Schematic representation of the differences between conservative and catabolic methionine metabolism in normal non-proliferating hepatocytes. In the presence of high methionine, quiescent (differentiated) hepatocytes rely primarily on methionine adenosyltransferase III (MATIII), which is activated by methionine, to generate SAMe and maintain methionine homeostasis. Excess SAMe is then converted to homocysteine, by the combined action of glycine N-methyltransferase (GNMT) and S-adenosylhomocysteine hydrolase, to avoid aberrant methylation reactions such as irregular methylation of histones and DNA. While GNMT is allosterically activated by SAMe, S-adenosylhomocysteine hydrolase is a reversible enzyme. Once formed, the excess homocysteine is used for the synthesis of cysteine and α-ketobutyrate as result of its transsulfuration (cycling homocysteine back to methionine is inhibited by SAMe). The transsulfuration pathway involves two enzymes that require pyridoxal phosphate as cofactor: cystathionine β-synthase (CBS), which is also allosterically activated by SAMe, and γ-cystathionase. Cysteine is then utilized for the synthesis of glutathione as well as other sulfur containing molecules such as taurine, while α-ketobutyrate is further metabolized in the mitochondria. We refer to this process as catabolic methionine metabolism. When methionine concentration is limiting MATI synthesizes most SAMe, which feeds the multiple methyl transferase (MTs) reactions required by the hepatic cells, to be then converted into homocysteine, and used primarily for the regeneration of methionine. This recycling of homocysteine when methionine is limiting allows normal methylation reactions to continue although results in reduced α-ketobutyrate and glutathione synthesis when compared with oxidative methionine metabolism. We refer to this process as conservative methionine metabolism.

Proliferating hepatocytes and liver cancer cells recycle most homocysteine to methionine (conservative methionine metabolism) regardless of whether this amino acid is present in high quantities or is limiting. Proliferating hepatocytes and liver cancer cells rely on methionine adenosyltransferase II (MATII, which is inhibited by SAMe) and the β-subunit (which lowers the K_m and K_i of MATII for methionine and SAMe respectively) to synthesize SAMe, which is used in multiple methyl transferase (MTs) reactions required by the proliferating cells to be converted into homocysteine, via S-adenosylhomocysteine, and used primarily for the regeneration of methionine. In liver tumors, the expression of CBS is less then 30% of that found in normal hepatic tissue. This recycling of homocysteine maximizes the utilization of methionine for protein synthesis and results in minimal α-ketobutyrate and glutathione synthesis. Homocysteine recycling is coupled to the synthesis of thymidine monophosphate (through the folate cycle), which is subsequently phosphorylated to thymidine triphosphate for use in DNA synthesis.