RESUMEN
S-Adenosylmethionine (AdoMet) is the major biological methyl donor. AdoMet's methyl group arises both from the diet (eg, methionine, choline, and betaine) and from de novo synthesis by the process of methylneogenesis. At least 50 AdoMet-dependent methylation reactions have been identified in mammals, and genomic analyses suggest that the final number will be much higher. Such methylation reactions play major roles in biosynthesis, regulation, and detoxification. Creatine synthesis is thought to account for the use of >70% of AdoMet-derived methyl groups in humans. This is not consistent with recent studies in mice, in which the phosphatidylethanolamine methyltransferase gene was deleted (PEMT-/-). Loss of this hepatic enzyme resulted in a 50% decrease in plasma homocysteine, which suggests that it accounts for a major component of whole-body AdoMet utilization. A reexamination of human creatine metabolism showed that dietary creatine can account for as much as 50% of daily creatine requirements in nonvegetarians and, therefore, that estimates of creatine synthesis need to be reduced. We suggest that creatine synthesis is responsible for a smaller proportion of AdoMet-derived methyl groups than has been suggested and that phosphatidylcholine synthesis via phosphatidylethanolamine methyltransferase is a major consumer of these methyl groups.
Asunto(s)
Creatina/biosíntesis , Fosfatidilcolinas/biosíntesis , Fosfatidiletanolamina N-Metiltransferasa/metabolismo , S-Adenosilmetionina/metabolismo , Animales , Creatina/administración & dosificación , Creatina/metabolismo , Creatinina/orina , Dieta , Humanos , Metilación , RatonesRESUMEN
Biological methylation reactions and homocysteine (Hcy) metabolism are intimately linked. In previous work, we have shown that phosphatidylethanolamine N-methyltransferase, an enzyme that methylates phosphatidylethanolamine to form phosphatidylcholine, plays a significant role in the regulation of plasma Hcy levels through an effect on methylation demand (Noga, A. A., Stead, L. M., Zhao, Y., Brosnan, M. E., Brosnan, J. T., and Vance, D. E. (2003) J. Biol. Chem. 278, 5952-5955). We have further investigated methylation demand and Hcy metabolism in liver-specific CTP:phosphocholine cytidylyltransferase-alpha (CTalpha) knockout mice, since flux through the phosphatidylethanolamine N-methyltransferase pathway is increased 2-fold to meet hepatic demand for phosphatidylcholine. Our data show that plasma Hcy is elevated by 20-40% in mice lacking hepatic CTalpha. CTalpha-deficient hepatocytes secrete 40% more Hcy into the medium than do control hepatocytes. Liver activity of betaine:homocysteine methyltransferase and methionine adenosyltransferase are elevated in the knockout mice as a mechanism for maintaining normal hepatic S-adenosylmethionine and S-adenosylhomocysteine levels. These data suggest that phospholipid methylation in the liver is a major consumer of AdoMet and a significant source of plasma Hcy.
Asunto(s)
Homocisteína/sangre , Fosfolípidos/metabolismo , Animales , Betaína-Homocisteína S-Metiltransferasa , Membrana Celular/metabolismo , Citidina Difosfato Colina/metabolismo , Citosol/metabolismo , Hepatocitos/metabolismo , Hígado/embriología , Metionina Adenosiltransferasa/metabolismo , Metilación , Metiltransferasas/metabolismo , Ratones , Ratones Noqueados , Fosfatidilcolinas/metabolismo , Fosfatidiletanolaminas/metabolismoRESUMEN
Elevated plasma homocysteine is a risk factor for cardiovascular disease and Alzheimer's disease. To understand the factors that determine the plasma homocysteine level it is necessary to appreciate the processes that produce homocysteine and those that remove it. Homocysteine is produced as a result of methylation reactions. Of the many methyltransferases, two are, normally, of the greatest quantitative importance. These are guanidinoacetate methyltransferase (that produces creatine) and phosphatidylethanolamine N-methyltransferase (that produces phosphatidylcholine). In addition, methylation of DOPA in patients with Parkinson's disease leads to increased homocysteine production. Homocysteine is removed either by its irreversible conversion to cysteine (transsulfuration) or by remethylation to methionine. There are two separate remethylation reactions, catalyzed by betaine:homocysteine methyltransferase and methionine synthase, respectively. The reactions that remove homocysteine are very sensitive to B vitamin status as both the transsulfuration enzymes contain pyridoxal phosphate, while methionine synthase contains cobalamin and receives its methyl group from the folic acid one-carbon pool. There are also important genetic influences on homocysteine metabolism.
Asunto(s)
Homocisteína/química , Metilación , Animales , Creatina/metabolismo , Guanidinoacetato N-Metiltransferasa , Homocisteína/sangre , Humanos , Levodopa/metabolismo , Metiltransferasas/metabolismo , Modelos Biológicos , Modelos Químicos , Enfermedad de Parkinson/metabolismo , Fosfatidilcolinas/metabolismo , Fosfatidiletanolamina N-Metiltransferasa , RatasRESUMEN
Mild hyperhomocysteinemia is an independent risk factor for cardiovascular disease. Homocysteine, a non-protein amino acid, is formed from S-adenosylhomocysteine and partially secreted into plasma. A potential source for homocysteine is methylation of the lipid phosphatidylethanolamine to phosphatidylcholine by phosphatidylethanolamine N-methyltransferase in the liver. We show that mice that lack phosphatidylethanolamine N-methyltransferase have plasma levels of homocysteine that are approximately 50% of those in wild-type mice. Hepatocytes isolated from methyltransferase-deficient mice secrete approximately 50% less homocysteine. Rat hepatoma cells transfected with phosphatidylethanolamine N-methyltransferase secrete more homocysteine than wild-type cells. Thus, phosphatidylethanolamine N-methyltransferase is an important source of plasma homocysteine and a potential therapeutic target for hyperhomocysteinemia.