Methionine metabolism

Although numerous cellular mechanisms are involved in food intake, many investigations over the past decades have pointed out defections in the methionine metabolic pathway as cause of carcinogenesis.[23][24] For instance, deficiencies of the main dietary sources of methyl donors, methionine and choline, lead to the formation of liver cancer in rodents.[25][26] Methionine is an essential amino acid that must be provided by dietary intake of proteins or methyl donors (choline and betaine found in beef, eggs and some vegetables). Assimilated methionine is transformed in S-adenosyl methionine (SAM) which is a key metabolite for polyamine synthesis, e.g. spermidine, and cysteine formation (see the figure on the right). Methionine breakdown products are also recycled back into methionine by homocysteine remethylation and methylthioadenosine (MTA) conversion (see the figure on the right). Vitamins B6, B12, folic acid and choline are essential cofactors for these reactions. SAM is the substrate for methylation reactions catalyzed by DNA, RNA and protein methyltransferases.
The products of these reactions are methylated DNA, RNA or proteins and S-adenosylhomocysteine (SAH). SAH has a negative feedback on its own production as an inhibitor of methyltransferase enzymes. Therefore SAM:SAH ratio directly regulates cellular methylation, whereas levels of vitamins B6, B12, folic acid and choline regulates indirectly the methylation state via the methionine metabolism cycle.[27][28] A near ubiquitous feature of cancer is a maladaption of the methionine metabolic pathway in response to genetic or environmental conditions resulting in depletion of SAM and/or SAM-dependent methylation. Whether it is deficiency in enzymes such as methylthioadenosine phosphorylase, methionine-dependency of cancer cells, high levels of polyamine synthesis in cancer, or induction of cancer through a diet deprived of extrinsic methyl donors or enhanced in methylation inhibitors, tumor formation is strongly correlated with a decrease in levels of SAM in mice, rats and humans.[29][30] Many indirect and thinly circumstantial theories have been put forth related to methylation status of DNA or attacks upon the capacity for DNA mutation and repair. The discovery that methyltransferases whose activity would be directly influenced by SAM levels also act as tumor suppressors potentially provides a more direct bridge. This has important ramifications for chemoprevention strategies as well as chemotherapy[31][32].[33][34]