Methionine metabolism in mammals. Adaptation to methionine excess.

Abstract

We conducted a systematic evaluation of the effects of increasing levels of dietary methionine on the metabolites and enzymes of methionine metabolism in rat liver.Significant decreases in hepatic concentrations of betaine and serine occurred when the dietary methionine was raised from 0.3 to 1.0%.We observed increased concentrations of S-adenosylhomocysteine in livers of rats fed 1.5% methionine and of S-adenosylmethionine and methionine only when the diet contained 3.0% methionine.Methionine supplementation resulted in decreased hepatic levels of methyltetrahydrofolate-homocysteine methyltransferase and increased levels of methionine adenosyltransferase, betaine-homocysteine methyltransferase, and cystathionine synthase.We used these data to simulate the regulatory locus formed by the enzymes which metabolize homocysteine in livers of rats fed 0.3% methionine, 1.5% methionine, and 3.0% methionine.In comparison to the model for the 0.3% methionine diet group, the model for the 3.0% methionine animals demonstrates a 12-fold increase in the synthesis of cystathionine, a 150% increase in flow through the betaine reaction, and a 550% increase in total metabolism of homocysteine.The concentrations of substrates and other metabolites are significant determinants of this apparent adaptation.Methionine is essential for the normal growth and development of mammals.This role derives from the unique participation of this amino acid, or its derivatives, in protein synthesis, in polyamine synthesis, and in, the many transmethylation reactions.Furthermore, homocysteine is an obligatory co-substrate in the metabolism of both tissue folates and choline.Mammalian livers contain a sensitive regulatory mechanism which allows either conservation or catabolism of methionine as a function of the dietary content of this nutrient.The enzymes which utilize homocysteine comprise this regulatory site (1, 2).Remethylation, by means of either betaine-homocysteine methyltransferase (EC 2.1.1.5)or 5-methyltetrahydrofolate-homocysteine methyltransferase (EC 2.1.1.13),regenerates methionine.Conversely, the synthesis of cystathionine irreversibly commits the homocysteine moiety to the transsulfuration sequence.Benevenga and co-workers (3-5) and Livesey (6) have questioned the role of the transmethylation-transsulfuration path-*