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 trans-sulphuration. 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
glutamine-transaminase 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 [29]. Exogenous
methional induces apoptosis in normal and
cancer cells in culture [28, 29] but not in those overexpressing the antiapoptotic gene bcl2 [30]. In physiologically-induced apoptosis e.g; trophic factor (IL3) withdrawal,
methional leakage is decreased [29] 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 [29]. MDA generated in situ from
1,3-propanediol, induces
DNA-
protein cross-linking [41].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 [40].
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].