REGULATION OF METHIONINE METABOLISM - EFFECTS OF NITROUS-OXIDE AND EXCESS DIETARY METHIONINE

Methionine is an essential amino acid that is also converted to S-adenosylmethionine, which is used by methyltransferases that methylate DNA, RNA, protein, lipid, etc., and form S-adenosylhomocysteine that is hydrolyzed to adenosine and homocysteine. When methionine is present in excess, glycine N-methyltransferase and cystathionine beta-synthase are thought to play important regulatory roles, with the former using the excess CH3- moiety to convert glycine to N-methylglycine, and the latter condensing homocysteine with serine to form cystathionine, which is cleaved by gamma-cystathionase to cysteine and alpha-ketobutyrate. When methionine is present in low amounts, the activities of the two regulatory enzymes are thought to decrease with the homocysteine being recycled to methionine by the cobalamin-dependent enzyme methionine synthase, which simultaneously converts 5-CH3-tetrahydrofolate to tetrahydrofolate. To test this model, we fed a large dose of L-methionine to normal subjects. Using newly developed assays, we observed the following increases in serum levels: methionine, 25 fold; N-methylglycine, fourfold; homocysteine, threefold; cystathionine, 15 fold; and cysteine, unchanged. When leukemia patients were treated for 4 days with 35% nitrous oxide, which markedly inhibits methionine synthase, methionine decreased 80% by day 1 and then either stabilized or returned to normal during days 2 through 4. N-methylglycine fell 50 to 70%, and homocysteine increased 14 fold, but cystathionine increased twofold after an initial decrease or stabilization. Cysteine fell 50% by day 1 and then moved in parallel with methionine. Except for the latter increase in cystathionine, all the data support the current model of methionine regulation and demonstrate that methionine homeostasis is maintained or at least stabilized, even under conditions of extreme excess or deprivation. The unexpected increase in cystathionine levels during nitrous oxide administration is similar to what has been observed in cobalamin and folate deficiency, although the mechanism and physiologic importance remain to be determined.