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)

Both serine hydroxymethyltransferase and aspartate aminotransferase belong to the alpha-class of pyridoxal-5'-phosphate (pyridoxalP)-dependent enzymes but exhibit different reaction and substrate specificities. A comparison of the X-ray structure of these two enzymes reveals that their active sites are nearly superimposable. In an attempt to change the reaction specificity of serine hydroxymethyltransferase to a transaminase, His 230 was mutated to Tyr which is the equivalent residue in aspartate aminotransferase. Surprisingly, the H230Y mutant was found to catalyze oxidation of NADH in an enzyme concentration dependent manner instead of utilizing L-aspartate as a substrate. The NADH oxidation could be linked to oxygen consumption or reduction of nitrobluetetrazolium. The reaction was inhibited by radical scavengers like superoxide dismutase and D-mannitol. The Km and kcat values for the reaction of the enzyme with NADH were 74 microM and 5. 2 x 10-3 s-1, respectively. This oxidation was not observed with either the wild type serine hydroxymethyltransferase or H230A, H230F or H230N mutants. Thus, mutation of H230 of sheep liver serine hydroxymethyltransferase to Tyr leads to induction of an NADH oxidation activity implying that tyrosyl radicals may be mediating the reaction.
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PMID:A change in reaction specificity of sheep liver serine hydroxymethyltransferase. Induction of NADH oxidation upon mutation of His230 to Tyr. 1067 98

The 3-D structural information is a prerequisite for a rational ligand design. In the absence of experimental data, model building on the basis of a known 3-D structure of a homologous protein is at present the only reliable method to obtain structural information. A homology model building study of the pyridoxal 5'-phosphate (PLP)-dependent histidine decarboxylase from Morganella morganii (HDC-MM) has been carried out based on the crystal structure of the aspartate aminotransferase from Escherichia coli (AAT-EC). The primary sequences of AAT-EC and HDC-MM were aligned by automated alignment procedure. A 3-D model of HDC-MM was constructed by copying the coordinates of the residues from the crystal structure of AAT-EC into the corresponding residues in HDC-MM. After energy-minimization of the resulting 3-D model of HDC-MM, possible active site residues were identified by fitting the substrate (l-histidine) into the proposed active-site. In our model, several residues, which have an important role in the AAT-EC active-site, are located in positions spatially identical to those in AAT-EC structure. The back-bone of the modelled active site pocket is constructed by residues; Gly-92, Gly-93, Thr-93, Ser-115, Asp-200, Ala-202, Ser-229 and Lys-232 together with residues Asn-8, His-119, Thr-171, His-198, Leu-203, His-231, Ser-236 and Ile-238. In the ligand binding site, it appears that the HDC-MM model will position l-histidine (substrate) in the area consisting of the residues; Glu-29, Ser-30, Leu-38, His-231 and Lys-232. The nitrogen atom of the imidazole ring (N2) of the substrate is predicted to interact with the carboxylate group of Ser-30. The alpha-carboxylate of histidine points toward the Lys-232 to have electrostatic interaction with its side chain nitrogen atom (N(Z)). In conclusion, this combination of sequence and 3-D structural homology between AAT-EC and HDC-MM model could provide insight in assigning the probable active site residues.
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PMID:Homology-based molecular modelling of PLP-dependent histidine decarboxylase from Mmorganella morganii. 1090 9

20 year old man 2 years treated for the seropositive rheumatoid arthritis was admitted for fever accompanied with jaundice, anemia and leukopenia. The underlying disease has been compensated already for long period of time, before his admission only Prednisone (in the dose of 5 mg daily) and Methotrexate (15 mg once a week) was given. His physical examination of admission was without any significant abnormalities, out of the routine laboratory examination the value of leukocytes count was 2.1 x 10(9)/L, erythrocytes 3.7 x 10(12)/L, hemoglobin 95 g/l, hematocrit 0.29, platelets 156 x 10(9)/L. Since admission to hospital the hepatic enzymes ALT, AST, GMT, ALP were about ten times elevated comparing to normal values, the coagulation examination has shown the decrease of Quick test to 55%. With respect to the permanent leukopenia the bone marrow aspiration was taken with the finding of the increase number the RES elements (18.4%) with the signs of hemophagocytosis. The phagocytic reticulum absorbs blood elements erythrocytes, normoblasts, granulocytes, platelets. According to the literature experience we started the combination of the immunosuppressive treatment consisting of corticosteroids and Cyclosporine. Already the day following the application of the high dose of corticosteroids the fever subsided, icterus went away gradually with the normalization of the liver tests. After 20 days of hospitalisation the patient was discharged in good shape. Now, after 4 months the is stabilized on the follow-up treatment of Prednisone a Cyclosporine.
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PMID:[Secondary hemophagocytic syndrome in a systemic disease]. 1095 9

As an antidepressant, bupropion is considered to be a safe agent that usually causes infrequent and mild increase of serum liver enzymes. Asymptomatic elevation of serum transaminases was previously reported only in a single case. We describe a patient who developed typical acute hepatitis after receiving six weeks of bupropion for depression. His presentation was characterized with acute onset of symptoms associated with significantly elevated ALT, AST, and LDH and acute hepatic inflammation. The clinical course of our patient, including incubation period, pattern of liver enzyme elevation, and time of recovery, was similar to, but much more severe than, the case reported by Oslin and Duffy. Discontinuation of bupropion was followed by a rapid resolution of clinical symptoms and liver enzymes. The incidence of bupropion-induced hepatitis remains to be defined even though it appears to be relatively low. Since the clinical application of bupropion is broader, we must be aware of the clinical entity of bupropion-induced hepatitis.
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PMID:Acute hepatitis induced by bupropion. 1105 34

A 19-year-old man suffered hepatic dysfunction after 5 months of exposure to N,N-dimethylformamide (DMF) at his job in the synthetic resins industry. Laboratory data revealed elevated levels of AST (578 IU/l), ALT (1193 IU/l), and gamma-GTP (107 IU/l), no viral infection with HAV, HBV, or HCV, and no history or evidence of hepatic injury, although he did have a slight abdominal abnormality and swelling which was detected by palpation. His urinary N-methylformamide level, as a biological exposure index of DMF, was 42.8 mg/l, indicating 10-30 ppm of DMF exposure. After 2 months he was reinstated in two workplaces, the former where he worked in the morning and the other in the afternoon where environmental DMF concentrations were less than those in the former workplace. On the 18th day after his reinstatement, his liver function became exasperated again. After the second period of medication and one month of rest from work, he had fully recovered and was reinstated, but to a workshop without DMF exposure.
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PMID:Causal relationship between a case of severe hepatic dysfunction and low exposure concentrations of N,N-dimethylformamide in the synthetics industry. 1121 89

Aspartate aminotransferases have been cloned and expressed from Crithidia fasciculata, Trypanosoma brucei brucei, Giardia intestinalis, and Plasmodium falciparum and have been found to play a role in the final step of methionine regeneration from methylthioadenosine. All five enzymes contain sequence motifs consistent with membership in the Ia subfamily of aminotransferases; the crithidial and giardial enzymes and one trypanosomal enzyme were identified as cytoplasmic aspartate aminotransferases, and the second trypanosomal enzyme was identified as a mitochondrial aspartate aminotransferase. The plasmodial enzyme contained unique sequence substitutions and appears to be highly divergent from the existing members of the Ia subfamily. In addition, the P. falciparum enzyme is the first aminotransferase found to lack the invariant residue G197 (P. K. Mehta, T. I. Hale, and P. Christen, Eur. J. Biochem. 214:549-561, 1993), a feature shared by sequences discovered in P. vivax and P. berghei. All five enzymes were able to catalyze aspartate-ketoglutarate, tyrosine-ketoglutarate, and amino acid-ketomethiobutyrate aminotransfer reactions. In the latter, glutamate, phenylalanine, tyrosine, tryptophan, and histidine were all found to be effective amino donors. The crithidial and trypanosomal cytosolic aminotransferases were also able to catalyze alanine-ketoglutarate and glutamine-ketoglutarate aminotransfer reactions and, in common with the giardial aminotransferase, were able to catalyze the leucine-ketomethiobutyrate aminotransfer reaction. In all cases, the kinetic constants were broadly similar, with the exception of that of the plasmodial enzyme, which catalyzed the transamination of ketomethiobutyrate significantly more slowly than aspartate-ketoglutarate aminotransfer. This result obtained with the recombinant P. falciparum aminotransferase parallels the results seen for total ketomethiobutyrate transamination in malarial homogenates; activity in the latter was much lower than that in homogenates from other organisms. Total ketomethiobutyrate transamination in Trichomonas vaginalis and G. intestinalis homogenates was extensive and involved lysine-ketomethiobutyrate enzyme activity in addition to the aspartate aminotransferase activity. The methionine production in these two species could be inhibited by the amino-oxy compounds canaline and carboxymethoxylamine. Canaline was also found to be an uncompetitive inhibitor of the plasmodial aspartate aminotransferase, with a K(i) of 27 microm.
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PMID:Methionine regeneration and aspartate aminotransferase in parasitic protozoa. 1144 76

Hepatoblastoma usually occurs in children, but a few cases have also been reported in adults. We report the unusual case of hepatoblastoma in an 18-year-old adult with chronic hepatitis B. He visited a local hospital with right upper abdominal pain. Abdominal ultrasound showed a large mass in the right lobe of his liver. He was referred to our hospital and admitted for further examination. At admission, liver function tests gave slightly elevated results (aspartate aminotransferase (AST) 103 IU/l, alanine aminotransferase (ALT) 63 IU/l). A test for hepatitis virus revealed that he was a hepatitis B surface antigen (HBsAg) carrier and had experienced seroconversion. His alpha-fetoprotein (AFP) was elevated to 1 548 000 IU/ml. Abdominal ultrasound showed a 109 x 96 x 80-mm mass with mosaic pattern in the right lobe of the liver and right portal vein thrombus. Abdominal computed tomography (CT) demonstrated a large low-density mass occupying the right lobe, with some high-density parts that showed calcification. From these results, we diagnosed hepatoblastoma in a young adult. A right lobectomy was performed. Pathological examination showed a highly differentiated hepatoblastoma. Adjuvant chemotherapy was performed with cisplatin and pirarubicin. The patient has been well and free of recurrence for 12 months, and his AFP level remains almost normal.
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PMID:Successfully resected hepatoblastoma in a young adult with chronic hepatitis B: report of a case. 1150 68

Protein denaturation occurs at sites of inflammation. We hypothesized that denatured protein may provide a more susceptible target for glycation, which is a known mediator of inflammation. We examined the effects of thermal denaturation on the susceptibility of protein glycation using glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and aspartate aminotransferase (AAT) as our target proteins. GAPDH and AAT are ubiquitous proteins that exhibited very different thermal stabilities. Glycating agents, methylglyoxal (MG) and glyceraldehyde (Glyc), caused an increase in the formation of advanced glycation endproducts (AGEs) in native and denatured GAPDH and AAT. The effects of the glycating agents were more pronounced with the denatured proteins. In addition to nitroblue tetrazolium (NBT)- reactivity, our measured endpoints were absorbance (lambda = 365 nm) and fluorescence (lambda(ex) = 370 nm; lambda(em) = 470 nm) properties that are typically associated with protein glycation. We also looked at carnosine's ability to prevent glycation of native and denatured protein. Carnosine, an endogenous histidine dipeptide, exhibits anti-inflammatory activity presumably due to its anti-oxidant and anti-glycation properties. Carnosine prevented Glyc-induced AGE formation in both native and denatured AAT suggesting that carnosine's anti-inflammatory activity may be due in part to carnosine's ability to prevent glycation of denatured protein.
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PMID:Effects of thermal denaturation on protein glycation. 1200 23

The homology of subunit primary sequence of 40 glutamate decarboxylases (GAD) of different origin was analyzed by multiple alignment. A phylogenetic tree was designed on the basis of the resulting data. The following groups are distinguished in the consensus tree: archeans, bacteria, plant eukaryotes, and animal eukaryotes. The latter are clearly divided into two branches according to two enzyme isoforms. Borders of PLP domains in each enzyme were detected. The consensus phylogenetic tree for PLP domains is structurally rather similar to that obtained for subunits. Twenty homologous motifs of from 15 to 87 amino acid residues were revealed in all GAD studied. The results revealed the division of all of the enzymes into groups with characteristic sets of motifs in each and a fixed order of their arrangement along the sequence. Thus, we can show the divergent evolution of the enzyme. The results of multiple alignments during structural analysis of the 40 GAD confirmed and extended our previous data on conserved residues that arrange the position of the coenzyme (PLP) in the enzyme active center. The following residues should be noted: lysine forming a Schiff base with the PLP aldehyde group, an adjacent histidine, and aspartic acid that establishes a link with nitrogen of the PLP pyridine ring. The homology of the primary sequence fragments was also found in the residues in contact with the PLP phosphate group. Comparison of the GAD amino acid sequence with that of another PLP enzyme, aspartate aminotransferase, revealed a binding site for carboxylic group of the substrate--glutamic acid. The structures carrying out a particular catalytic function of all GAD studied were detected, i.e., convergent evolution of the enzyme was revealed.
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PMID:Glutamate decarboxylase: computer studies of enzyme evolution. 1246 Jan 16

The ybdL gene of Escherichia coli codes for a protein of unknown function. Sequence analysis showed moderate homology to several vitamin B(6) dependent enzymes, suggesting that it may bind pyridoxal-5'-phosphate. The structure analysis of YbdL to 2.35 A resolution by protein crystallography verifies that it is a PLP dependent enzyme of fold type I, the typical aspartate aminotransferase fold. The active site contains a bound pyridoxal-5'-phosphate, covalently attached to the conserved active site lysine residue Lys236. The pattern of conserved amino acids in the putative substrate binding pocket of the enzyme reveals that it is most closely related to a hyperthermophilic aromatic residue aminotransferase from the archeon Pyrococcus horikoshii. Activity tests with 10 amino acids as amino-donors reveal, however, a preference for Met, followed by His and Phe, results which can be rationalized by modelization studies.
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PMID:Crystal structure and reactivity of YbdL from Escherichia coli identify a methionine aminotransferase function. 1528 32


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