Metabolic regulatory properties of S-adenosylmethionine and S-adenosylhomocysteine

Abstract

In mammalian liver, two intersecting pathways, remethylation and transsulfuration, compete for homocysteine that has been formed from methionine. Remethylation of homocysteine, employing either methyltetrahydrofolate or betaine as the methyl donor, forms a methionine cycle that functions to conserve methionine. In contrast, the transsulfuration sequence -- cystathionine synthase and cystathionase -- serves to irreversibly catabolize the homocysteine while synthesizing cysteine. The rate of homocysteine formation and its distribution between these two pathways are the sites for metabolic regulation and coordination. The mechanisms for regulation include both the tissue content and the kinetic properties of the component enzymes as well as the concentrations of their substrates and other metabolic effectors. Adenosylmethionine and adenosylhomocysteine are important regulatory metabolites and may use one or more mechanisms to affect the enzymes. Adenosylmethionine is a positive effector of its own synthesis, cystathionine synthase and glycine methyltransferase but impairs both homocysteine methylases. Thus, the concentration of adenosylmethionine may be self-regulatory in mammalian liver. By means of other enzymatic mechanisms, the hepatic concentration of adenosylhomocysteine, an index of homocysteine accumulation, is also self-regulated. These considerations pertain primarily to liver, which has the unique capacity to synthesize more adenosylmethionine in the presence of excess methionine. However, there are organ-specific patterns of methionine metabolism and its regulation. All tissues possess the methionine cycle with methyltetrahydrofolate as the methyl donor but only liver, kidney, pancreas, intestine and brain also contain the transsulfuration pathway. The limitation of adenosylmethionine concentrations may make adenosylhomocysteine a more significant metabolic regulator in extrahepatic tissues. However, estimates of regulatory changes based on determinations of the plasma concentrations of the two metabolites are of limited value and must be used with caution. In addition, the recent description of "cystathionine (CBS) domains" in proteins not involved with methionine metabolism raises the possibility that abnormal concentrations of the adenosyl metabolites may impact on other metabolic pathways.