848 Biochemical Society Transactions (2008) Volume 36, part 5 S-adenosylmethionine and proliferation: new pathways, new targets Nuria Mart´ ınez-L ´ opez*, Marta Varela-Rey*, Usue Ariz*, Nieves Embade*, Mercedes Vazquez-Chantada*, David Fernandez-Ramos*, Laura Gomez-Santos*, Shelly C. Lu†, Jose M. Mato* and Maria L. Martinez-Chantar* 1 *Unidad de Metabol ´ omica, CIC bioGUNE (Asociacion Centro de Investigaci ´ on Cooperativa en Biociencias), Parque Tecnol ´ ogico de Bizkaia, Edificio 801A, 48160 Derio (Bizkaia), Spain, and †Keck School of Medicine, USC (University of Southern California), Los Angeles, CA 90089, U.S.A. Abstract SAMe (S-adenosylmethionine) is the main methyl donor group in the cell. MAT (methionine adenosyl- transferase) is the unique enzyme responsible for the synthesis of SAMe from methionine and ATP, and SAMe is the common point between the three principal metabolic pathways: polyamines, transmethylation and transsulfuration that converge into the methionine cycle. SAMe is now also considered a key regulator of metabolism, proliferation, differentiation, apoptosis and cell death. Recent results show a new signalling pathway implicated in the proliferation of the hepatocyte, where AMPK (AMP-activated protein kinase) and HuR, modulated by SAMe, take place in HGF (hepatocyte growth factor)-mediated cell growth. Abnormalities in methionine metabolism occur in several animal models of alcoholic liver injury, and it is also altered in patients with liver disease. Both high and low levels of SAMe predispose to liver injury. In this regard, knockout mouse models have been developed for the enzymes responsible for SAMe synthesis and catabolism, MAT1A and GNMT (glycine N-methyltransferase) respectively. These knockout mice develop steatosis and HCC (hepatocellular carcinoma), and both models closely replicate the pathologies of human disease, which makes them extremely useful to elucidate the mechanism underlying liver disease. These new findings open a wide range of possibilities to discover novel targets for clinical applications. SAMe metabolism Since its discovery, SAMe (S-adenosylmethionine; also known as AdoMet and SAM) has emerged as an important molecule that controls numerous cellular functions. Liver plays a central role in the homoeostasis of SAMe as the major site of its synthesis and degradation [1]. The liver is where up to half of the daily intake of methionine is converted into SAMe and up to 85 % of all methylation reactions take place [2]. MAT (methionine adenosyltransferase) is the only en- zyme responsible for biosynthesis of SAMe from methionine and ATP [1], making it indispensable for the survival of an organism. In mammals, of the two genes (MAT1A, MAT2A) that encode MAT, MAT1A is mainly expressed in adult liver, whereas MAT2A is expressed in all extrahepatic tissues. MAT2A and its gene product also predominate in the fetal liver and are progressively replaced by MAT1A during de- velopment [3,4]. In the liver, MAT1A expression is associated with a differentiated phenotype, whereas MAT2A expression is associated with rapid growth and de-differentiation. SAMe is the link to three key metabolic pathways: polyamine synthesis, transmethylation and transsulfuration Key words: glycine N-methyltransferase (GNMT), HuR, liver, methionine adenosyltransferase (MAT), non-alcoholic steatohepatitis (NASH), S-adenosylmethionine (SAMe). Abbreviations used: AMPK, AMP-activated protein kinase; BHMT, betaine homocysteine methyltransferase; CBS, cystathionine β-synthase; GNMT, glycine N-methyltransferase; HCC, hepatocellular carcinoma; HGF, hepatocyte growth factor; MAT, methionine adenosyltransferase; MTA, methylthioadenosine; MTHFR, methylenetetrahydrofolate reductase; NASH, non-alcoholic steatohepatitis; OA, okadaic acid; PP, protein phosphatase; SAMe, S-adenosylmethionine. 1 To whom any correspondence should be addressed (email mlmartinez@cicbiogune.es). (Figure 1). In polyamine synthesis, SAMe is decarboxylated and the remaining propylamino moiety is donated to putres- cine to form spermidine and MTA (methylthioadenosine) and to spermidine to form spermine and a second molecule of MTA. In transmethylation, SAMe donates its methyl group to a large variety of acceptor molecules in reactions catalysed by methyltransferases. SAMe is largely regulated by GNMT (glycine N-methyltransferase) [5], the major methyltrans- ferase that accounts for 1 % of the soluble protein in rat liver [6,7]. The transsulfuration pathway is particularly active in the liver, making SAMe an important precursor of glutathione (GSH) [8]. All mammalian tissues express MAT and methionine synthase, whereas BHMT (betaine homocysteine methyltransferase) is limited to the liver and kidney. In the liver, SAMe inhibits MTHFR (methylenetetrahydrofolate re- ductase) and methionine synthase, and activates CBS (cysta- thionine β -synthase) [9,10]. Thus, when SAMe is depleted, homocysteine is channelled to remethylation to regenerate SAMe, whereas when SAMe level is high, homocysteine is channelled to the transsulfuration pathway. SAMe and proliferation In hepatocytes, SAMe levels control the differentiation status of the hepatocyte. Regarding this point, quiescent and proliferating hepatocytes display different SAMe contents, being lower in the growing cells [11]. In addition, after partial hepatectomy the levels of SAMe are decreased dramatically, coinciding with the onset of DNA synthesis and the induction C  The Authors Journal compilation C  2008 Biochemical Society Biochem. Soc. Trans. (2008) 36, 848–852; doi:10.1042/BST0360848 Biochemical Society Transactions www.biochemsoctrans.org