Methionine-Derived Metabolites in Apoptosis: Therapeutic Opportunities for Inhibitors of their Metabolism in Chemoresistant Cancer Cells
Abstract:Methionine, in addition to its role in protein synthesis, participates in 3 important cellular functions: as AdoMet in transmethylation; as decarboxylated-AdoMet in aminopropylation; as homocysteine its demethylated form, in transsulphuration. Here we provide evidence from the literature and from our own work for a fourth role for its oxoacid: 4- methylthio-2-oxo-butanoate (MTOB) in apoptosis [28,29]. MTOB enters 2 pathways: (a) transamination by glutaminetransaminase K to methionine[13,14].(b)oxidative decarboxylation by the mitochondrial Branched-Chain-Oxo-Acid- Dehydrogenase-Complex to methional and finally to methylthiopropanoyl CoA (MTPCoA) [26,27]. Some of the methional formed after MTOB decarboxylation leaks into the cytoplasm as free methional . Exogenous methional induces apoptosis in normal and cancer cells in culture [28, 29] but not in those overexpressing the antiapoptotic gene bcl2 . In physiologically-induced apoptosis e.g. trophic factor (IL3) withdrawal, methional leakage is decreased  suggesting that MTPCoA is also involved in apoptosis. Both methional and MTPCoA give rise to metabolites that may act as cross-linking agents. In the case of methional, the CH3-S moiety is lost and malondialdehyde (MDA) is formed when methional is subjected to •OH attack . MDA generated in situ from 1,3-propanediol, induces DNA-protein cross-linking .With regard to MTPCoA, it is metabolized to malonic semialdehyde CoA (MASACoA) with loss of the CH3-S moiety [48,49 ]. The capacity of MASACoA to form cross-links has not yet been established experimentally, but it could be a substrate for one of the histone acyl transferases [50, 51] and so form amides via the CoA at one end and imines by its CHO group at the other, with amino groups on proteins. Chromatin cross-linking/condensation is one of the hall-marks of apoptosis . Methional, MDA and other apoptogenic aldehydes like 4-hydroxy-2-nonenal are oxidized by ALDHs to non-apoptogenic carboxylic acids [29, 44, 45, 68] but retain their apoptotic activity when the ALDHs are inhibited [98, 110]. MASACoA would also lose its cross-linking capacity if its CoA moiety were putatively hydrolysed by ALDHs and/or acylCoA thioesterases [56, 58, 88, 89]. ALDH inhibitors that control cellular MDA and possibly MASACoA homeostasis are cited as examples of targeted therapeutic approaches in chemoresistant cancers [62, 84, 97, 98, 110].
Document Type: Research Article
Affiliations: Laboratoire d'Immunochimie, Faculte de Medecine Lyon-Sud, Chemin du Petit Revoyet BP.12, 69921 Oullins cedex, France. Present address: CERMA, BioPark d'Archamps, F-74160, France.
Publication date: October 1, 2009
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