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PubMed1981

Cytosine arabinoside deamination in human leukaemic myeloblasts and resistance to cytosine arabinoside therapy.

1. The conversion of cytosine arabinoside into its active metabolite cytosine arabinoside triphosphate, and catabolism by deamination to uracil arabinoside, was measured in intact marrow myeloblasts from patients with acute myeloid leukaemia. The ratio of uracil arabinoside/cytosine arabinoside triphosphate ranged from 0.32 to 19.11. 2. The effect of tetrahydrouridine, and inhibitor of cytosine arabinoside deamination, on cytosine arabinoside triphosphate production was studied. The greatest increase of cytosine arabinoside triphosphate production caused by addition of tetrahydrouridine was 27%. 3. The increase in cytosine arabinoside triphosphate production wad not related to the ratio of uracil arabinoside/cytosine arabinoside triphosphate or to the deaminase activity per 10(6) cells. It wa proportional to the percentage change of cytosine arabinoside in the incubation medium. 4. The sensitivity of DNA synthesis to inhibition by cytosine arabinoside was measured in myeloblasts from 11 patients. Addition of tetrahydrouridine did not increase the sensitivity of the marrow to cytosine arabinoside. 5. Cytosine arabinoside deamination is unlikely to be an important mechanism of resistance in myeloblasts in vivo, although it may produce apparent resistance in vitro.

Adult↗
PubMed1990

Comparison of alanine production after L-leucine and AMP deamination in an enzymatic model and in muscle specimens.

The amination of 2-oxoglutarate to glutamate by the deamination of leucine followed by the transamination of pyruvate to alanine in skeletal muscle is generally accepted. However, alanine formation following AMP deamination by AMP deaminase is still questionable even though it is theoretically possible. For this reason, we investigated in an enzymatic model the dependence of alanine yield both on the increasing concentration of AMP and leucine as amino group donors as well as on AMP deaminase and leucine dehydrogenase augmentation. Up to a concentration of 375 microM neither of the amino group donors produced a difference in the glutamate nor alanine yield. At a concentration of 500 microM ammonia formation was less, but alanine production was higher when leucine was present as a starting material. However, in muscle samples obtained from trained or untrained rats we did not find an increase in alanine yield when AMP was added to the muscle sample, even though NH3 production was significantly higher in samples with than in those without AMP. This discrepancy might be further elucidated by hindquarter perfusion experiments, in which alanine release would be determined after AMP deamination enhanced by electrostimulation of these muscle groups.

AMP Deaminase↗
PubMedDate not supplied

Deamination of cyclaradine by adenosine deaminase under high pressure.

The deamination of cyclaradine corresponding to a carbocyclic analogue of ara-A having anti-HSV activity by adenosine deaminase was examined under various pressure. The deamination of (+)- and (+/-)-cyclaradine was remarkably facilitated by high pressure, and the rate was increased with increasing of pressure. However, (-)-cyclaradine was not deaminated even under high pressure.

Adenosine Deaminase↗
PubMed1982

Affinity labeling via deamination reactions.

An electrophilic center at saturated carbon generated by the departure of molecular nitrogen shows minimum discrimination between various nucleophiles. The generation of such a center in the active site of a protein is therefore an attractive way of labeling that active site. The chemistry of deamination reactions will be discussed with respect to the practicality of triggering the deamination in the active sites of proteins. Successful applications of this principle using the N-nitrosamide functionality, the alkyl aryl triazene functionality, and the diazo functionality will be described. Reasons why active-site reagents incorporating this type of covert electrophilicity are more specific than those incorporating an overtly electrophilic center (such as -CO-CH2-Halogen) will be advanced. The actual and potential application of deamination precursors to the specific inhibition of physiological activities in living cells will be discussed.

Affinity Labels↗
PubMed1994

The rate of hydrolytic deamination of 5-methylcytosine in double-stranded DNA.

The modified base, 5-methylcytosine, constitutes approximately 1% of human DNA, but sites containing 5-methylcytosine account for at least 30% of all germline and somatic point mutations. A genetic assay with a sensitivity of 1 in 10(7), based on reversion to neomycin resistance of a mutant pSV2-neo plasmid, was utilized to determine and compare the deamination rates of 5-methylcytosine and cytosine in double-stranded DNA for the first time. The rate constants for spontaneous hydrolytic deamination of 5-methylcytosine and cytosine in double-stranded DNA at 37 degrees C were 5.8 x 10(-13) s-1 and 2.6 x 10(-13) s-1, respectively. These rates are more than sufficient to explain the observed frequency of mutation at sites containing 5-methylcytosine and emphasize the importance of hydrolytic deamination as a major source of human mutations.

5-Methylcytosine↗
PubMed1980

Simultaneous decrease in deamination of 5'-adenylic acid and 5'-deoxy-5'-S-isobutylthioadenosine in chick-embryo fibroblasts infected by Rous sarcoma virus.

The rate of deamination of 5'-deoxy-5'-S-isobutylthioadenosine [(iBuS5'Ado] in chick embryo fibroblasts was substantially reduced after their infection and morphological transformation by Rous sarcoma virus. Concomitant with the reduction in rate of (iBuS)5'Ado deamination there was a decrease in adenosine deaminase and 5'-adenylic acid deaminase activities. The drop of these activities was related to infection and not to the expression of the src gene. (iBuS)5'Ado was deaminated by at least three enzymes or isoenzymes whose apparent molecular weights have been estimated to be 295000, 121000 and 37000 respectively. Two of these enzymes have been characterized as 5'-adenylic acid deaminase and the heavy form of adenosine deaminase, respectively.

Adenosine Deaminase↗
PubMed1993

The glutamine cyclotransferase reaction of Streptococcus bovis: a novel mechanism of deriving energy from non-oxidative and non-reductive deamination.

Streptococcus bovis deaminated glutamine by a mechanism that did not involve glutaminase. Since pyroglutamate and ammonia were the only end-products, it appeared that glutamine deamination was catalyzed by a cyclotransferase reaction. Stationary S. bovis cells had essentially no intracellular ATP or membrane potential (delta psi), however, when they were provided with glutamine, intracellular ATP and delta psi increased to 0.52 mM and 158 mV, respectively. When glutamine-energized cells were treated with N,N-dicyclohexylcarbodiimide (DCCD, 150 microM), there was an even greater increase in intracellular ATP (> 5-fold) and the delta psi was dissipated. Because toluene-treated cells produced ATP from ADP and Pi, it did not appear that the cell membrane was directly involved in glutamine-dependent ATP generation. The rate of ammonia production was directly proportional to the glutamine concentration, but the stoichiometry of ATP to ammonia was always 1 to 1. Based on these results, it appeared that glutamine was deaminated by glutamine cyclotransferase which was coupled to ATP formation. The membrane bound ATPase then used the ATP to create a delta psi.

Acyltransferases↗
PubMed1981

Influence of deaminated metabolites on the relaxing effect of dopamine on dog saphenous vein.

The relaxing effect of dopamine was studied on the dog isolated saphenous vein contracted by prostaglandin F2alpha after alpha-adrenoceptor blockade by phentolamine. This effect is partially inhibited by propranolol and haloperidol suggesting that dopamine has two types of receptors in this vessel: beta- and dopaminergic receptors. However, the results obtained after treatment with drugs that interfere with deamination of catecholamines or after denervating the venous tissue led us to conclude that the agonist substance is not dopamine, but probably one of its deaminated metabolites or a secondary condensation product, namely tetrahydropapaveroline. Adrenaline has also been used to compare the behaviour of the two amines when interference in the deamination process is produced. The dissimilar results obtained with adrenaline are in good agreement with the hypothesis.

Animals↗
PubMed1989

Deamination of hordenine by monoamine oxidase and its action on vasa deferentia of the rat.

The selectivity of the naturally occurring amine, N,N-dimethyltyramine (hordenine) for monoamine oxidase (MAO) and its action upon isolated vasa deferentia of the rat was investigated. Hordenine was deaminated by rat liver MAO with a Michaelis constant of 479 microM and maximum velocity of 128 nmol (mg protein)-1 h-1 compared with 144 microM and 482 nmol (mg protein)-1 h-1 for tyramine. Studies, with selective irreversible inhibitors of MAO, showed that hordenine was a highly selective substrate for MAO-B of liver and that it was not deaminated by the MAO-A of intestinal epithelium. In contrast to tyramine, hordenine did not produce contractions of isolated vasa deferentia. However, 25 microM hordenine potentiated contractile responses of vasa, from control animals, to submaximal doses of noradrenaline and inhibited responses to tyramine. It did not alter responses, to noradrenaline, of vasa denervated by chronic pretreatment of rats with guanethidine. Therefore, it appears that hordenine acted as an inhibitor of noradrenaline uptake, in isolated vasa deferentia. These results indicate that dietary-hordenine is unlikely to be deaminated by intestinal MAO as this is predominantly MAO-A. Consequently, it is likely to be absorbed and could affect the sympathetic nervous system, by virtue of its action as an inhibitor of noradrenaline uptake.

Alkaloids↗
PubMed1991

DNA deaminating ability and genotoxicity of nitric oxide and its progenitors.

Nitric oxide (NO), a multifaceted bioregulatory agent and an environmental pollutant, can also cause genomic alterations. In vitro, NO deaminated deoxynucleosides, deoxynucleotides, and intact DNA at physiological pH. That similar DNA damage can also occur in vivo was tested by treating Salmonella typhimurium strain TA1535 with three NO-releasing compounds, including nitroglycerin. All proved mutagenic. Observed DNA sequence changes were greater than 99% C----T transitions in the hisG46 (CCC) target codon, consistent with a cytosine-deamination mechanism. Because exposure to endogenously and exogenously produced NO is extensive, this mechanism may contribute to the incidence of deamination-related genetic disease and cancer.

Codon↗
PubMed2003

Involvement of SSAO-mediated deamination in adipose glucose transport and weight gain in obese diabetic KKAy mice.

Semicarbazide-sensitive amine oxidase (SSAO) is located on outer surfaces of adipocytes and endothelial and vascular smooth muscle cells. This enzyme catalyzes deamination of methylamine and aminoacetone, leading to production of toxic formaldehyde and methylglyoxal, respectively, as well as hydrogen peroxide and ammonium. Several lines of evidence suggest that increased SSAO activity is related to chronic inflammation and vascular disorders related to diabetic complications. We found that a highly potent and selective SSAO inhibitor, (E)-2-(4-fluorophenethyl)-3-fluoroallylamine (FPFA), was capable of reducing numbers of atherosclerotic lesions as well as weight gain in obese KKAy mice fed an atherogenic diet. SSAO inhibitors cause a moderate and long-lasting hyperglycemia. Such an increase in serum glucose is a result of reduction of glucose uptake by adipocytes. SSAO-mediated deamination of endogenous methylamine substrates induces adipocyte glucose uptake and lipogenesis. Highly selective SSAO inhibitors can effectively block induced glucose uptake. The results suggest that increased SSAO-mediated deamination may be concomitantly related to obesity and vascular disorders associated with type 2 diabetes.

Adipocytes↗
PubMed1989

Synthesis of alpha-deuterium-labelled cyclohexylamine and its deamination by rabbit liver microsomes.

In order to investigate the isotope effect on the microsomal oxidative deamination of cyclohexylamine, alpha-deuterium(D)-labelled cyclohexylamine was synthesized. The deuterium labelling was found exclusively at the alpha-position with a purity of greater than 99 atom percent. Metabolic studies in vitro indicate that a significant deuterium isotope effect operates in the oxidative deamination of alpha-D-labelled cyclohexylamine. On incubation with rabbit liver microsomes in the presence of reduced nicotinamide adenine dinucleotide phosphate (NADPH) and oxygen, the ratio of apparent deamination rate constants (kH/kD) was 2.0 +/- 0.2 (mean +/- S.D.).

Animals↗
PubMed1997

New neplanocin analogues. IX. A practical preparation of (6'R)-6'-C-methylneplanocin A (RMNPA), a potent antiviral agent, and the determination of its 6'-configuration. Diastereoselective deamination by adenosine deaminase.

We previously synthesized (6'R)- and (6'S)-6'-C-methylneplanocin A's (2a and 2b, respectively), and found that one of them has a potent antiviral activity, though its 6'-configuration has not been confirmed. This report describes the determination of the 6'-configuration and practical preparation of the antivirally active diastereomer. The 6'-configuration of the active diastereomer was determined as R by the modified Mosher's method as well as by synthesizing 2b from the known cyclopentenone derivative 10. A practical method for preparing the 6'R-diastereomer was developed by using diastereoselective deamination with Ado deaminase as the key step. Treatment of the diastereomeric mixture of 2a and 2b, which was prepared via an addition reaction of Me3Al with the 6'-formyl derivative 3, with Ado deaminase from calf intestine, deaminated 2b selectively to give the corresponding (6'S)-inosine congener 5, and left the desired 2a not deaminated. After silica gel column chromatography, 2a was obtained in a pure form.

Adenosine↗
PubMed1981

Studies on beta-phenylethylamine deamination by human placental monoamine oxidase.

Kinetical properties of human placental monoamine oxidase (MAO) were investigated in studies on inhibitors and mixed substrates. MAO activity was determined by a radioisotopic assay. Lineweaver-Burk plots were linear at higher and lower concentrations of PEA, whereas at intermediate substrate concentrations, a downward curving plot was obtained. The Km values of the low- and high-affinity sites for PEA deamination were estimated. Studies with mixed substrates showed that 5-HT was a competitive inhibitor and tyramine a mixed-type inhibitor of deamination at high concentrations of PEA, whereas both were non-competitive inhibitors at lower concentrations of PEA. After pre-incubation of human placental mitochondrial preparations with deprenyl, Lineweaver-Burk plots were completely linear, and the Km value was the same as that obtained at low concentrations of PEA in the absence of deprenyl. Tyramine and 5-HT were competitive inhibitors of PEA deamination by deprenyl-treated MAO. From these results it is concluded that there are two kinds of MAO with high- and low-affinity sites for PEA in mitochondria of human placenta, corresponding to type B and A Mao, and that tyramine, 5-HT and PEA share a substrate-binding site on type A Mao, while tyramine and 5-HT bind to a site on type B MAO that is different from the PEA binding site.

Deamination↗
PubMed1990

Participation of type A monoamine oxidase in the activated deamination of brain monoamines shortly after reperfusion in rats.

Changes in monoamine levels during and after ischemia and effects of RS-8359, a type A monoamine oxidase (MAO-A) inhibitor, were studied in the cerebral cortex, hippocampus, and striatum of rats killed by microwave irradiation. The patterns of the changes in norepinephrine (NE), dopamine (DA), and serotonin (5HT) levels were similar during ischemia: All these monoamines decreased in all three regions. After reperfusion, however, the three monoamines showed different patterns of changes: NE, except in the striatum, decreased further; DA increased over the controls; 5HT remained suppressed in all three regions. With regard to the metabolites of the monoamines, the changes during and after reperfusion were almost similar in all regions: O-methylated metabolites, normetanephrine and 3-methoxytyramine, markedly increased during ischemia; After reperfusion, the elevated levels of normetanephrine and 3-methoxytyramine returned to normal, while deaminated metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindoleacetic acid, homovanillic acid (HVA), and 3-methoxy-4-hydroxy-phenylethyleneglycol clearly increased. RS-8359 pretreatment (30 mg/kg, p.o.) at an hour prior to ischemia elevated the levels of NE in the cortex and hippocampus during ischemia and inhibited the increases in DOPAC and HVA levels and the decrease in 3MT levels at 30 min after reperfusion. These results suggest that deamination of NE, DA, and 5HT is activated by the increases in the substrates for MAO in all three regions, except the noradrenergic system in the striatum, and that MAO-A participates in the activated deamination after reperfusion.

Animals↗
PubMed2025

DHX15 inhibits mouse APOBEC3 deamination.

APOBEC3 family proteins are critical host factors that counteract and prevent the replication of retroviruses and other viruses through cytidine deamination. Human APOBEC3 proteins inactivate HIV-1 through the introduction of lethal mutations to viral genomes. In contrast, mouse APOBEC3 does not induce DNA hypermutation of murine retroviruses, although it retains functional cytidine deaminase activity. Why mouse APOBEC3 does not effectively deaminate murine retroviruses is still unknown. In this study, we found that the dead box helicase DHX15 interacts with mouse APOBEC3 and inhibits its deamination activity. DHX15 was packaged into murine leukemia virus (MLV) virions independent of its binding with APOBEC3. Moreover, DHX15 knockdown inhibited MLV replication and resulted in more G-to-A mutations in proviral DNA. Finally, DHX15 knockdown induced DNA damage in murine cells, suggesting that it plays a role in preserving genome integrity in cells expressing mouse APOBEC3 protein.

Animals↗
PubMed2006

Involvement of semicarbazide-sensitive amine oxidase-mediated deamination in lipopolysaccharide-induced pulmonary inflammation.

Semicarbazide-sensitive amine oxidase (SSAO) resides on the vascular endothelium and smooth muscle cell surface and is capable of deaminating short chain aliphatic amines and producing toxic aldehydes and hydrogen peroxide. The enzyme, also known as a vascular adhesion protein-1, is involved in the inflammation process. This intriguing protein with dual functions is increased in the serum of diabetic and heart failure patients. In the present study we assessed the involvement of SSAO in a lipopolysaccharide-induced pulmonary inflammation model using transgenic mice that overexpress human vascular adhesion protein-1. Overexpression of SSAO activity increased the formation of protein-formaldehyde deposits in tissues. Lysine residues of proteins were the primary targets for cross-linkage with formaldehyde derived from deamination of methylamine. Lipo-polysaccharide-induced increases in inflammatory cells in the bronchoalveolar lavage (BAL) fluid were significantly higher in the transgenic than in the nontransgenic mice. BAL cell counts were also higher in the untreated transgenic than in nontransgenic mice. Blocking SSAO activity with a selective inhibitor significantly reduced the number of neutrophils as well as levels of macrophage inflammatory protein-1alpha, granulocyte colony-stimulating factor, tumor necrosis factor-alpha, and interleukin-6 in the BAL fluid. Inhalation of methylamine also increased BAL neutrophil counts. Together, these results suggest a role for SSAO-mediated deamination in pulmonary inflammation.

Amine Oxidase (Copper-Containing)↗
PubMed1997

Pharmacokinetics of high-dose cytarabine and its deamination product--a reappraisal.

Cytarabine is intracellularly activated and correlations have been established between the pharmacokinetic behaviour of active metabolites and their antileukemic effect. Recently, a good response to high-dose treatment of leukemias has additionally been attributed to a so-called low deamination phenotype of cytarabine inactivation. Consequently, these findings would support plasma level monitoring of cytarabine and its metabolite uracil arabinoside in high-dose cytarabine regimens. This pharmacokinetic study presents data attempting to reevaluate these observations. Thirty-seven patients were treated by 3-h high-dose cytarabine infusions (9 patients 1000 mg/m2, 28 patients 3000 mg/m2) as part of their treatment for acute leukemia. Serial blood samples during and post infusion were analysed for cytarabine (araC) and its deamination product uracil arabinoside (araU) using HPLC with UV-detection. Considerable interindividual variation was observed in end-infusion plasma concentrations of araC (1000 mg/m2: 2.1-fold, 3000 mg/m2: 5.5-fold) and araU (1000 mg/m2: 2.7-fold, 3000 mg/m2: 2.9-fold). The median ratio of end infusion concentrations araU/araC (on a molar basis) was 5.6 (S.D. 3.0), extreme ratio values were 2 and 14. No differences of the araU/araC ratio were found between the two dosages used. Minimum plasma araC concentrations at the end of infusion were 10.5 micromol/l and 22.0 micromol/l at a dose of 1000 and 3000 mg/m2, respectively. In our European study population a "fast" deamination phenotype of cytarabine (araU/araC ratio > 14) was not be observed.

Acute Disease↗