S-adenosylmethionine synthetase in cultured normal and oncogenically-transformed human and rat cells

Oden, Kristine L.; Carson, Karen; Mecham, James O.; Hoffman, Robert M.; Clarke, Steven

doi:10.1016/0304-4165(83)90173-3

Cited by 14 publications

(4 citation statements)

References 11 publications

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“…However, this is not supported by Oden et al (31) who found only a single AdoMet synthetase enzyme in several normal and transformed cell lines, and no alteration in the activity of the enzyme could be detected. They showed that the Met pool of Metdependent cells was 20 times lower than that found in Met-independent cells.…”

Section: Effects On Met Metabolismmentioning

confidence: 57%

“…The changes in AdoMet/AdoHcy ratio in Hcy-tl-supplemented medium could be explained by the fact that Hey is a substrate for AdoHcy hydrolase in the synthetic direction (29), and accumulation of AdoHcy would result. AdoHcy is a potent inhibitor of a number of AdoMet-dependent methyl-transferases (31) and would reduce the AdoMet consumption. Isozymes of AdoMet synthetase (methionine adenosyl transferase) with different K m values for Met and with different sensitivity to feedback inhibition by AdoMet, have been demonstrated in mammalian tissues.…”

Section: Effects On Met Metabolismmentioning

confidence: 99%

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Growth support and toxicity of homocysteine and its effects on methionine metabolism in non-transformed and chemically transformed C3H/10T1/2 cells

Djurhuus¹,

Svardal²,

Ueland³

et al. 1988

Carcinogenesis

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The effects of homocysteine (Hcy) on one non-transformed (Cl 8) and two malignant clones (Cl 16 and Cl T422) of the C3H/10T1/2 mouse embryo fibroblasts, were examined with regard to toxicity, ability to support growth and effects on methionine (Met) metabolism and glutathione level. Homocysteine in its reduced form (Hcy-SH) was toxic to all cell lines, and the LD90 was estimated to be 1.0 X 10(-4) M for Cl 8 and Cl 16 cells measured by plating efficiency, 0.8 X 10(-4) M for Cl 8 and 0.3 X 10(-4) M for Cl 16 when measured by total cell growth. At toxic concentrations, Hcy-SH showed a drastic effect on cell morphology both in the presence and absence of Met. The same effect was demonstrated with L-cysteine. No toxic effect was seen with homocystine (Hcy-SS-Hcy) or homocysteine thiolactone (Hcy-tl) at similar concentrations. Hcy-tl supported growth of both the non-transformed and malignant cells in Met-deficient medium but with decreasing efficiency in the order Cl 8, Cl 16 and Cl T422. The growth rate constant compared to that of Met-supplemented medium was 0.62 for Cl 8, 0.44 for Cl 16 and 0.38 for Cl T422 cells. The intracellular level of S-adenosylhomocysteine (AdoHcy) increased in all three cell lines in Hcy-tl-supplemented medium. The S-adenosylmethionine (AdoMet) content increased in Cl 8 cells, was constant in Cl 16 cells and decreased in Cl T422 cells under the same conditions. This resulted in a constant ratio of AdoMet/AdoHcy in the non-transformed cells (Cl 8) whereas this ratio decreased by 40% in Cl 16 and by 72% in Cl T422 cells when Hcy-tl replaced Met in the medium. The ability of Hcy-tl to support growth thus seemed to correlate well with alteration in Met metabolism in this cell culture system. The intracellular level of glutathione (GSH) was measured during exponential growth, but showed small variations between non-transformed cells and Cl 16 cells. However, Cl T422 cells showed a distinct lower level of GSH in Met-supplemented medium, and this increased 3- to 4-fold when Met was replaced with Hcy-tl.

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Section: Effects On Met Metabolismmentioning

confidence: 57%

Section: Effects On Met Metabolismmentioning

confidence: 99%

Growth support and toxicity of homocysteine and its effects on methionine metabolism in non-transformed and chemically transformed C3H/10T1/2 cells

Djurhuus¹,

Svardal²,

Ueland³

et al. 1988

Carcinogenesis

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“…Radioactivity would be expected to be incorporated into proteins both as methionyl residues and as methyl groups that modify the side chains of various amino acids (22). The latter reaction is dependent upon the conversion of methionine to the methyl group donor S-adenosylmethionine, a reaction catalyzed by a synthetase present in human and rat fibroblasts (23 Radiolabeled proteins from crude lysates of these fibroblasts were fractionated by electrophoresis in polyacrylamide gels in the presence of sodium dodecyl sulfate (Fig. 2).…”

Section: Resultsmentioning

confidence: 99%

Posttranslational modification of the Ha-ras oncogene protein: evidence for a third class of protein carboxyl methyltransferases.

Clarke

Vogel

Deschenes

et al. 1988

Proc. Natl. Acad. Sci. U.S.A.

360

212

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The ras oncogene products require membrane localization for their function, and this is thought to be accomplished by the addition of a palmitoyl group to a cysteine residue near the carboxyl terminus of the nascent chain. A lipidated carboxyl-terminal cysteine residue is also found in sequence-related yeast sex factors, and in at least two cases, the a-carboxyl group is also methyl esterified. To determine if ras

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“…Similar changes in AdoMet did not occur in cultured mammalian cells and may explain why MDL 73811 selectively kills the parasites while having no apparent toxic effects on the mammalian host. A possible explanation for these data is that mammalian AdoMet synthetase is known to be regulated by AdoMet (Oden et al, 1983;Geller et al, 1986), whereas the trypanosome enzyme may be poorly regulated.…”

Section: Discussionmentioning

confidence: 99%

Antitrypanosomal effects of polyamine biosynthesis inhibitors correlate with increases in Trypanosoma brucei brucei S-adenosyl-l-methionine

Byers¹,

Bush²,

McCann³

et al. 1991

Biochemical Journal

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We reported recently that administration of ([(Z)-4-amino-2-butenyl]methylamino)-5'-deoxyadenosine (MDL 73811), an enzyme-activated irreversible inhibitor of S-adenosyl-L-methionine decarboxylase (AdoMetDC; EC 4.1.1.50), a key enzyme in the synthesis of spermidine, cures African trypanosome infections in mice. The precise mechanism of action of MDL 73811 was not clear because a rapid disappearance of trypanosomes from the bloodstream of treated rats occurred before significant depletion of spermidine. Administration of MDL 73811 to Trypanosoma brucei brucei-infected rats resulted in a 70% decrease in parasitaemia within 1 h and a complete disappearance of parasites by 5 h. The reduction in parasitaemia was accompanied by complete inhibition of AdoMetDC activity by 10 min after injection of MDL 73811; inhibition was sustained for at least 4 h. Polyamine levels in trypanosomes were unaffected during the first 1 h in which the marked decrease in parasitaemia was observed, but parasite AdoMet levels increased 20-fold within this time. In contrast, exposure of cultured mammalian cells to MDL 73811 resulted in only a 1.5-2-fold increase in AdoMet levels over a 6 h time course. Experiments with inhibitors of ornithine decarboxylase (ODC) also suggested that the increased AdoMet levels might be an important factor for antitrypanosomal efficacy. Trypanosomes taken from rats treated for 36 h with eflornithine, an inhibitor of ODC, were depleted of putrescine and had markedly decreased spermidine levels. These organisms also had less than 10% of control AdoMetDC activity, and had elevated decarboxy AdoMet (greater than 4000-fold) and AdoMet (up to 50-fold) levels. The methyl ester of alpha-monofluromethyl-3,4-dehydro-ornithine (delta-MFMO-CH3), which cures murine T. b. brucei infections, and the ethyl ester analogue of this compound (delta-MFMO-C2H5), which does not cure this infection, become ODC inhibitors upon hydrolysis and thus were tested for their effects on trypanosomal polyamines, AdoMet and decarboxy AdoMet levels. Although both esters of delta-MFMO depleted trypanosomal polyamines, AdoMet and decarboxy AdoMet levels were elevated in T. b. brucei from infected mice treated with delta-MFMO-CH3 but not in parasites from mice treated with the delta-MFMO-C2H5. These data suggest that inhibition of AdoMetDC, either directly with MDL 73811 or indirectly with inhibitors of ODC, apparently leads to a trypanosome-specific elevation of AdoMet. It is possible that major changes in AdoMet, rather than changes in polyamines, may be responsible for the antitrypanosomal effects of these drugs.

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S-adenosylmethionine synthetase in cultured normal and oncogenically-transformed human and rat cells

Cited by 14 publications

References 11 publications

Growth support and toxicity of homocysteine and its effects on methionine metabolism in non-transformed and chemically transformed C3H/10T1/2 cells

Growth support and toxicity of homocysteine and its effects on methionine metabolism in non-transformed and chemically transformed C3H/10T1/2 cells

Posttranslational modification of the Ha-ras oncogene protein: evidence for a third class of protein carboxyl methyltransferases.

Antitrypanosomal effects of polyamine biosynthesis inhibitors correlate with increases in Trypanosoma brucei brucei S-adenosyl-l-methionine

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