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

---

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

Pigs which were deficient in vitamin E and/or selenium had the following parameters weekly determined from six to 13 weeks of age: Packed cell volume, hemoglobin concentration, red cell and white cell counts, red cell indices, reticulocyte count, serum iron, serum total iron binding capacity, myeloid: erythroid ratio, serum glutamic-oxaloacetic transaminase and creatine phosphokinase activities and body weight. Except for the myeloid:erythroid ratio and serum creatine phosphokinase activity, these parameters were not found to be significantly affected by either vitamin E deficiency, selenium deficiency or deficiency of both. The myeloid:erythroid ratio was increased (p less than 0.01) in association with selenium deficiency, which tends to indicate decreased erythropoiesis but was not reflected in the peripheral red cell picture. Evidence of dyserythropoiesis was not found to be a significant feature in serial bone marrow aspiration biopsies of vitamin E and/or selenium deficient pigs. Even if the serum glutamic-oxaloacetic transaminase activities were not found to be significantly affected by either vitamin E deficiency, selenium deficiency or deficiency in both as compared to replete animals, a few animals, especially in the group deficient in both vitamin E and selenium, presented quite marked transient increases of serum glutamic-oxaloacetic transaminase activity which was interpreted to reflect the occurrence of acute episodes of hepatosis dietetica. Serum creatine phosphokinase activities were found to be increased in association with vitamin E deficiency (p less than 0.01), selenium deficiency (less than 0.05) and the interaction was also significant (p less than 0.01). It was concluded that the serum creatine phosphokinase activity increases reflect the occurrence of subclinical muscular dystrophy and that vitamin E and selenium deficiencies have marked additive effects in the induction of skeletal muscular dystrophy.
...
PMID:Studies on vitamin E and selenium deficiency in young pigs. I. Hematological and biochemical changes. 83 88

The hepatic abnormalities that developed after the splenectomy in 10 subjects with idiopathic myelofibrosis were analyzed. In all patients in whom a liver biopsy was performed during the splenectomy, extramedullary hematopoiesis was demonstrated, consisting of dysmorphic megakaryocytes primarily localized in the sinusoids, often accompanied by erythroid precursors. Following splenectomy, a significant increase in both the liver size and serum levels of alkaline phosphatase, bilirubin or gamma-glutamyl transpeptidase was found within 6 months, whereas no such increase was observed in the serum aspartate transaminase and alanine transaminase concentrations. In addition, 2 patients developed acute liver failure leading to death at 3 and 4 weeks from splenectomy, respectively. In contrast with these findings, no hepatic alterations were observed in 10 chronic myeloid leukemia patients who were also submitted to splenectomy.
...
PMID:Liver dysfunction following splenectomy in idiopathic myelofibrosis: a study of 10 patients. 167 28

The author has performed in vivo investigations of the methotrexate (MTX) accumulation, kinetics and polyglutamate metabolism in erythrocytes, neutrophils and myeloid bone marrow cells during clinical MTX therapy of patients with acute lymphoblastic leukemia (ALL), non-Hodgkin lymphoma and psoriasis. On the basis of these studies the clinical applicability of monitoring erythrocyte MTX concentrations in children with ALL and adult psoriasis patients have been evaluated. To accomplish this task a set of methods has been developed: 1) An automated enzymatic assay adapted for a centrifugal analyzer was used to measure MTX concentrations between 10 and 60 nmol/l in erythrocytes and serum. 2) For the study of MTX kinetics in myeloid cells, age fractionated erythrocytes and HPLC fractionated methotrexate polyglutamates a sequential radioligand binding assay with a range of 1-8 (and 1-16) nmol/l was employed. 3) Discontinuous Percoll gradients of increasing densities were used to separate myeloid cells and erythrocytes of increasing mean cell age. Declining reticulocyte counts and erythrocyte-aspartate aminotransferase activity were taken as parameters of increasing mean erythrocyte age. 4) In order to study MTX polyglutamate metabolism a high performance liquid chromatography (HPLC) procedure was set up using tetrabutylammonium phosphate in acetonitrile in an automatically generated gradient buffer system. The MTX polyglutamates were separated, and the concentrations determined by the radioligand binding assay. The individual polyglutamates were identified by comparisons with the retention times of MTX polyglutamate standards (MTX-glu1+2+3+4+6+7) which were detected spectrophotometrically at 304 nm. During 24 hour infusions MTX was incorporated predominantly in the proliferating myeloid bone marrow cells before appearing in circulating neutrophils about seven days later. Evidence for MTX incorporation in the erythroid precursors of the bone marrow was provided by demonstrating high MTX content in density fractionated reticulocyte enriched erythrocyte populations. During weekly low dose MTX treatment the erythrocyte MTX concentration reached a constant level (steady state ery-MTX) after 4-6 weeks. MTX concentrations in age fractionated red blood cells and the terminal decline of the ery-MTX and its polyglutamate forms after cessation of MTX administration revealed that maintenance of the steady state ery-MTX depended on three conditions: 1) The amount of MTX added to the circulation via MTX containing reticulocytes. 2) The in vivo efflux of MTX from circulating erythrocytes, and 3) The loss of MTX with age dependent destruction of red blood cells. The in vivo efflux of MTX accounted for a loss of MTX which was 3-4 times greater than the amount that was lost with age dependent erythrocyte destruction.(ABSTRACT TRUNCATED AT 400 WORDS)
...
PMID:In vivo methotrexate kinetics and metabolism in human hematopoietic cells. Clinical significance of methotrexate concentrations in erythrocytes. 217 86

Clarified slurry oil (CSO), the heavy residual fraction from the fluidized catalytic cracker, was applied to the shaven backs of groups of 10 male and 10 female Sprague-Dawley rats 5 days/week for 13 weeks at doses of 8, 30, 125, or 500 mg/kg/day, and to another group for 2 weeks at doses of 2000 mg/kg/day. The rats were fitted with cardboard Elizabethan collars to minimize the ingestion of the test material, which was applied undiluted and remained uncovered on the skin. A similar group of rats served as controls; they were treated in the same manner except that no CSO was applied to their skin. There was a dose-related mortality and depression of body weight gain in the rats treated with CSO at doses of 30 mg/kg/day or greater; none of the rats dosed at 2000 mg/kg/day survived more than 2 weeks. The primary target organs of CSO toxicity were the liver, thymus, and bone marrow. The effects on the liver included increased weight (250% at 500 mg/kg/day), cholangiolitis, diffuse liver cell degeneration and hypertrophy, necrosis, fibrosis, decreased serum glucose, increased levels of alkaline phosphatase, aspartate aminotransferase, alanine amino transferase, bilirubin, and triglycerides. The thymus was found to be small and upon microscopic examination to be atrophic or hypoplastic. Erythroid hypoplasia was found in the bone marrow of some of the rats dosed at 30 mg/kg/day and increased in severity with increasing dose. The erythroid hypoplasia was accompanied by a dose-related anemia. Even in the rats dosed at 8 mg/kg/day, very slight abnormalities in the bile ducts were observed upon microscopic examination of the liver. Chromatographic separation and analyses demonstrated that CSO contains about 58% 3- to 5-ring polycyclic aromatic hydrocarbons (PAHs) and approximately 8-10% carbazole derivatives. In vitro and in vivo skin penetration studies demonstrated that the carbazole materials penetrate through the skin to a considerable extent (about 44%); less penetration was observed with 2- or 3-ring (8-13%) or 5-ring PAHs (3%).
...
PMID:Systemic toxicity from subchronic dermal exposure, chemical characterization, and dermal penetration of catalytically cracked clarified slurry oil. 359 Jan 98

Heme biosynthesis was examined in erythroid tissue of a 4-yr-old girl with severe sideroblastic anemia since infancy, as documented by the presence of intramitochondrial deposits of iron in erythroblasts. Free red cell protoporphyrin, urinary porphyrins, and activities of erythrocyte porphobilinogen synthase, uroporphyrinogen 1 synthase, aspartate aminotransferase, and pyridoxine kinase were normal or increased. Bone marrow ferrochelatase activity was normal. Activity of bone marrow delta-aminolaevulinate (ALA) synthase was markedly reduced to 7 pmole ALA/10(6) erythroblasts/30 min (normal 127 +/- 29) but was enhanced fivefold by pyridoxal phosphate (normal 0%--25% increase). Therapy with oral pyridoxine and parenteral pyridoxal-5'-phosphate did not increase effective red cell production. The sideroblastic anemia in this patient appears to be related to a congenital defect in the initial step of heme biosynthesis.
...
PMID:Bone marrow delta-aminolaevulinate synthase deficiency in a female with congenital sideroblastic anemia. 735 Sep 30

5-Aminolevulinate synthase (EC 2.3.1.37) catalyzes the first reaction in the heme biosynthetic pathway in nonplant eukaryotes and some prokaryotes. Homology sequence modeling between 5-aminolevulinate synthase and some other alpha-family pyridoxal 5'-phosphate-dependent enzymes indicated that the residue corresponding to the Arg-439 of murine erythroid 5-aminolevulinate synthase is a conserved residue in this family of pyridoxal 5'-phosphate-dependent enzymes. Further, this conserved arginine residue in several enzymes, e.g., aspartate aminotransferase, for which the three-dimensional structure is known, has been shown to interact with the substrate carboxyl group. To test whether Arg-439 is involved in substrate binding in murine erythroid 5-aminolevulinate synthase, Arg-439 and Arg-433 of murine erythroid 5-aminolevulinate synthase were each replaced by Lys and Leu using site-directed mutagenesis. The R439K mutant retained 77% of the wild-type activity; its K(m) values for both substrates increased 9-13-fold, while the activity of R433K increased 2-fold and the K(m) values for both substrates remained unchanged. R439L had no measurable activity as determined using a standard 5-aminolevulinate synthase enzyme-coupled activity assay. In contrast, the kinetic parameters for R433L were comparable to those of the wild-type. Dissociation constants (Kd) for glycine increased 5-fold for R439K and at least 30-fold for R439L, while Kd values for glycine for both R433K and R433L mutants were similar to those of the wild-type. However, there was not much difference in methylamine binding among the mutants and the wild-type, excepting of a 10-fold increase in K(d)methylamine for R439L. R439K proved much less thermostable than the wild-type enzyme, with the thermotransition temperature, T1/2, determined to be 8.3 degrees C lower than that of the wild-type enzyme. In addition, in vivo complementation analysis demonstrated that in the active site of murine erythroid 5-aminolevulinate synthase, R439 is contributed from the same subunit as K313 (which is involved in the Schiff base linkage of the pyridoxal 5'-phosphate cofactor) and D279 (which interacts electrostatically with the ring nitrogen of the cofactor), while another subunit provides R149. Taken together, these findings suggest that Arg-439 plays an important role in substrate binding of murine erythroid 5-aminolevulinate synthase.
...
PMID:Role of arginine 439 in substrate binding of 5-aminolevulinate synthase. 948 17

5-Aminolevulinate synthase (ALAS) catalyzes the first step in the heme biosynthetic pathway in nonplant eukaryotes and some prokaryotes, which is the condensation of glycine with succinyl-coenzyme A to yield coenzyme A, carbon dioxide, and 5-aminolevulinate. ALAS requires pyridoxal 5'-phosphate as an essential cofactor and functions as a homodimer. D279 in murine erythroid enzyme was found to be conserved in all aminolevulinate synthases and appeared to be homologous to D222 in aspartate aminotransferase, where the side chain of the residue stabilizes the protonated form of the cofactor ring nitrogen, thus enhancing the electron sink function of the cofactor during enzyme catalysis. D279A mutation in ALAS resulted in no detectable enzymatic activity under standard assay conditions, and the conservative D279E mutation reduced the catalytic efficiency for succinyl-CoA 30-fold. The D279A mutation resulted in a 19-fold increase in the dissociation constant for binding of the pyridoxal 5'-phosphate cofactor. UV-visible and CD spectroscopic analyses indicated that the D279A mutant binds the cofactor in a different mode at the active site. In contrast to the wild-type and D279E mutant, the D279A mutant failed to catalyze the formation of a quinonoid intermediate upon binding of 5-aminolevulinate. Importantly, this partial reaction could be rescued in D279A by reconstitution of the mutant with the cofactor analogue N-methyl-PLP. The steady-state kinetic isotope effect when deuteroglycine was substituted for glycine was small for the wild-type enzyme (kH/kD = 1.2 +/- 0.1), but a strong isotope effect was observed with the D279E mutant (kH/kD = 7.7 +/- 0.3). pH titration of the external aldimine formed with ALA indicated the D279E mutation increased the apparent pKa for quinonoid formation from 8.10 to 8.25. The results are consistent with the proposal that D279 plays a crucial role in aminolevulinate synthase catalysis by enhancing the electron sink function of the cofactor.
...
PMID:Aspartate-279 in aminolevulinate synthase affects enzyme catalysis through enhancing the function of the pyridoxal 5'-phosphate cofactor. 952 72

5-Aminolevulinate synthase (EC 2.3.1.37) is the first enzyme in the heme biosynthesis in nonplant eukaryotes and some prokaryotes. It functions as a homodimer and requires pyridoxal 5'-phosphate as an essential cofactor. Tyr-121 is a conserved residue in all known sequences of 5-aminolevulinate synthases. Further, it corresponds to Tyr-70 of Escherichia coli aspartate aminotransferase, which has been shown to interact with the cofactor and prevent the dissociation of the cofactor from the enzyme. To test whether Tyr-121 is involved in cofactor binding in murine erythroid 5-aminolevulinate synthase, Tyr-121 of murine erythroid 5-aminolevulinate synthase was substituted by Phe and His using site-directed mutagenesis. The Y121F mutant retained 36% of the wild-type activity and the Km value for substrate glycine increased 34-fold, while the activity of the Y121H mutant decreased to 5% of the wild-type activity and the Km value for glycine increased fivefold. The pKa1 values in the pH-activity profiles of the wild-type and mutant enzymes were 6.41, 6.54, and 6.65 for wild-type, Y121F, and Y121H, respectively. The UV-visible and CD spectra of Y121F and Y121H mutants were similar to those of the wild-type with the exception of an absorption maximum shift (420 --> 395 nm) for the Y121F mutant in the visible spectrum region, suggesting that the cofactor binds the Y121F mutant enzyme in a more unrestrained manner. Y121F and Y121H mutant enzymes also exhibited lower affinity than the wild-type for the cofactor, reflected in the Kd values for pyridoxal 5'-phosphate (26.5, 6.75, and 1.78 microM for Y121F, Y121H, and the wild-type, respectively). Further, Y121F and Y121H proved less thermostable than the wild type. Taken together, these findings indicate that Tyr-121 plays a critical role in cofactor binding of murine erythroid 5-aminolevulinate synthase.
...
PMID:The role of tyrosine 121 in cofactor binding of 5-aminolevulinate synthase. 960 26

A 51-year-old man presented with severe anemia, mild splenomegaly and elevated serum aspartate aminotransferase and serum alanine aminotransferase levels. The bone marrow findings were consistent with pure red cell aplasia (PRCA) with a 'maturation arrest' at the level of pronormoblast. The patient has been transfusion-dependent for 8 months. Following diagnosis of chronic active hepatitis due to hepatitis C virus (HCV), therapy with interferon-alpha was initiated. Two weeks later, the hemoglobin level stabilized, and he has not required any transfusion ever since. In spite of ongoing HCV viremia, cessation of interferon therapy, and deterioration of the liver function tests, the patient, followed for 2 years, maintains a high-normal hemoglobin level. To the best of our knowledge, this is the first report of prolonged PRCA corrected by interferon-alpha therapy, with or without an ongoing HCV infection. We speculate that the 'maturation arrest' of the erythroid lineage seen in the bone marrow was the result of an immune mechanism, possibly induced by the HCV, and that the elimination of this mechanism, rather than the elimination of the HCV, provided the opportunity for regeneration of erythropoiesis.
...
PMID:Pure red cell aplasia responsive to interferon-alpha in a patient with hepatitis C virus infection. 997 47

In the present study, the genotoxic, hematoxic effects, and their relation with pathological and biochemical parameters of hexane were investigated. Cytogenetic evaluation performed on the bone marrow indicated that chromosome aberrations increased at both hexane doses in relation to the negative controls. Decreased hematocrit, hemoglobin concentrations, and mean corpuscular volume were observed on the whole blood counts. Conjugated dienes (CD), glutathione (GSH), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and catalase (CAT) were increased. Histological examinations showed intracytoplasmic vacuolisation, nuclei with lower chromatin, and parenchymatous degenerations in the dose groups. In the bone marrow slides, depletion of the erythroid series were observed. In conclusion, hexane seems to be a genotoxic and hematoxic agent leading to degeneration and lipid peroxidation in exposed groups.
...
PMID:Genotoxic, hematoxic, pathological, and biochemical effects of hexane on Swiss albino rats. 1107 17


1 2 3 4 5 6 7 8 9 10 Next >>

---