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At least 433 records · Page 24Linked to original sources
PubMed1986

4-aminobutyrate: 2-oxoglutarate transaminase-containing neurons in the perinuclear zone of the rat supraoptic nucleus.

A pharmaco-histochemical method for demonstrating the enzyme 4-aminobutyrate: 2-oxoglutarate transaminase was applied to the sections of the rat supraoptic nucleus region. The reactions of GABAergic interneurons and their relationship to neurosecretory neurons were studied. Medium-sized neurons heavily stained for transaminase were detected in the perinuclear zone just dorsal to the supraoptic nucleus. Neurons within the supraoptic nucleus were not stained. However, the perikarya of some neurosecretory neurons in the dorsal region of the supraoptic nucleus, as well as in discrete groups scattered throughout the nucleus; were surrounded by the granular reaction products. The results strongly suggest that these strongly positive neurons in the perinuclear zone send axons to the supraoptic nucleus, where they richly divide into many branches, which synapse on the perikarya of some vasopressin and oxytocin cells.

4-Aminobutyrate Transaminase↗
PubMed1998

Novel biosynthetic approaches to the production of unnatural amino acids using transaminases.

Transaminase enzymes are being increasingly applied to the large-scale synthesis of unnatural and nonproteinogenic amino acids. Typically displaying relaxed substrate specificity, rapid reaction rates and lacking the need for cofactor regeneration, they possess many characteristics that make them desirable as effective biocatalysts. By judiciously combining the transaminase reaction with additional enzymatic steps, this approach can be used very efficiently to prepare a broad range of D- and L-amino acids.

Amino Acids↗
PubMed2003

A comparison in the progression of liver fibrosis in chronic hepatitis C between persistently normal and elevated transaminase.

BACKGROUND: Detectable serum hepatitis C virus (HCV) RNA in HCV patients with persistently normal alanine transaminase (PNALT) has been found to be associated with significant liver damage. AIMS: The primary outcome of this study was to compare the histological progression of fibrosis in patients with PNALT and elevated alanine transaminase (ALT). METHODS: Forty patients with PNALT (Group 1) and 41 patients with elevated ALT (Group 2) were recruited into this study. Only patients with fibrosis of F0 to F2 were recruited into this study. RESULTS: The median time to second liver biopsies was 6.3 (range 2.0-11.1) years. Nine patients (22.5%) in Group 1 and 17 patients (41.5%) from Group 2 had progression of fibrosis. There was a trend towards a significantly higher cumulative probability of fibrosis progression in Group 2 (P=0.06). In patients with an initial F0 to F1 fibrosis, there was a significant difference in cumulative probability of fibrosis progression between Groups 1 and 2 (22.6% (7/31) vs. 43.3% (13/31), respectively, P=0.02). CONCLUSIONS: Anti-HCV patients with PNALT with an initial fibrosis of F0 or F1 were less likely to develop progression of fibrosis than those with elevated ALT, although patients with PNALT may have histologically and clinically progressive disease.

Adult↗
PubMed1980

Physiology of parasites: transaminases (GOT and GPT) in the root-knot nematode, Meloidogyne lucknowica Singh 1969, and effect of sex on its enzyme levels.

The glutamic-pyruvic transaminase (GPT) activity was found to be greater than the glutamicoxalacetic transaminase (GOT) activity in the mixed as well as in separate sexes of M. lucknowica. The sexual differences were 44.26% in GOT levels and 41.8% in GPT levels of the two sexes of the parasite, and the females showed higher enzymatic activity than their males.

Alanine Transaminase↗
PubMed2002

Effects of sodium fluoride on total serum protein levels and transaminase activity in rats.

Transaminase activity and serum total protein level were investigated in adult rats after oral treating with sodium fluoride at three doses, 10, 20 and 30 mg/kg daily for 90 days. After 90 days, the average total serum protein level of the rats in the treatment group decreased significantly compared with that in the control [1.9 +/- 0.1 (mean +/- S.D., n = 140) vs. 3.1 +/- 0.2] mg/dl, P< 0.05. Serum transaminase activity in the treatment group increased compared with that in the control [5.3 +/- 0.4 (mean +/- S.D., n = 140) vs. 3.2 +/- 0.3] micromol/min per ml, P < 0.05.

Animals↗
PubMed1995

L-alanine: 4,5-dioxovalerate transaminase in Leishmania donovani that differs from mammalian enzyme.

Leishmania protozoans are the causative agents of leishmaniasis, a major parasitic disease in humans. The parasites manifest a nutritional requirement for heme compounds since they are deficient in heme biosynthesis. In this study we have demonstrated for the first time the presence of the enzyme L-alanine: 4,5-dioxovalerate transaminase in Leishmania donovani. This enzyme catalyzes the synthesis of 5-aminolevulinic acid (ALA), the first committed step in heme synthesis. Thus the defect in heme biosynthesis pathway in Leishmania must lie at some enzymatic level subsequent to synthesis of ALA. The enzyme was found to be present in both virulent and avirulent strains of L. donovani. The virulent promastigotes showed a 41% higher specific activity as compared to the avirulent strain. The enzyme activity was found to be inhibited in the presence of heme and methylglyoxal. Immunoblot analysis revealed that L-alanine: 4,5-dioxovalerate transaminase in L. donovani was immunologically different from that in mammals.

Alanine↗
PubMed2000

Synthesis of a cationic pyridoxamine conjugation reagent and application to the mechanistic analysis of an artificial transaminase.

An N-methylated, cationic pyridoxamine conjugation reagent was synthesized and tethered via a disulfide bond to a cysteine residue inside the cavity of intestinal fatty acid binding protein. The conjugate was characterized and the kinetic parameters compared to its nonmethylated pyridoxamine analogue. Kinetic isotope effects were used for further mechanistic analysis. Taken together, these experiments suggest that a step distinct from deprotonation of the ketimine in the pyridoxamine to pyridoxal reaction is what limits the rate of the artificial transaminase IFABP-Px. However, the internal energetics of reactions catalyzed by the conjugate containing the N-methylated cofactor appear to be different suggesting that the MPx reagent will be useful in future experiments designed to alter the catalytic properties of semisynthetic transaminases.

Carrier Proteins↗
PubMed1998

Effects of metal ions on the rates and enantioselectivities of reactions catalyzed by a series of semisynthetic transaminases created by site directed mutagenesis.

Fatty acid binding proteins are a class of small 15 kDa proteins with a simple architecture that forms a large solvent sequestered cavity. In previous work, we demonstrated that reductive amination reactions could be performed in this cavity by covalent attachment of a pyridoxamine cofactor and that the rate, enantioselectivity and substrate specificity of these reactions could be altered by site directed mutagenesis. Herein, we show that the chemistry performed by these conjugates can be extended to include catalytic transamination and describe the effects of added metal ions on reaction rate and enantioselectivity. We conclude that metal ions can be used to increase the rate of reactions catalyzed by semisynthetic transaminases; however, the addition of metal ions can also retard the reaction rate. Furthermore, it appears that the presence of metal ions almost always results in an erosion of reaction enantioselectivity. This limits their utility as a practical means of increasing reaction rate. The results reported here, for four independent systems, should be considered in future designs of artificial transaminases.

Carrier Proteins↗
PubMed2001

Specific host-guest interactions in a protein-based artificial transaminase.

Artificial enzymes can be created by covalent attachment of a catalytic active group to a protein scaffold. Recently, we assembled an artificial transaminase by conjugation of intestinal fatty acid binding protein (IFABP) with a pyridoxamine derivative via a disulfide bond; the resulting construct catalyzed a transamination reaction 200-fold faster than free pyridoxamine. To identify the origin of this increased catalytic efficiency computer modeling was first used to identify two putative residues, Y14 and R126, that were in close proximity to the gamma-carboxylate group of the substrate, alpha-ketoglutartate. These positions were mutated to phenylalanine and methionine, respectively, and used to prepare semisynthetic transaminases by conjugation to pyridoxamine (Px) or an N-methylated derivative (MPx). Kinetic analysis of the resulting constructs showed that the R126M mutation reduced substrate affinity 3- to 6-fold while the additional Y14F mutation had a negligible effect. These results are consistent with a model for substrate recognition that involves an electrostatic interaction between the cationic guanidinium group of R126 and the anionic carboxylate from the substrate. Interestingly, one of the conjugates that contains an N-methylated pyridoxamine catalyzes a transamination reaction with a k(cat)' value of 1.1h(-1) which is the fastest value for k(cat) we have thus far obtained and is 34-fold greater than that for the free cofactor in the absence of the protein.

Amino Acid Substitution↗
PubMed1989

Effects of D-serine on bacterial D-amino acid transaminase: accumulation of an intermediate and inactivation of the enzyme.

Incubation of pure bacterial D-amino acid transaminase with D-serine or erythro-beta-hydroxy-DL-aspartic acid, which are relatively poor substrates, leads to generation of a new absorbance band at 493 nm that is probably the quinonoid intermediate. The 420-nm absorbance band (due to the pyridoxal phosphate coenzyme) decreases, and the 338-nm absorbance band (due to the pyridoxamine phosphate or some other form of the coenzyme) increases. A negative Cotton effect at 493 nm in the circular dichroism spectra is also generated. Closely related D amino acids do not lead to generation of this new absorption band, which has a half-life of the order of several hours. Treatment of the enzyme with the good substrate D-alanine leads to a small but detectable amount of the same absorbance band. D-Serine but not erythro-beta-hydroxyaspartate leads to inactivation of D-amino acid transaminase, and D-alanine affords partial protection. The results indicate that D-serine is a unique type of inhibitor in which the initial steps of the half-reaction of transamination are so slow that a quinonoid intermediate with a 493-nm absorption band accumulates. A derivative formed from this intermediate inactivates the enzyme.

Circular Dichroism↗
PubMed2002

Degradation pathway of the phosphonate ciliatine: crystal structure of 2-aminoethylphosphonate transaminase.

Phosphonates allow certain organisms to thrive in otherwise hostile environments, and 2-aminoethylphosphonate (AEP) is a precursor of many cellular phosphonates. AEP transaminase (AEPT) is an enzyme essential to phosphonate synthesis and degradation pathways. The crystal structure of AEP transaminase was determined by multiwavelength anomalous diffraction of 66 selenium atoms. The refined structure at 2.2 A resolution revealed an overall fold and active site location similar to those of the dimeric, two-domain structure of type I aminotransferases. The active site contains a cofactor, pyridoxal 5'-phosphate (PLP), and the product phosphonoacetaldehyde. Comparison with other type I aminotransferase structures shows that the PLP-protein interactions are conserved. Modeling of bound substrates and products reveals the structural basis for AEP recognition and the stereospecificity of proton elimination at the alpha-carbon and indicates conformational changes along the reaction pathway.

Aminoethylphosphonic Acid↗
PubMedDate not supplied

Visual electrophysiological effect of a GABA transaminase blocker.

Vigabatrin is an antiepileptic drug for the treatment of partial seizures. The anticonvulsant effect is achieved by irreversible inhibition of the enzyme GABA-transaminase which catalyses the inactivation of GABA. Vigabatrin has been associated with visual field loss and electrophysiological abnormalities. The purpose of the study was to determine any alterations in normal volunteers of the visual field and the visual electrophysiology resulting from a short exposure to vigabatrin. A three-way, double-blind study of placebo, carbamazepine and vigabatrin was undertaken at baseline and on days two, four and nine. Seven subjects completed all three cycles and 14 subjects (six females and eight males; mean age 27.3 years SD 6.7) completed at least one cycle. Static threshold automated perimetry comprised Humphrey Visual Field Analyzer Programs 30-2 and 30/60-2. Electro-oculography and electroretinograms were performed with undilated pupils using the Medelec Ganzfeld stimulator GS2000. The visual field was unaffected by placebo, carbamazepine or vigabatrin. The group mean amplitudes and latencies for the scotopic ERG, 30 Hz flicker ERG and the oscillatory potentials remained unchanged for any cycle. The group mean photopic ERG b-wave latency increased from baseline (p<0.05); no significant change occurred with carbamazepine or placebo. The group mean Arden Index for vigabatrin decreased from baseline to day 9 (p<0.01); no significant differences were present for carbamazepine or placebo. Vigabatrin has a rapid effect on both the photopic ERG and the EOG; however, the changes merely reflect alterations in retinal GABA levels secondary to concomitant blocking of GABA transaminase by existing vigabatrin therapy.

4-Aminobutyrate Transaminase↗
PubMed1999

GABA-transaminase antisense oligodeoxynucleotide modulates cocaine- and pentylenetetrazol-induced seizures in mice.

The mechanism of action of many anticonvulsive agents is to increase the function of the GABAergic system. Inhibition of GABA-Transaminase (GABA-T), the degradative enzyme for GABA, increases GABA levels in the brain. In this study, antisense oligodeoxynucleotides (ASO) targeted at the start codon region of GABA-Transaminase mRNA were used to modify seizure activity. Mice were treated, by intracerebroventricular injection, with antisense oligos or appropriate controls. At various times after treatment, the animals were challenged with cocaine (70 mg/kg, i.p.) and observed for seizure activity. At 15 hours after treatment, 1.152 and 1.44 nmol antisense oligo blocked cocaine-induced seizures. There was no effect of antisense oligo 8 or 36 hours after treatment. In addition, treatment with 7.2 nmol antisense oligo prevented pentylenetetrazol-induced seizures. These data demonstrate the modulation of seizure threshold using antisense oligodeoxynucleotides to GABA-T.

4-Aminobutyrate Transaminase↗
PubMed1997

Evidence for both in vivo and in vitro interaction between vigabatrin and alanine transaminase.

AIMS: Decreases in plasma alanine transaminase (ALA-T) activity of 20-100% have been reported following the use of vigabatrin (Sabril) in patients with uncontrolled epilepsy. This effect has a potential clinical significance as it may mask signs of early, underlying hepatic disease. It is particularly significant in a patient population known to have a higher than average risk of hepatotoxicity due to treatment with other anti-epilepsy drugs or to an independent, but concomitant, disease process. Vigabatrin is a highly specific enzyme antagonist. There is an almost 1000-fold difference between its activity against gamma-amino butyric acid aminotransaminase and ALA-T. However, some activity against other transaminases is not unexpected, and it, is important to determine the degree of vigabatrin's effect against ALA-T in man. METHODS: Two in vitro experiments, using serum samples spiked with vigabatrin, confirmed the presence of an interaction between vigabatrin and ALA-T, and formed the basis for the design of a study in five healthy male volunteers, in whom serum ALA-T activity was measured before and after a single dose of 1.5 g of vigabatrin. RESULTS: Serial sampling confirmed the presence of an in vivo interaction between vigabatrin and ALA-T, causing an inhibition of enzyme activity of 30-40%. A further 20% reduction was found in vitro in samples taken at the time of the peak plasma vigabatrin concentration after they had been stored for 6 h. CONCLUSIONS: The clinical significance of these findings is that the levels of ALA-T activity determined in patients receiving vigabatrin may be inaccurate. The "real' values must be assumed to be higher than those reported after routine testing. To obtain the most relistic measurement of ALA-T activity in patiets, samples should be taken at the times of trough plasma concentration and processed as soon as possible afterwards. Samples stored for any length of time at or above room temperature may also give even more false results.

Adult↗
PubMed1999

Transaminase elevation on placebo during phase I trials: prevalence and significance.

AIMS: To evaluate the prevalence of transaminase elevation on placebo during Phase I trials. METHODS: Retrospective review of pooled transaminase data collected on placebo during 13 Phase I trials in 93 healthy volunteers hospitalized for 14 days, with determination of the prevalence of abnormally high values. RESULTS: 20.4% of the 93 subjects showed at least one ALT value above the upper limit of the normal range (ULN), and 7.5% had at least one value twice ULN. CONCLUSIONS: Laboratory safety results of Phase I trials should be interpreted with caution, in the light of data on placebo, to avoid premature discontinuation of the development of safe drugs wrongly believed to be hepatotoxic.

Alanine Transaminase↗
PubMed2001

Pilot study of interferon-alpha and ribavirin treatment in patients with chronic hepatitis C and normal transaminase values.

Combination interferon-alpha (IFN-alpha) and ribavirin treatment has become standard therapy for patients with chronic hepatitis C and elevated transaminase levels (> 1.5 x upper limit of normal). No previous study has specifically examined the efficacy of this treatment in patients with normal transaminase values. In this pilot study, we treated 19 patients, with normal or near-normal ALT values on at least three occasions, and histologically mild disease, with induction IFN-alpha2b, 5 mega units daily for 4 weeks, then 3 mega units thrice weekly for 44 week, plus concomitant ribavirin 1000 mg or 1200 mg daily for 48 weeks. Nine of the 19 (47%) showed sustained virological response, defined as undetectable HCV-RNA at 24 weeks after the end of treatment. No ALT flares were observed in any patient. We conclude that combination induction IFN-alpha and ribavirin therapy may be effective in patients with normal-ALT, and appears not to induce flares of ALT activity. Controlled trials of this treatment in this subgroup of patients with hepatitis C are warranted.

Adolescent↗
PubMed1977

Disparity between insulin and proinsulin on stimulation of hepatic tyrosine transaminase.

The ability of insulin and proinsulin to stimulate tyrosine transaminase in dexamethasone-treated cultured rat liver cells was compared. Insulin increased this enzyme whereas proinsulin was seemingly without effect. Since proinsulin was not degraded by these cells, failure of stimulation of hepatic tyrosine transaminase could not be due to rapid destruction of the prohormone. This is the first demonstration of an action of insulin that cannot be duplicated by proinsulin.

Animals↗
PubMed1998

Kaikasaponin III and soyasaponin I, major triterpene saponins of Abrus cantoniensis, act on GOT and GPT: influence on transaminase elevation of rat liver cells concomitantly exposed to CCl4 for one hour.

The antihepatotoxic activities of soyasaponin I and kaikasaponin III, triterpenoidal saponins isolated from Abri Herba, the whole plant of Abrus cantoniensis, were studied on liver injury induced by CCl4 in primary cultured rat hepatocytes. The antihepatotoxic activities of these saponins and glycyrrhizin (positive control) were demonstrated by measuring the levels of glutamic pyruvic transaminase (GPT) and glutamic oxaloacetic transaminase (GOT). Soyasaponin I inhibited the elevation of GOT and GPT activities. The activities were comparable to those of glycyrrhizin. On the other hand, kaikasaponin III was more effective than soyasaponin I and glycyrrhizin. Kaikasaponin III showed the antihepatotoxic activity at less than 100 micrograms/ml. Furthermore, the highest activity was observed even in the lower doses (50, 100 micrograms/ml). However, soyasaponin I and kaikasaponin III showed some toxicity at the highest dose (500 micrograms/ml), though glycyrrhizin did not show toxicity at any dose.

Alanine Transaminase↗