Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.5.1.4 (deaminase)
 5,113 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The characteristics of isoniazid amidase which hydrolyzes isoniazid to isonicotinic acid and hydrazine was examined in vitro using rat liver subcellular fractions. The activity of isoniazid amidase was estimated from the amount of hydrazine produced from a substrate, isoniazid, by means of GC-MS. High activity of the amidase was observed in the microsomal and lysosomal fractions, and at pH 7.4-7.8 in the microsomal fraction. The amidase was not inhibited by acetanilide, but by procaine and bis(p-nitrophenyl)phosphate. As expected, acetylisoniazid, a main metabolite of isoniazid, also inhibited the amidase. Not only the microsomal monooxygenase but also amidase was strongly induced by pretreatment with phenobarbital, 3-methylcholanthrene and rifampicin, respectively.
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PMID:Metabolic hydrolysis of isoniazid by subcellular fractions of rat liver. 649 51

In view of the 20- to 80-fold elevation of deoxycytidine-5'-phosphate (dCMP) deaminase in many human malignant tumors, we have utilized 5-fluorodeoxycytidine ( FdCyd ) coadministered with tetrahydrouridine ( H4Urd ) as a combination of antitumor agents against two murine solid tumors which possess high levels of dCMP deaminase. This approach is based on our past studies in which we demonstrated that FdCyd is an excellent substrate for mammalian 2'-deoxycytidine kinase, and that H4Urd increases the toxicity of FdCyd in the mouse. Cell culture studies utilizing 2'- deoxytetrahydrouridine which inhibits cytidine deaminase and as 2'- deoxytetrahydrouridine -5'-monophosphate inhibits dCMP deaminase, provide indirect evidence for the pathway that we had proposed in the past, 2'- Deoxytetrahydrouridine antagonized the toxicity of FdCyd to a greater extent than did H4Urd and showed marked antagonism in cytidine deaminase-deficient cells. Cell lines lacking both cytidine and 2'-deoxycytidine-5'-monophosphate deaminase were markedly resistant to FdCyd . Thymidine and deoxyuridine antagonized toxicity in a manner consistent with the proposed pathway of anabolism of FdCyd and consistent with its resulting in the inhibition of thymidylate synthetase. We have established the efficacy of FdCyd + H4Urd chemotherapy utilizing adenocarcinoma 755 and Lewis lung carcinoma in C57BL X DBA/2 F1 mice. An example of an optimum schedule versus Lewis lung carcinoma is FdCyd , 10 to 12 mg/kg, plus H4Urd , 25 mg/kg, coadministered simultaneously, once per day on Days 1 to 7 after tumor implantation. Tumor inhibitions on Days 12, 14, and 16 were 95, 90, and 80%, respectively, with 8% maximum weight loss. Comparative studies were undertaken only with Lewis lung carcinoma and it was established that FdCyd + H4Urd surpasses the efficacies of 5-fluorouracil and 5-fluorodeoxyuridine as well as FdCyd when administered without H4Urd . We propose that the administration of FdCyd with H4Urd can result in preferential, tumor-directed conversion of a nontoxic nucleoside analogue to a toxic antimetabolite by an enzyme that is markedly elevated in human tumor tissue. The analogues of deoxycytidine are resistant to catabolism and are anabolized by a different subset of enzymes than are 5-fluorouracil or 5-fluorodeoxyuridine; therefore, it is a novel approach. Not only are there intrinsic selectivity, metabolic stability, and the advantages that accrue from prodrug therapy in this strategy, but in addition, the potential for an exclusively DNA-directed effect exists. This is in contrast to approaches with 5-fluorouracil and 5-fluorodeoxyuridine, in which, in addition to DNA effects, parallel effe
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PMID:Use of 5-fluorodeoxycytidine and tetrahydrouridine to exploit high levels of deoxycytidylate deaminase in tumors to achieve DNA- and target-directed therapies. 653 64

The relationship between the hepatotoxicity and metabolism of isoniazid and its metabolites, acetylisoniazid and acetylhydrazine, has been investigated. Toxic doses of acetylisoniazid and acetylhydrazine, radiolabeled in the acetyl group, were found to bind covalently to liver protein in vivo. This binding was mediated by the microsomal enzyme system as indicated by the effects of pretreatments altering the activity of these enzymes. Metabolic studies revealed that the pretreatments increased the metabolism of the acetylhydrazine moiety of acetyl-labeled acetylisoniazid and of acetylhydrazine itself by the microsomal enzyme system. Pretreatment with the acyl amidase inhibitor, bis-p-nitrophenyl phosphate, inhibited the hydrolysis of acetylisoniazid to isonicotinic acid plus acetylhydrazine and concomitantly decreased the covalent binding of acetyl-labeled acetylisoniazid. The changes in the metabolism of isoniazid, acetylisoniazid and acetylhydrazine effected by various pretreatments paralleled changes in the severity of the hepatic necrosis caused by the compounds. These results strongly suggest that acetylhydrazine is the metabolite responsible for the hepatic necrosis caused by isoniazid and that mirosomal metabolism of acetylhydrazine in vivo leads to the production of a reactive acylating species capable of reacting covalently with tissue macromolecules.
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PMID:Isoniazid hepatoxicity: the relationship between covalent binding and metabolism in vivo. 676 40

1. Cytosol from pig skeletal muscle, but not heart, contains an inhibitor of AMP-deaminase (AMP-D, EC 3.5.4.6) which reduces AMP-D activity 8-fold. 2. Heart and skeletal muscle AMP-D have been purified to apparent homogeneity by cellulose phosphate and DEAE-Sephacel chromatography. 3. AMP-D from skeletal muscle is inhibited more severely than the heart enzyme by an increase in adenylate energy charge to levels exceeding 0.4. Nevertheless both enzymes seem to be regulated by the energy charge, which contrasts with reports for rabbit heart AMP-D.
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PMID:Regulation of porcine heart and skeletal muscle AMP-deaminase by adenylate energy charge. 685 80

Down-regulation ("curb") of hexose transport in Chinese hamster lung fibroblasts has been studied in a metabolic mutant highly defective in phosphoglucose isomerase (PGI; glucosephosphate isomerase; D-glucose-6-phosphate ketol-isomerase, EC 5.3.1.9). In the parental strain (PGI+) glucose as well as glucosamine and mannose were able to elicit a curb of the hexose transport system. In the PGI mutant, only glucose was able to mediate a transport curb. The inability of glucosamine and mannose to promote a transport curb in the PGI strain must be ascribed to the fact that the 6-esters of these aldohexoses are converted by their own specific deaminase and isomerase to fructose 6-phosphate, which initiates the pyruvate-tricarboxylate energy-yielding pathway but cannot be converted to glucose 6-phosphate in the mutant. The latter ester can be metabolized, but its metabolism in the mutant is confined to the pentose shunt. It is shown that inhibitors such as 2,4-dinitrophenol and malonate exert only slight inhibition of the pentose shunt yet release the glucose-mediated curb elicited by glucose and glucosamine in the parental PGI+ strain and also the glucose transport curb persisting in the PGI mutant.
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PMID:Down-regulation of the hexose transport system: metabolic basis studied with a fibroblast mutant lacking phosphoglucose isomerase. 695 19

Two amidases have been partially purified from the slime mold Dictyostelium discoideum; these act sequentially on the beta-hydroxymyristyl-amide groups present in the lipopolysaccharide derivative (4'-O-phosphoryl-N-beta-hydroxymyristyl-D-glucosaminyl)-beta-(1 leads to 6)-N-beta-hydroxymyristyl-D-glucosamine-1-phosphate (III). Amidase-I, which specifically removes the myristyl chain near the 1-phosphate of compound III (apparent Km, 3.7 microM), has been purified 110-fold from a lysate of D. discoideum NC4 cultivated on Escherichia coli. The partially purified enzyme contains no other amidase or phosphatase activities; however, an esterase activity can be detected. The second amidase has been purified about 12-fold from the extracellular fluid of D. discoideum AX3 cultured axenically. This amidase hydrolyzes the distal amide linkage in III (apparent Km, approximately 20 microM) only after prior deacylation of the first site by amidase-I. The preparation is free from phosphatases and glycosidases that can act on lipopolysaccharide. The differential expression of the amidases in D. discoideum and some of their kinetic properties have been described. The amidases should prove useful in structure-function studies of lipopolysaccharide.
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PMID:Fatty acyl amidases from Dictyostelium discoideum that act on lipopolysaccharide and derivatives. I. Partial purification and properties. 710 2

The substrate specificities of two fatty acyl amidases partially purified from the slime mold Dictyostelium discoideum have been studied. The amidase act on lipopolysaccharide derivatives, such as (4'-O-phosphoryl-N-beta-hydroxymyristyl-D-glucosaminyl)-beta-(1 leads to 6)-N-beta-hydroxymyristyl-D-glucosamine-1-phosphate (III) in a sequential manner. Amidase-I removes the beta-hydroxymyristyl residue present on the amino group adjacent to the 1-phosphate and the product formed is a substrate for amidase-II; the latter removes the remaining beta-hydroxymyristyl residue from the distal amino group. Compound III itself is resistant to amidase-II. Removal of the C-1 or C-4 phosphate groups does not influence recognition by the amidases or their sequential action. Both amidases are specific for long chain fatty amide linkages. Thus, a formyl group on the glucosamine amino group adjacent to the C-1 phosphate is not hydrolyzed by amidase-I; however, this substituent does not hinder the action of amidase-II on the distal fatty acyl amide. The presence of the beta-hydroxyl group in myristyl-amide residues is not required for hydrolysis. Further, while amidase-I requires disaccharide structures for its action, amidase-II acts on monosaccharides as well. Finally, the effects of a variety of substrate analogs and divalent ions on the activity of the enzymes are reported.
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PMID:Fatty acyl amidases from Dictyostelium discoideum that act on lipopolysaccharide and derivatives. II. Aspects of substrate specificity. 710 3

The binding characteristics of T2 phage induced deoxycytidylate deaminase were examined through the use of ultrafiltration and equilibrium dialysis. The positive effectors, 5-(hydroxymethyl)deoxycytidine 5'-triphosphate and deoxycytidine 5'-triphosphate, were bound in a highly cooperative manner, which is consistent with the allosteric effects promoted by these compounds. Their respective S0.5 values were 8 and 2 microM. A similar degree of cooperativity was associated with the binding of such competitive inhibitors of deoxycytidylate deaminase as dGMP, 4-N-hydroxydeoxycytidine 5'-monophosphate, and tetrahydrodeoxyuridylate. The negative effector, dTTP, also inhibited the binding of dCTP in a pH-dependent manner, which is consistent with its previously demonstrated inhibition of catalysis [Maley, G. F., Guarino, D. U., & Maley, F. (1972) J. Biol. Chem. 247, 931-939]. The binding of dTTP could be demonstrated only at low phosphate concentrations and did not appear to be cooperative. The number of binding sites for the allosteric ligands, substrate, and substrate inhibitors was shown to be six, which coincides with the number of enzyme subunits. It was established by CD difference spectroscopy that dCTP, at concentrations normally employed to demonstrate enzyme activation, effects a dramatic conformation transition in the deaminase, as indicated by a sharp decrease in ellipticity at about 280 nm. The nature of this response suggests that the microenvironment of some of the enzyme's tyrosyl residues had been perturbed by the presence of this allosteric nucleotide.
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PMID:Allosteric transitions associated with the binding of substrate and effector ligands to T2 phage induced deoxycytidylate deaminase. 713 6

Muscle actin is, in most cases, prepared from an acetone-dried powder of the myosin-removed myofibrils under low-salt conditions in the presence of ATP. In this paper, it is shown that G-actin can be directly extracted from the myosin-removed myofibrils without acetone treatment. The extraction conditions are the same as those used for the extraction of G-actin from the dried powder: extraction of the myosin-removed myofibrils for 1 h with 2 mM Tris-HCl, pH 8.0, in the presence of 0.5 mM ATP. However, the crude G-actin directly extracted from the myosin-removed myofibrils loses its polymerizability after prolonged extraction. Measurements of inorganic phosphate and thin layer chromatography of the adenine nucleotides of the crude G-actin solution show that free ATP added to the extraction buffer is sequentially hydrolyzed to ADP and AMP, and then finally converted to IMP. The instability of the G-(ADP)-actin, depolymerized from the ends of actin filaments, explains the loss in polymerizability of G-actin during the extraction. Residual ATPase, adenylate kinase, and deaminase contained in the myofibrils may account for the decomposition of ATP.
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PMID:Direct extraction of G-actin from the myosin-removed myofibrils under the conditions of low ionic strength. 716 Dec 61

1. The liberation of ammonia from adenosine 5'-phosphate (AMP) and adenosine and the release of inorganic phosphate from AMP were investigated in homogenates of bovine and human parotid glands. 2. Adenosine phosphate deaminase (AMP deaminase) was purified from bovine and human parotid glands. The enzyme preparations obtained were free from adenosine deaminase and 5'-nucleotidase activities. 3. AMP incubated with human parotid gland homogenate produced inosine 5'-phosphate, adenosine, inosine and ammonia. The amount of ammonia accumulating in the incubation mixture was equal to the sum of inosine 5'-phosphate plus inosine. 4. These results demonstrate the presence in human parotid of AMP deaminase and adenosine deaminase.
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PMID:Deamination of adenosine 5'-phosphate and adenosine as a possible source of ammonia in human and bovine parotid glands. 724 42


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