Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.6.1.1 (aspartate aminotransferase)
21,665 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

L-Leucine and its nonmetabolized analogue, 2-aminobicyclo-[2,2,1]heptane-2-carboxylic acid (BCH) activate glutamate dehydrogenase in pancreatic islets, whether the reaction velocity is measured in the direction of glutamate synthesis or glutamate deamination. The rate of glutamate oxidative deamination is increased by ADP and inhibited by 2-ketoglutarate, NH4+ and GTP. The islet homogenate catalyzes the transamination between L-glutamate and either 2-ketoisocaproate or pyruvate, and between 2-ketoglutarate and L-leucine, L-aspartate, L-alanine, L-isoleucine, L-valine, L-norvaline or L-norleucine, but not b (+/-) BCH. The glutamate-aspartate transaminase is preferentially located in mitochondria relative to other transaminases. The parallel effects of L-leucine and BCH on glutamate dehydrogenase and their vastly different abilities to act as transamination partners may account for both analogies and discrepancies in the metabolic and functional responses of the islets to these two branched-chain amino acids.
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PMID:The stimulus-secretion coupling of amino acid-induced insulin release. XI. Kinetics of deamination and transamination reactions. 675 75

Normal serum concentrations of methionine, leucine, isoleucine and valine have been found in 10 anaesthetists using nitrous oxide under their regular working conditions without scavenging of patients' exhaled gas. Mean inhaled concentrations of nitrous oxide ranged from 150 to 400 p.p.m. The results indicate either that there was no significant inhibition of methionine synthase (attributable to oxidation of vitamin B12 by nitrous oxide) or that methionine concentrations were maintained by dietary intake or by the alternative betaine pathway of methylation of homocysteine. In either case, anaesthetists working under these conditions should not be at risk from reduced methionine concentrations. We also report normal serum activities of aspartate transaminase and gamma glutamyl transpeptidase.
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PMID:Serum methionine and hepatic enzyme activity in anaesthetists exposed to nitrous oxide. 708 22

Schiff base formation between pyridoxal 5'-phosphate and model compounds of increasing complexity (i.e. L-valine and poly-L-lysine) and between pyridoxal 5'-phosphate and the apoenzyme of aspartate aminotransferase has been analyzed by microcalorimetric methods. The apparent pKa values and protonation enthalpy values for the relevant groups ionizing in the pH 4-9 range have been determined for the Schiff bases of L-valine and of poly-L-lysine. Upon Schiff base formation, the only noticeable change is the lowering of the ring nitrogen pK, accompanied by an increase of the relative delta H. In the poly-L-lysine Schiff base, however, the delta H relative to the protonation of the phosphate dianion becomes more negative. This behavior suggests a multiple interaction between the polymer and the ligand. The intrinsic heat of formation is small (congruent to -1 kcal/mol), of the same order of magnitude for both Schiff bases, and appears to be independent of the nature of the aminic reagent. The heat of reaction of pyridoxal 5'-phosphate with aspartate apoaminotransferase has been determined in the pH 6.2-8.8 range at 19 degrees C and at 25 degrees C. Each isotherm is characterized by a lack of proton evolution, a result that is unexpected on the basis of the known pK values of the reagents, and by a sharp pH dependence of the enthalpy change. Moreover, comparison of the two isotherms allows: (a) detection of a protonation-dependent effect (pK 7.5 at 25 degrees C), (b) exclusion of a preferential binding of the coenzyme to the apoenzyme in a particular ionization state; and (c) suggestion of a tightening of the protein molecule upon holoenzyme formation.
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PMID:A calorimetric study of the interaction of pyridoxal 5'-phosphate with aspartate apoaminotransferase and model compounds. 708 61

Serum amino acid (AA) profiles are altered in epilepsy. It is not clear whether this is due to the disease process itself or to other variables such as seizure type, seizure frequency, duration of illness, medication, or altered liver function. We investigated serum AA profiles and liver enzymes in 73 epileptic patients and 90 healthy subjects and evaluated the data by analysis of variance to discriminate between age, sex, seizure type, duration of illness, seizure frequency, antiepileptic drug (AED) and increased serum liver enzyme levels, and their putative interaction with the serum AA profile. There was no correlation between the changes in the AA profile and age, duration of illness, seizure frequency, and seizure type. Seventy-two percent of the AED-treated patients and 33% of the unmedicated patients showed an increase in one or several serum liver enzymes [alanine aminotransferase (ALT), aspartate aminotransferase (AST), and/or gamma-glutamyl transferase (gamma-GT)]; particularly gamma-GT. We observed a significant increase in serum concentrations of glutamine and glycine and decreased levels of taurine, threonine, serine, valine, methionine, isoleucine, leucine, phenylalanine, histidine, tryptophan, and arginine in AED-treated patients but not in unmedicated patients. These results show that the changes in the serum AA profiles of epileptic patients treated with AEDs occur in patients with alteration of serum liver enzymes; whether this implies a causal relation is still uncertain.
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PMID:Serum amino acids, liver status, and antiepileptic drug therapy in epilepsy. 809 92

The azomethine (Schiff base) linkage between the epsilon-amino group of active-site lysine 258 and the carbonyl moiety of enzyme-bound pyridoxal 5'-phosphate (PLP) normally exhibits absorbance maxima at ca. 360 (high-pH form) or ca. 430 nm (low-pH form). However, the absorbance maximum is shifted from 358 to 386 nm, a value which is similar to that of free PLP (lambda max = 388 nm), in a mutant form of Escherichia coli aspartate aminotransferase (AATase) in which tyrosine 225, which normally donates a hydrogen bond to the phenolate function of PLP, has been replaced with phenylalanine (Y225F). This spectral shift suggested that PLP binds to Y225F as the free aldehyde. The following evidence from isotope-edited classical Raman spectroscopy proves conclusively that the near-UV spectrum is anomalous and that PLP is bound to Y225F as a Schiff base: (1) A strong cofactor peak at 1630 cm-1 in the holoenzyme-minus-apoenzyme difference spectrum of the unprotonated form of Y225F is red-shifted by 18 cm-1 in enzyme labeled with 15N at lysine 258 and other positions. (2) This isotope-induced red shift is similar to that observed in the unprotonated form of the model Schiff base, PLP-valine. (3) The Raman spectrum of Y225F is unchanged in H(2)18O, while peaks at ca. 1670 cm-1 in the spectrum of free PLP or in that of a mutant of AATase in which Lys-258 is replaced with Ala, are red-shifted by ca. 30 cm-1 in H(2)18O.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Structure of the complex between pyridoxal 5'-phosphate and the tyrosine 225 to phenylalanine mutant of Escherichia coli aspartate aminotransferase determined by isotope-edited classical Raman difference spectroscopy. 834 9

Gabapentin is a novel anticonvulsant drug. The anticonvulsant mechanism of gabapentin is not known. Based on the amino acid structure of gabapentin we explored its possible effects on glutamate and gamma-aminobutyric acid (GABA) metabolism in brain as they may relate to its anticonvulsant mechanisms of action. Gabapentin was tested for its effects on seven enzymes in the metabolic pathways of these two neurotransmitters: alanine aminotransferase (AL-T), aspartate aminotransferase (AS-T), GABA aminotransferase (GABA-T), branched-chain amino acid aminotransferase (BCAA-T), glutamine synthetase (Gln-S), glutaminase (GLNase), and glutamate dehydrogenase (GDH). In the presence of 10 mM gabapentin, only GABA-T, BCAA-T, and GDH activities were affected by this drug. Inhibition of GABA-T by gabapentin was weak (33%). The Ki values for inhibition of cytosolic and mitochondrial forms of GABA-T (17-20 mM) were much higher than the Km values for GABA (1.5-1.9 mM). It is, therefore, unlikely that inhibition of GABA-T by gabapentin is clinically relevant. As with leucine, gabapentin stimulated GDH activity. The GDH activity in rat brain synaptosomes was activated 6-fold and 3.4-fold, respectively, at saturating concentrations (10 mM) of leucine and gabapentin. The half-maximal stimulation by gabapentin was observed at approximately 1.5 mM. Gabapentin is not a substrate of BCAA-T, but it exhibited a potent competitive inhibition of both cytosolic and mitochondrial forms of brain BCAA-T. Inhibition of BCAA-T by this drug was reversible. The Ki values (0.8-1.4 mM) for inhibition of transamination by gabapentin were close to the apparent Km values for the branched-chain amino acids (BCAA) L-leucine, L-isoleucine, and L-valine (0.6-1.2 mM), suggesting that gabapentin may significantly reduce synthesis of glutamate from BCAA in brain by acting on BCAA-T.
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PMID:Effects of anticonvulsant drug gabapentin on the enzymes in metabolic pathways of glutamate and GABA. 856 62

The adiabatic compressibility (beta s) was determined, by means of the precise sound velocity and density measurements, for a series of single amino acid substituted mutant enzymes of Escherichia coli dihydrofolate reductase (DHFR) and aspartate aminotransferase (AspAT). Interestingly, the beta s values of both DHFR and AspAT were influenced markedly by the mutations at glycine-121 and valine-39, respectively, in which the magnitude of the change was proportional to the enzyme activity. This result demonstrates that the local change of the primary structure plays an important role in atomic packing and protein dynamics, which leads to the modified stability and enzymatic function. This is the first report on the compressibility of mutant proteins.
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PMID:A large compressibility change of protein induced by a single amino acid substitution. 886 93

Six naturally occurring but rare alleles of sn-glycerol-3-phosphate dehydrogenase (Gpdh) in Drosophila melanogaster have been investigated in this study. They all belong to a class of GpdhUF (ultra-fast) alleles, because their electrophoretic mobilities are faster than that of the GpdhF (fast) allele. The GpdhUF variants are widespread, and have been reported from five continents. DNA sequence analysis has shown that the change in electrophoretic mobility was in each allele caused by a single amino acid residue substitution in the encoded protein. In the XiamenUF allele it is a substitution of lysine (AAA) to asparagine (AAT) in exon 1 (residue 3). An asparagine (AAT) to aspartate (GAT) change was found in exon 6 (residue 336) in the IowaUF and NetherlandsUF alleles. The mobility of the RaleighUF allele was altered by a valine (GTG) to glutamate (GAG) substitution in exon 3 (residue 76). Two mutations were detected in the BrazzavilleUF allele: a lysine (AAG) to methionine (ATG) substitution in exon 2 (residue 68) is responsible for the ultra-fast phenotype of this variant, while a tyrosine (TAT) to phenylalanine (TTT) substitution in exon 4 (residue 244) is not expected to alter the electrophoretic mobility of the encoded protein. These results indicate that the GpdhUF alleles originate from different mutational events, and only two of them--IowaUF and NetherlandsUF--might share a common ancestry. The GPDH activity of the IowaUF allele is intermediate between those of the GpdhS and GpdhF control stocks. The other GpdhUF variants have lower activities than the controls: XiamenUF--83%, RaleighUF--80% and BrazzavilleUF--73% of the GpdhF control.
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PMID:Molecular structure of rare but geographically widespread sn-glycerol-3-phosphate dehydrogenase 'ultra-fast' electrophoretic alleles in Drosophila melanogaster. 890 Nov 36

The cDNA encoding the precursor polypeptide for schistostatins, allatostatin-like peptides which have been shown to inhibit peristaltic movements of the lateral oviducts of Schistocerca gregaria, has been cloned and sequenced. Translation of this sequence reveals the presence of a pre-proschistostatin consisting of 283 amino acids. It contains ten different peptide sequences which are flanked by dibasic cleavage sites and C-terminal amidation signals. Eight of these peptides were identical to the schistostatins (or Scg-ASTs) that were previously purified from Schistocerca gregaria brain extracts. Two novel peptide sequences were discovered. One of these is the first AST-like peptide which has a C-terminal valine residue. Two peptides contain within their sequence an internal dibasic site which suggests a possible role for alternative processing and/or degradation. The schistostatin precursor differs from cockroach pre-proallatostatins in size, in sequence and in organization. It contains a lower number of peptides (10 versus 13 or 14) which are interrupted only once by an acidic spacer region (versus four in Diploptera punctata and Periplaneta americana). Northern analysis showed the presence of a 2.4 kb mRNA band in the locust central nervous system and midgut. This indicates that schistostatins, like other ASTs, are a good example of insect brain/gut peptides.
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PMID:Molecular cloning of the precursor cDNA for schistostatins, locust allatostatin-like peptides with myoinhibiting properties. 890 49

The possibility that postmortem biochemical changes in blood might parallel drug redistribution and thus serve as markers was explored in a detailed case study. Eighteen blood and 14 tissue and fluid samples were taken at autopsy 16 h after the death of a 34-year-old female from amitriptyline overdose. Ranges of drug concentrations in blood were amitriptyline 1.8 to 20.2 micrograms/mL, nortriptyline 0.6 to 7.3 micrograms/mL, levels were lowest in femoral vein and highest in pulmonary vein blood. Corresponding levels of 17 amino acids showed markedly different patterns of site-to-site variability. There was a strong positive correlation between individual amino acid and drug concentrations in pulmonary blood samples (n = 5), particularly for glycine, leucine, methionine, serine, and valine. In blood samples from the great veins and right heart (n = 10), the correlation was less strong (r = 0.6 to 0.7). Methionine showed a strong positive correlation in pulmonary samples (r = 0.93), and negative correlation in great veing samples (r = -0.68). Lactic acid showed a strong negative correlation in pulmonary samples (r = -0.93) but a positive correlation in great vein samples (r = 0.71). Alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, gamma-glutamyl transferase, glucose, and bilirubin had a weak positive correlation with drug levels in great vein samples but not pulmonary samples. The results suggest that hepatic enzymes are relatively poor markers for postmortem hepatic drug shifts but that amino acids, particularly methionine, may be useful markers for pulmonary drug shifts.
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PMID:Possible markers for postmortem drug redistribution. 898 78


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