978

[Cytospectrophotometric study of GABA-transaminase in the rat cerebellar cortex].

Modification of the histochemical method for detection of GABA-transaminase activity is suggested. Optimal concentrations of the substrates and cofactors are chosen on the basis of kinetic study of the enzymatic reaction in the cryostat sections of the rat cerebellar cortex by the quantitative microspectrophotometric method. The method is intended for the quantitative histochemical analysis of GABA-transaminase activity in the brain sections.

4-Aminobutyrate Transaminase↗
PubMed1982

Abnormal serum transaminase levels in patients with hemophilia A.

In a cooperative study of 1,332 hemophiliacs, the results of a variety of liver function tests were correlated with the intensity and type of exposure to plasma products. After three sets of measurements of six-month intervals, 72% of patients had at least one abnormal transaminase value and 21.1% and 23.6% of patients had persistently elevated SGOT and SGPT levels, respectively, on all three measurements. Patients who had received no factor VIII during the previous year had fewer abnormalities than treated patients. Only those treated patients who received less than 50 units of factor VIII per kilogram per six months had fewer transaminase abnormalities if they used cryoprecipitate than if they used concentrate, but these patient groups are not strictly comparable, in that the cryoprecipitate-treated group contained a higher proportion of patients with mild hemophilia than did the concentrate-treated group.

Alanine Transaminase↗
PubMed1984

Prolonged elevation of transaminase concentration in children with unsuspected myopathy.

Prolonged elevation of the serum transaminase concentration in an asymptomatic child is usually thought to be secondary to liver disease. Four children with unexplained persistent elevation of serum transaminase concentration were referred to a pediatric gastroenterologist for studies of liver disease. Subsequent evaluation disclosed abnormal muscle biopsy findings in all four patients. This experience suggests that an appropriate workup for occult myopathy is indicated in such patients before invasive diagnostic procedures for evaluation of liver disease are undertaken.

Adolescent↗
PubMed2002

Substrate inhibition mode of omega-transaminase from Vibrio fluvialis JS17 is dependent on the chirality of substrate.

Substrate inhibition is a common phenomenon in enzyme chemistry, which is observed only with a fast-reacting substrate enantiomer. We report here for the first time substrate inhibition of an enantioselective enzyme by both substrate enantiomers. The enantioselective substrate inhibition, i.e., different mode of inhibition by each substrate enantiomer, of (S)-specific omega-transaminase was found with various chiral amines. A kinetic model based on ping-pong bi-bi mechanism has been developed and kinetic parameters were measured. The kinetic model reveals that the inhibition by (R)-amine results from formation of Michaelis complex with enzyme-pyridoxal 5'-phosphate, whereas the inhibition by (S)-amine results from the formation of the complex with enzyme-pyridoxamine 5'-phosphate. Substrate inhibition constants (K(SI)) of each (S)-enantiomer of four chiral amines showed a linear correlation with those of cognate (R)-amines. Such a correlation was also found between the K(SI) values and Michaelis constants of (S)-amines. These correlations indicate that recognition mechanisms and active site structures of both enzyme-pyridoxal 5'-phosphate, enzyme-pyridoxamine 5'-phosphate are similar. Taken together with the results, high propensity for non-productive substrate binding strongly suggests that binding pockets of the omega-transaminase is loosely defined, which accounts for the enantioselective substrate inhibition.

Amines↗
PubMed2007

One-pot synthesis of amino-alcohols using a de-novo transketolase and beta-alanine: pyruvate transaminase pathway in Escherichia coli.

Biocatalysis continues to emerge as a powerful technique for the efficient synthesis of optically pure pharmaceuticals that are difficult to access via conventional chemistry. The power of biocatalysis can be enhanced if two or more reactions can be achieved by a single whole cell biocatalyst containing a pathway designed de-novo to facilitate a required synthetic sequence. The enzymes transketolase (TK) and transaminase (TAm) respectively catalyze asymmetric carbon--carbon bond formation and amine group addition to suitable substrate molecules. The ability of a transaminase to accept the product of the transketolase reaction can allow the two catalysts to be employed in series to create chiral amino-alcohols from achiral substrates. As proof of principle, the beta-alanine: pyruvate aminotransferase (beta-A:P TAm) from Pseudomonas aeruginosa has been cloned, to create plasmid pQR428, for overexpression in E.coli strain BL21gold(DE3). Production of the beta-A:P TAm alongside the native transketolase (overexpressed from plasmid pQR411), in a single E.coli host, has created a novel biocatalyst capable of the synthesis of chiral amino alcohols via a synthetic two-step pathway. The feasibility of using the biocatalyst has been demonstrated by the formation of a single diastereoisomer of 2-amino-1,3,4-butanetriol (ABT) product, in up to 21% mol/mol yield, by the beta-A:P TAm, via transamination of L-erythrulose synthesized by TK, from achiral substrates glycolaldehyde (GA) and beta-hydroxypyruvate (beta-HPA). ABT synthesis was achieved in a one-pot process, using either whole cells of the dual plasmid strain or cell lysate, while the dual alcohol-amine functionality of ABT makes it an excellent synthon for many pharmaceutical syntheses.

Amino Alcohols↗
PubMed2000

Prediction of liver allograft fibrosis after transplantation for hepatitis C virus: persistent elevation of serum transaminase levels versus necroinflammatory activity.

Recurrence of hepatitis C virus (HCV) after orthotopic liver transplantation (OLT) remains a significant source of morbidity and mortality. Factors that reliably predict allograft injury from HCV have not been identified. Demographics, clinical data, and histopathological characteristics of recipients with and without persistently elevated serum transaminase levels (PEST) were compared. Twenty-four patients with HCV-induced end-stage liver disease who underwent OLT between October 1995 and December 1998 were entered into a longitudinal, prospective evaluation for identification of parameters associated with graft injury. Liver biopsies were performed preoperatively and between posttransplantation days 1 to 28, 29 to 60, 61 to 180, 181 to 360, and then every 6 to 12 months thereafter. Biopsy specimens were reviewed in a blinded fashion and scored for rejection, necroinflammatory activity, extent of fibrosis, and infiltrating cell type, location, and magnitude. Transplant recipients with PEST (alanine transaminase level >1.5 times normal for 3 consecutive months) and cholestatic hepatitis showed an increased viral load compared with their own preoperative values (16-fold and 256-fold, respectively). Compared with control transplant recipients, PEST was associated with macrovesicular steatosis within 28 days after OLT (P <.05) and showed an increased rate of fibrosis (P <.003) despite similar degrees of rejection and necroinflammatory activity. There was no difference in demographics or immunosuppression. Macrovesicular steatosis may be the earliest predictor of graft fibrosis. Despite similar degrees of necroinflammatory activity, transplant recipients with PEST had an increased rate of fibrosis that could be predicted on average within 6 months posttransplantation.

Alanine Transaminase↗
PubMed1993

Transaminase reaction rates, transport activities and TCA cycle analysis by post-steady state 13C NMR.

In this work, we present the post-steady state analysis of the TCA cycle and a closed form solution to the rate of label washout from the C4 carbon of glutamic acid through the transaminases and the malate-aspartate shuttle and then through alpha-ketoglutarate dehydrogenase. We demonstrate using a model of this problem that the rate of label washout depends not only on the flux through alpha-ketoglutarate dehydrogenase, but most importantly on the activity of the malate-aspartate shuttle as determined by the forward and reverse fluxes through the transaminases and by the rate of transport of glutamate and alpha-ketoglutarate across the mitochondrial membrane.

Animals↗