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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The S-adenosylhomocysteine (SAH) hydrolase inhibitor adenosine dialdehyde was used in isolated guinea pig hearts to determine the contribution of the transmethylation pathway to cardiac adenosine formation. This inhibitor did not alter cardiac hemodynamics but effectively inhibited SAH-hydrolase activity under in vitro and in vivo conditions. In normoxic perfused hearts adenosine dialdehyde (10 microM) caused tissue levels of SAH to linearly increase at a rate of 160 pmol/g/min over 60 min. At the same time adenosine dialdehyde decreased release of adenosine into the coronary effluent perfusate by 16 pmol/min (34%). Hypoxic perfusion (30% O2) of guinea-pig hearts increased release of adenosine from 43 to 3700 pmol/min. However, rate of SAH formation in the presence of adenosine dialdehyde was only slightly enhanced from 160 to 200 pmol/g/min and adenosine dialdehyde did not significantly alter the hypoxia induced adenosine release. Since all experiments were performed in the presence of the adenosine deaminase inhibitor EHNA (5 microM) the results demonstrate: (1) the transmethylation pathway of the heart contributes one third to global cardiac adenosine production under normoxic conditions and provides a constant source of adenosine independent of tissue oxygenation. (2) The majority of SAH-derived adenosine is salvaged most likely via adenosine kinase. (3) The hypoxia induced adenosine production is predominantly derived from enhanced 5' AMP hydrolysis.
J Mol Cell Cardiol 1989 Aug
PMID:Contribution of S-adenosylhomocysteine to cardiac adenosine formation. 277 14

9-(trans-2',trans-3'-dihydroxycyclopent-4'-enyl)-adenine (DHC), a specific inhibitor of S-adenosyl-L-homocysteine (AdoHcy) hydrolase, has been used in this study to elucidate the mechanism by which DL-homocysteine (Hcy) potentiates the antiviral effects of AdoHcy hydrolase inhibitors as reported by De Clercq [Biochem. Pharmacol. 36:2567-2575 (1987)]. The potentiating effects of Hcy on the antiviral effects of DHCA were determined using murine L929 cells infected with vaccinia virus. When virus-infected cells were incubated with DHCA alone or in combination with various concentrations of Hcy, the following IC50 values (concentrations of the drug required to reduce by 50% viral plaque formation) were observed: 0.30 microM (0 mM Hcy), 0.15 microM (0.3 mM Hcy), 0.09 microM (1.0 mM Hcy), and 0.04 microM (3.0 mM Hcy). In the drug combination studies, increased cellular toxicity, compared with DHCA alone, was observed only at the highest concentration of Hcy (3.0 mM); thus, at lower concentrations Hcy increased the antiviral effectiveness [ID50 (concentration of the drug required to reduce the increase in cell number by 50%)/IC50] of DHCA. For example the following ID50/IC50 values were observed for DHCA alone or in combination with Hcy: 64 (0 mM Hcy), 113 (0.3 mM Hcy), 151 (1.0 mM Hcy), and 88 (3.0 mM Hcy). In these studies, Hcy was also observed to potentiate the increase in cellular levels of AdoHcy and the ratio of AdoHcy/S-adenosyl-L-methionine (AdoMet) in DHCA-treated cells. In earlier studies, our laboratory has shown that antiviral effects of DHCA are caused by only slight elevations in intracellular levels of AdoHcy [from 50 pmol/mg of protein (controls) to 100-200 pmol/mg of protein (drug-treated)] and slight elevations in the ratios of AdoHcy/AdoMet [from 0.05-0.1 (control) to 0.15-0.20 (drug-treated)]. Thus, in the presence of Hcy, lower concentrations of DHCA are needed to increase the intracellular concentration of AdoHcy and the AdoHcy/AdoMet ratio to levels that suppress replication of vaccinia virus. Murine L929 cells were shown to contain DHCA-sensitive and DHCA-insensitive forms of AdoHcy hydrolase. Based on the results of labeling experiments using [2,8-3H]adenosine and [35S]methionine, the elevated levels of AdoHcy were shown to arise from the reaction of [2,8-3H]adenosine and Hcy, catalyzed by the DHCA-insensitive form of AdoHcy hydrolase.
Mol Pharmacol 1989 Sep
PMID:Elucidation of the mechanism by which homocysteine potentiates the anti-vaccinia virus effects of the S-adenosylhomocysteine hydrolase inhibitor 9-(trans-2',trans-3'-dihydroxycyclopent-4'-enyl)-adenine. 277 28

Activities of several adenosine metabolizing enzymes were examined in capillary preparations isolated from rabbit ventricle. Vmax and Km values for 5'-nucleotidase were 2.3 nmol/min/mg and 10 microM, respectively. For adenosine deaminase the corresponding values were 7.8 nmol/min/mg and 32 microM. S-adenosyl-homocysteine hydrolase, which forms adenosine by the hydrolysis of S-adenosylhomo-cysteine, was also present (Vmax, 0.07 nmol/min/mg; Km, 0.81 microM), as were adenosine kinase (Vmax, 0.2 nmol/min/mg; Km, 0.52 microM) and purine nucleoside phosphorylase (Vmax, 13.8 nmol/min/mg; Km, 96 microM). These enzymes were also present in microvessels (capillaries and arterioles) purified from rabbit brain. Activities of several enzymes, especially 5'-nucleotidase and adenosine deaminase, were much lower in myocytes isolated from rabbit ventricle. The study provides evidence that endothelial cells of the microvasculature from heart and brain are capable of activity forming and degrading adenosine. It is possible that adenosine formed by these cells may contribute to the local regulation of blood flow.
J Mol Cell Cardiol 1986 Jan
PMID:Adenosine metabolism in microvessels from heart and brain. 300 95

Growth of Trichomonas vaginalis in a semi-defined medium was inhibited by 5 mM DL-alpha-difluoromethylornithine (DFMO). Using high pressure liquid chromatography (HPLC) analysis, putrescine and cadaverine levels were found to be 90 and 100% reduced, respectively after 120 h exposure, whilst spermidine and spermine levels were unchanged. Putrescine (40 microM) and cadaverine (6 microM) were detected in the spent media from control cultures. Neither of these diamines was detected in spent media from 72 h DFMO-treated cultures. Changes in intracellular levels of amine precursors were also determined by HPLC. There was a transient increase in ornithine to 39 nmol (mg protein)-1 at 48 h in the DFMO-treated cells while it remained undetectable in control cells throughout the experiment. Arginine and citrulline levels remained high, decreasing to control levels only after 72 h. Only spermine (1 mM) rescued DFMO-treated cells, and this is discussed with respect to the presence of a putative spermine-specific oxidase designated by its sensitivity to aminoguanidine. Aerobic incubation of growing (normal) cells with [14C]spermine resulted in the production of an unknown metabolite (19% of total label), whose content was reduced to 5% under anaerobic conditions. Decarboxylated S-adenosylmethionine remained undetectable in DFMO-treated cells, and the methylation index (ratio of S-adenosylmethionine to S-adenosylhomocysteine) did not change from the control value of 9.3. Ornithine decarboxylase, S-adenosylmethionine synthetase, S-adenosylmethionine:L-homocysteine methyltransferase, and S-adenosylhomocysteine hydrolase enzyme activities were detected. However, S-adenosylmethionine decarboxylase, spermidine synthase or spermine synthase were not detected. These findings are discussed with reference to the arginine dihydrolase pathway whose end products are putrescine and ATP.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Biochem Parasitol 1988 Oct
PMID:Effect of DL-alpha-difluoromethylornithine on polyamine synthesis and interconversion in Trichomonas vaginalis grown in a semi-defined medium. 314 9

DL-ethionine increases the activity of liver biotinidase, an enzyme which hydrolyzes biotinylesters and biotinylpeptides. Chronic DL-ethionine feeding increases transiently the activity of biotinidase in mouse and rat liver, after which it remains elevated in the serum. In the present work we show that both isomers of DL-ethionine are equally good enhancers of the liver biotinidase, while, 3-ethylthiopropionate, the toxic metabolite of DL-ethionine, has no effect on the biotinidase activity of either liver or serum. We have also employed two different combinations of inhibitors of the hydrolytic pathway of SAH, a transmethylation product and potent inhibitor of methylation. It was found that these inhibitors (EHNA and Ara-A, 2-deoxycoformycin and adenosine) increase the activity of serum biotinidase as was the case with ethionine. Because SAH does not ethylate biomolecules, these changes in biotinidase activity, which can not be prevented by adenine, biotin or lecithin are most probably related to the inhibition of methylation.
Mol Cell Biochem 1987 Jul
PMID:Enhancement of biotinidase activity in mouse serum by inhibitors of methylation. 349 18

Adenosine dialdehyde (2'-O-[(R)-formyl(adenin-9-yl)methyl]-(R)-glyceraldehyde), formed by periodate oxidation of adenosine, is a potent inhibitor of S-adenosylhomocysteine hydrolase (EC 3.3.1.1.) in mouse L929 cells. Consequently, the dialdehyde produces an increase in intracellular levels of S-adenosylhomocysteine and subsequent inhibition of S-adenosylmethionine-dependent macromolecular methylations. In the present study we show that adenosine dialdehyde is also a potent inhibitor of vaccinia virus plaque formation in monolayer cultures of L cells. When added to the culture medium immediately following attachment of the virus, concentrations of the dialdehyde as low as 0.5 microM produce greater than 90% inhibition of plaque formation after 72 hr. The efficacy of the compound is greatest when added within 8 hr of virus attachment and gradually decreases in a time-dependent manner when added after this point. Treatment of L cells with 5 microM adenosine dialdehyde for 60 min prior to virus infection causes a transient, but virtually complete loss of S-adenosylhomocysteine hydrolase activity and subsequent 3-fold increase in the intracellular S-adenosylhomocysteine/S-adenosylmethionine ratio. Continuous exposure of infected cells to the dialdehyde results in prolonged inhibition of S-adenosylhomocysteine hydrolase accompanied by a 10-fold increase in the S-adenosylhomocysteine/S-adenosylmethionine ratio. Associated with these changes in the dialdehyde-treated, infected cells are an inhibition of early virus-specific protein synthesis and a 13% decrease in methylation of the cytoplasmic poly A+-mRNA. The antiviral action of this compound thus appears to be related to a decrease in viral mRNA methylation (e.g., the 5'-terminal cap structure) which results in suppressed translation of viral proteins essential for virus replication.
Mol Pharmacol 1987 May
PMID:Adenosine dialdehyde: a potent inhibitor of vaccinia virus multiplication in mouse L929 cells. 357 93

The nucleoside analogue, 3-deazaadenosine (c3-Ado), serves both as a substrate and as an inhibitor of S-adenosylhomocysteine (AdoHcy) hydrolase, and the ability of this compound to induce accumulation of intracellular AdoHcy and S-3-deazaadenosylhomocysteine (c3-AdoHcy) in various cells and species has been widely documented. We here report on the effect of c3-Ado on the disposition of homocysteine (Hcy) and c3-AdoHcy in isolated rat hepatocytes and in non-transformed (Cl 8) and malignant (Cl 16) C3H/10T1/2 mouse embryo fibroblasts in culture. Both the liver cells and fibroblasts release large amounts of Hcy into the extracellular medium, whereas small amounts are retained within the cells. c3-Ado (100-300 microM) nearly completely inhibits cellular Hcy egress. Intracellular Hcy in liver cells exposed to c3-Ado is in fact increased in proportion to intracellular buildup of AdoHcy, whereas c3-Ado nearly deprives the malignant Cl 16 cells of intracellular Hcy and decreases it markedly in Cl 8 cells. Adenosine exerts a similar effect as c3-Ado on Hcy and AdoHcy in liver cells, but concentrations in the mM range are required, and the effect subsides within hours. In liver cells, c3-Ado(300 microm) induces a higher level of c3-AdoHcy than of AdoHcy. In the malignant (Cl 16) fibroblasts, c3-AdoHcy content approaches the amount of AdoHcy whereas, in the non-transformed (Cl 8) fibroblasts, relatively small amounts of c3-AdoHcy are formed. Notably, c3-AdoHcy is released from all cell types in proportion to the intracellular amount, suggesting that c3-AdoHcy is efficiently handled by the mechanism responsible for the cellular egress of nucleosidylhomocysteine. The possible role of Hcy and c3-AdoHcy in the mechanism of action of c3-Ado is discussed.
Mol Pharmacol 1986 Aug
PMID:Disposition of homocysteine and S-3-deazaadenosylhomocysteine in cells exposed to 3-deazaadenosine. 373 40

The ability of Schistosoma mansoni schistosomula to evade in vitro cytotoxic activity of antibodies plus complement is shown to be increased by incubation with Concanavalin A (Con A) or with non-immune inactivated human serum. This effect was not observed if S-adenosyl-homocysteine (SAH) a methyltransferase inhibitor was added to the incubation medium. Methyl group incorporation occurs in schistosomulum phospholipids if parasites are incubated in Earle's balanced salt solution. This incorporation is increased by Con A addition and this increase is inhibited by SAH. Supernatants of schistosomula incubated in culture media containing Con A were able to promote phospholipid methylation, showing that methyltransferases were liberated into the culture media. The possible roles played by these phenomena in host-parasite interactions are discussed.
Mol Biochem Parasitol 1986 Nov
PMID:Schistosoma mansoni: phospholipid methylation and the escape of schistosomula from in vitro cytotoxic reaction. 378 93

Rat pancreatic islets methylate phosphatidylethanolamine (PE) lipids to form phosphatidylcholine (PC) with S-adenosyl-L-[methy-3H]methionine as the methyl donor. Islet PE-N-methyltransferase had activity optima at pH 6-7 and 8-9. S-Adenosyl-L-homocysteine, sodium deoxycholate, and Triton X-100 inhibited methylation in islet homogenates. Addition of phosphatidyl-N-monomethylethanolamine and phosphatidyl-N,N-dimethylethanolamine (PDME) enhanced [3H]methyl incorporation into PDME and PC, respectively. Isoproterenol, but not glucose, stimulated phospholipid methylation in islet homogenates. Propranolol inhibited the isoproterenol effect. In intact islets, glucose or isoproterenol stimulated insulin release and incorporation of [3H]methyl groups from [methyl-3H]methionine into phospholipids. Isoproterenol enhanced to a similar extent glucose-stimulated methylation and hormone release. Neither 2-deoxyglucose, tolbutamide, nor 8-bromo-cyclic AMP stimulated islet phospholipid methylation. The methyl-transferase inhibitor 3-deazaadenosine inhibited both glucose and isoproterenol-stimulated methyltransferase activity and insulin release. Propranolol inhibited the beta-adrenergic potentiation of glucose-induced phospholipid methylation and insulin release. These data suggest that PE-N-methyltransferase plays a role in amplification of the islet cell stimulus-secretion coupling response to certain secretagogues.
Mol Pharmacol 1985 Jan
PMID:Phosphatidylethanolamine N-methylation and insulin release in isolated pancreatic islets of the rat. 388 Aug 66

S-Adenosylhomocysteine hydrolase has been detected in crude homogenates of Trichomonas vaginalis, Tritrichomonas foetus and Trichomitus batrachorum at activities of 14, 1.2 and 3.3 nmol min-1 mg-1 protein, respectively. The enzyme from T. vaginalis was found to be soluble with pH optimum of 8.0 and apparent Km values for adenosine and homocysteine of 100 and 155 microM, respectively. Ara A was shown to inhibit the T. vaginalis enzyme but only at relatively high concentration (I50 100 microM), whereas sinefungin and 2'-deoxyadenosine had only small inhibitory effects. EDTA (I50 6 mM) and various divalent cations also inhibited the enzyme from T. vaginalis.
Mol Biochem Parasitol 1985 Oct
PMID:S-Adenosylhomocysteine hydrolase activity in Trichomonas vaginalis and other trichomonads. 393 51


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