Methionine-sparing effect of cystine in human subjects.

In his autobiography, Vincent du Vigneaud (1) identifies Rose as one of the early and major influences on the direction of his future research. Rose’s own contributions were extraordinary and included “the methionine sparing effect of cystine,” a phenomenon that he described in a series of studies extending over 2 decades until 1955. Using rats as the experimental animals, Rose and his collaborators showed that cystine could replace much, but not all, of the dietary requirement for methionine. When it was shown subsequently that cystine was not a precursor of methionine, it was apparent that cystine was affecting the metabolism of methionine. In 1967, Mudd and I (2) used these nutritional conditions in a first attempt to define the mechanisms of metabolic adaptation. Almost 20 y later our group presented a more detailed analysis of the basis for the metabolic effect of cystine (3). In this issue of the Journal, Fukagawa et al (4) report only a suggestion of a “modest sparing effect of dietary cystine on methionine oxidation. ” Is it possible that the mechanism, which is so apparent in laboratory animals, is irrelevant to human metabolism? I think not. The answer rests in both the extraordinary complexities of mammalian methionine metabolism as well as with the ambitious and exceptionally difficult methods of this talented group. Our initial hypothesis was a simplification (2). We suggested that mammalian methionine metabolism is the sum of 2 pathways, the methionine cycle and transsulfuration, and that both the rate of cycling as well as the distribution of homocysteine between the 2 sequences was the basis for metabolic regulation. In our current concept (5, 6) these 2 pathways may be separated in time and space. Only the liver contains both sequences in complete form. Every tissue possesses the methionine cycle and thus can synthesize S-adenosylmethionine (AdoMet), the methyl donor in numerous transmethylation reactions. Their common product, S-adenosylhomocysteine, is cleaved to yield adenosine and homocysteine. Finally, all tissues can synthesize 5-methyltetrahydrofolate (methylTHF), which is used to resynthesize methionine. Thus, all cells can conserve methionine and recycle folates. However, this pathway is incapable of metabolizing excess homocysteine (and methionine) and it is likely that export from the cell is a normal process for detoxification. Transsulfuration, the conversion of methionine to cystathionine and then cysteine, is restricted in the rat to liver, kidney, small intestine, and pancreas. Methionine is a source of cysteine only in these tissues. All other tissues require an exogenous supply of the amino acid—either from the diet or as an export, as cyst(e)ine or glutathione—from tissues capable of transsulfuration. In the brain, transsulfuration is incomplete and cystathionine accumulates without conversion to cysteine. Although it appears that the major function of transsulfuration is the elimination of excess homocysteine (methionine), the significance of the synthesis of glutathione and cysteine remains undefined. There are additional tissue-specific variations. In humans and primates, the liver and kidney possess a second enzyme that uses betaine as the methyl donor for the remethylation of homocysteine. Lastly, liver alone contains a unique, high Michaelis constant (Km), isoenzyme for the synthesis of AdoMet. Thus, only the liver responds to excess methionine with increased AdoMet formation. Conversely, the concentration of AdoMet in other tissues varies within a much narrower range. Two mechanisms provide for the regulation of hepatic methionine metabolism (5, 6). The first is changes in the concentration of the relevant enzymes in response to sustained perturbations. The marked tissue variations provide an obvious example. Other examples are age, diet, and hormone administration. The second mechanism is inherent in the kinetic properties of the enzymes. Thus, the transsulfuration enzymes can increase product formation at higher concentrations of substrates whereas the methionine cycle may be functioning near maximum capacity at normal concentrations. Modulation by effector metabolites appears central to regulation. In the past, I suggested that AdoMet served as a switch—high concentrations turning on transsulfuration while limiting remethylation. This may be relevant primarily in the liver because of the restricted range of AdoMet concentrations in extrahepatic tissues. However,