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:3.5.1.4 (deaminase)
5,113 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Extracts of solid mouse tumors were examined for deoxycytidine kinase and deaminase activities. 1beta-D-Arabinofuranosylcytosine nucleotide was formed at a rate of 45 nmoles/hr by Glioma 26/57 and only 14 nmoles/hr by Ridgway osteogenic sarcoma. Deaminase activity was highest in Lewis lung (114 nmoles of 1-Beta-D-arabinofurano-syluridine formed per hr) and in CaD2 (104 nmoles of u-beta-D-arabinofuranosyluridine formed per hr). Deaminase activity in tumor extracts is sensitive to freezing, while deaminase activity in monkey serum is not. It was observed that kinase activity varies by as much as 50% in different cell lines of the same tumor. In the presence of tetrahydrouridine, kinase activity was significantly increased in most of the tumors studied.
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PMID:Kinase and deaminase activity in a variety of subcutaneous mouse tumors. 16 84

Certain D-arabinosyl nucleosides, notably arabinosyl cytosine (araC) and arabinosyl adenine (araA), are useful in the treatment of certain leukemias and some DNA virus infections, respectively. The compounds are lethal to animal cells and some bacteria. Despite extensive deamination, the parent nucleosides are transported within sensitive cells and phosphorylated to the mono-, di- and triphosphates. AraCTP and araATP are good specific competitive inhibitors of tumor cell of virus-induced DNA polymerases, competing with dCTP and dATP respectively. In addition to markedly inhibiting DNA synthesis, the aranucleotides enter newly formed DNA in internucleotide linkage. Sensitivity to the nucleosides appears to correlate with the relative ratio of formation of the triphosphate via a nucleoside kinase to degradation of the nucleoside via a nucleoside deaminase. Inhibition of the deaminase increases formation of the aranucleoside triphosphate in leukemic or virus-infected cells and markedly increases the toxicity of the nucleosides. Combinations of inhibitors of the deaminases and of the aranucleoside are being explored in clinical situations. In addition, the slow penetration of aranucleotides into cells has been observed and some of these 5'-phosphates are useful antiviral agents, e.g., against herpes virus in herpetic kiratitis.
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PMID:The mechanisms of lethal action of arabinosyl cytosine (araC) and arabinosyl adenine (araA). 32 34

Thirteen experimental mouse neoplasms were tested by cytidine (CR)-deaminase and deoxycytidine (dCR)-kinase levels. Four neoplasms, Sarcoma T241, Adenocarcinoma E0771, Lewis lung carcinoma (LL), and Sarcoma 180 Japan (S180J), considered to have high deaminase and sufficient dCR-kinase activities, were tested in vivo for combination chemotherapy with cytosine arabinoside (ara-C) and the CR-deaminase inhibitor, tetrahydrouridine (THU). THU did not significantly improve the growth inhibition of ara-C in a wide range of combinations in T241, E0771, LL, and the solid form of S180J, but more than doubled the survival time of the S180J ascites-bearing animals. Toxicity in the form of weight loss and toxic deaths was observed in some but not all groups, especially at high dosages of ara-C and THU. Tissue distribution of [3H]-ara-C and [14C]-THU in T241-bearing mice revealed an accelerated clearance of ara-C-derived radioactivity under the influence of THU in the tumor and five host tissues, but not in the small intestines. With the exception of the small intestines, clearance of THU-derived radioactivity was faster in all tissues studied compared to the clearance of [3H]-ara-C-derived radioactivity. Intracellular CR-deaminase levels were inhibited significantly, ie, dose dependent, in tumor and host kidney after a single ip injection of THU to E0771--bearing mice. In the solid S180J, with or without simultaneous ip administration of THU, [3H]-ara-C was not converted to 5'-di- and tri-phosphates at all. In mice bearing the ascites form of S180J, [3H]-ara-C was extensively converted to ara-C 5'-di- and tri-phosphates. THU increased both overall ara-C-derived radioactivity and the relative amounts of ara-C 5'-di- and tri-phosphates.
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PMID:Combinations of tetrahydrouridine and cytosine arabinoside in mouse tumors. 58 1

Certain D-arabinosyl nucleosides, notably D-arabinosyl cytosine (araC) and D-arabinosyl adenine (araA), are useful in the treatment of certain leukemias and some DNA virus infections, respectively. The compounds are lethal to animal cells and some bacteria. Despite extensive deamination, the parent nucleosides are transported within sensitive cells and phosphorylated to the mono-, di- and triphosphates. AraCTP and araATP are good specific competitive inhibitors of tumor cell or virus-induced DNA polymerases, competing with dCTP and dATP, respectively. In addition to markedly inhibiting DNA synthesis, the aranucleotides enter newly formed DNA in internucleotide linkage. Sensitivity to the nucleosides appears to correlate with the relative ratio of formation of the triphosphate via a nucleoside kinase to degradation of the nucleoside via a nucleoside deaminase. Inhibition of the deaminase increases formation of the aranucleoside triphosphate in leukemic or virus-infected cells and markedly increases the toxicity of the nucleosides. Combinations of inhibitors of the deaminases and of the arnaucleoside are being explored in clinical situations. In addition, the slow penetration of aranucleotides into cells has been observed and some of these 5'-phosphates are useful antiviral agents, e.g. against herpes virus in herpetic keratitis.
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PMID:The lethality of aranucleotides. 82 87

The regulatory properties of adenylate deaminase (EC 3.5.4.6) from Ehrlich ascites tumor cells suggest that the reaction catalyzed by this enzyme serves to protect the cell against sharp decreases in the adenylate energy charge by removing adenosine 5'-monophosphate generated when the rate of utilization of adenosine triphosphate is suddenly increased. The enzyme is effectively inhibited under normal physiological conditions of high energy charge (0.9) and 4 to 5 mM adenine nucleotide pool size. The reaction is sharply activated by a decrease in the energy charge in the physiological range (0.9 to 0.6). At low energy charge (0.6), decrease in the size of the pool causes a marked and nonlinear decrease in the rate of the deaminase reaction. This effect presumably serves to prevent excessive depletion of the adenine nucleotide pool. Calculations based on the kinetic data obtained in this study show that the AMP deaminase reaction can account for the well-established alteration of adenine nucleotide metabolism that is observed following addition of glucose or 2-deoxyglucose to intact ascites cells.
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PMID:Role of the adenylate deaminase reaction in regulation of adenine nucleotide metabolism in Ehrlich ascites tumor cells. 94 36

The 6C3HED lymphosarcoma, a tumor cell line very sensitive to 9-beta-D-arabinofuranosyladenine (ara-A), and 6C3HED/ara-A, a line resistant to ara-A, were studied. Both were responsive to 9-beta-D-arabinofuranosylcytosine (ara-C). Two lines of cells. L1210 and L1210/ara-C, are both resistant to ara-A and have very high levels of the deaminase that inactivates ara-A. When an effective inhibitor of the deaminase, 2'-deoxycoformycin, was combined with ara-A in the treatment of mice bearing L1210 or L1210/ara-C tumors, both became responsive to ara-A. Studies are reported on the extent of effects of 2'-deoxycoformycin at several dose levels and the duration of its effect in tumor cells and normal tissues. Single doses produce essentially complete inhibition of the deaminase, and little recovery was seen before 24 hr. However, DNA synthesis in normal tissues recovered more quickly. It is suggested that ara-A and ara-C, the former as a new derivative (9-beta-D-arabinofuranosyladenine 5'-phosphate) and possibly combined with 2'-deoxycoformycin, be regarded as potentially alternative drugs for the treatment of neoplasms.
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PMID:Enhancement of the antitumor activity of arabinofuranosyladenine of 2'-deoxycoformycin. 94 95

The phosphorylation of 1-beta-D-arabinofuranosylcytosine (ara-C) was studied in cell-free extracts from a variety of solid mouse tumors, L1210 ascites and in normal liver and spleen. Two apparent Michaelis constants were observed for kinase activity in Lewis lung (Km1, 4.15 muM; Km2 58.1 muM), sarcoma 180 (Km1 6.66 muM; Km2 56.18 muM), adenocarcinoma 755 (Km1 4.34 muM; Km2 50.0 muM) and l1210 (Km1 29.41 muM; Km2 41.67 muM). The Km1 values generally ranged from 5 to 20 muM 3H-ara-C while the Km2 values ranged from 20 to 60 muM 3H-ara-C. Normal spleen (Km 47.6 muM), normal liver (Km 10.0 muM) and Ridgway osteogenic sarcoma (Km 31.2 muM) had single Km values. In the presence of tetrahydrouridine (H4U), the in vitro phosphorylation of ara-C was increased as much as 91% in cell-free extracts from adenocarcinoma 755; lesser increases were observed in other tumor extracts. At low substrate concentrations, the apparent Km decreased or did not change in the presence of H4U, while at higher substrate concentrations the apparent Km was increased or did not change in the presence of H4U. In the presence of H4U, Vmax for kinase activity increased most in those tumors possessing deaminase activity.
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PMID:Influence of tetrahydrouridine on the phosphorylation of 1-beta-D-arabinofuranosyl-cytosine (ara-C) by enzymes from solid tumors in vitro. 105 9

The distribution of cyclocytidine and cytosine arabinoside has been studied in normal BDF mice and in mice bearing 6-day solid L1210 lymphocytic leukemia by whole-body radioautography, bioassay, and radiochemical techniques. Radioactivity was widely distributed throughout the tissues between 15 minutes and 12 hours after a single intravenous dose of either cyclocytidine-2-14C or cytosine arabinoside-2-14C. Whole-body radioautograms demonstrated that for most tissues, cytosine arabinoside-derived 14C was uniformly excreted by 48 hours; cyclocytidine-derived 14C, however, was localized in certain tissues as early as 15 minutes after drug administration and was retained in these sites for 48 hours. Depot loci of 14C included salivary and adrenal glands, fat, cardiac muscle, gastrointestinal tract, and L1210 tumor. The distribution and persistence of cyclocytidine-derived radioactivity is consistent with other reports of toxicity induced by the drug in these tissues. Radiochromatography and bioassay data from BDF mice dosed intraperitoneally with cyclocytidine demonstrated that 65%-95% of the 14C-radioactivity in a number of tissues was the parent compound itself. Thus, cyclocytidine contributed in large measur to the generation of the radioautograms. This study demonstrates that the retention of cyclocytidine in body tissues may serve to effect the sustained release of the deaminase-resistant chemotherapeutic drug from these depot sites and thus prolong cytotoxic levels of drug in tumor tissue.
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PMID:Comparative studies of cyclocytidine (NSC-145668) and cytosine arabinoside (NSC-63878) in mice. 120 80

During protein biosynthesis, processing of the N terminus of many proteins may occur through acetylation and deacetylation. The enzyme acylpeptide hydrolase is likely involved in deacetylation of nascent peptide chains or of bioactive peptides. The related enzyme, acylase, hydrolyzes the acetyl amino acid product of the acylpeptide hydrolase reaction to acetate and a free amino acid. There is a reciprocal relationship between the substrates for these enzymes (i.e., substrates for one enzyme are competitive inhibitors for the other). In several cultured cell lines, including normal and malignant cells, the ratio of acylpeptide hydrolase to acylase enzyme activities appears to be coordinated and characteristic for a given cell type. Thus, in normal cultured lung cells, hamster ovary cells, hepatoma cells, and lymphocyte cells, nearly equal amounts of these enzymes are expressed, conducive to optimal processing of acetylated N-terminal residues. Four lines of erythroleukemic cell lines were found to express nearly twice as much acylase as acylpeptide hydrolase activity. In the Ehrlich ascites tumor cell line, where 80% of the proteins have been reported to remain acetylated at their N terminus, acylpeptide hydrolase is hardly expressed but acylase activity is not reduced. The 3p21 region of human chromosome 3, which contains the DNF15S2 locus that encodes acylpeptide hydrolase (Jones et al., Proc Natl Acad Sci USA 1991;88:2194), undergoes deletion in some carcinoma cells; the gene that encodes for the acylase is also present on region 3p of the same chromosome. We found that both acylpeptide hydrolase and acylase activities are practically absent in six small-cell lung carcinoma cell lines tested.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Deficiency of acylpeptide hydrolase in small-cell lung carcinoma cell lines. 132 31

Palytoxin (PTX), one of the most toxic nonprotein molecules known, is cytotoxic at picomolar concentrations against a wide variety of cell types. In contrast to most cytotoxins, PTX exerts its activity extracellularly. A method for targeting PTX to tumor cells is described in which a monoclonal antibody-enzyme conjugate activates a PTX prodrug at surfaces of tumor cells. The prodrug, N-(4'-hydroxyphenylacetyl)palytoxin (NHPAP), was prepared by reacting PTX with an active ester of 4-hydroxyphenylacetic acid. NHPAP was 1000 times less toxic than PTX to a panel of carcinoma and lymphoma cell lines. The cytotoxic activity of the combination of penicillin G amidase from Escherichia coli with NHPAP was equal to PTX. Two cell lines that were multidrug resistant showed no enhanced resistance to NHPAP +/- penicillin G amidase. Immunologically specific activation of NHPAP took place when H2981 cells (L6 antigen positive) were treated with the monoclonal antibody conjugate L6-penicillin G amidase followed by NHPAP. This system is distinguished from other prodrug activation schemes, since the released drug exerts its activity extracellularly, has high potency, and may be able to overcome the multidrug resistant phenotype.
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PMID:N-(4'-hydroxyphenylacetyl)palytoxin: a palytoxin prodrug that can be activated by a monoclonal antibody-penicillin G amidase conjugate. 135 20


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