Temporal evaluation of methionine synthase and related metabolites in the MAC15A mouse adenocarcinoma animal model

Alison Blackburn, Michael C. Bibby, Mark D. Lucock, Anna Nicolaou

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    Methionine dependence is unique to cancer cells and defined as the inability to grow in a methionine-deprived environment even if supplemented with the metabolic precursor homocysteine. Cobalamin-dependent methionine synthase (MS) catalyses the formation of methionine and tetrahydrofolate from homocysteine and methyltetrahydrofolate, thus linking the methionine and folate pathways. The apparent altered methionine metabolism in methionine-dependent cancer cells suggests a role for MS, although results to date are conflicting. We have analysed key metabolites of the MS-associated transmethylation, transsulphuration and folate pathways of the methionine-dependent MAC15A tumour model as a function of tumour progression over a 10-day period. MS activity increased 2-fold from day 1 to day 10. Cysteine, homocysteine, S-adenosylmethionine and S-adenosylhomocysteine levels in tumour cytosolic fractions decreased as a function of tumour progression. Plasma cysteine levels also decreased, whilst the distribution of folates in erythrocytes was altered, with a maximum increase in methyltetrahydrofolate observed by day 5. The increasing MS activity and decreasing cysteine levels suggest an increasing methionine requirement by the tumour, whilst the induction of enzyme activity indicates that MS is not defective in the methionine-dependent MAC15A tumour. The decrease in tumour S-adenosylmethionine and S-adenosylhomocysteine levels suggests that methionine is required for some function other than cellular methylation, e.g., incorporation into protein. Overall, the results support a theory of methionine conservation in response to tumour growth, where the methionine-dependent HAC15A tumour has a higher than normal methionine requirement. © 2004 Wiley-Liss, Inc.
    Original languageEnglish
    Pages (from-to)577-584
    Number of pages7
    JournalInternational Journal of Cancer
    Issue number4
    Publication statusPublished - 20 Nov 2004


    • Folates
    • MAC15A mouse
    • Methionine synthase
    • S-adenosylmethionine
    • Sulphur-amino acids


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