S-adenosylmethionine and proliferation: new pathways, new targets.
SAMe (S-adenosylmethionine) is the main methyl donor group in the cell. MAT (methionine adenosyltransferase) 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.
Martínez-López
Nuria
N
Unidad de Metabolómica, CIC bioGUNE (Asociacion Centro de Investigación Cooperativa en Biociencias), Parque Tecnológico de Bizkaia, Edificio 801A, 48160 Derio (Bizkaia), Spain.
Varela-Rey
Marta
M
Ariz
Usue
U
Embade
Nieves
N
Vazquez-Chantada
Mercedes
M
Fernandez-Ramos
David
D
Gomez-Santos
Laura
L
Lu
Shelly C
SC
Mato
Jose M
JM
Martinez-Chantar
Maria L
ML
D055372:AMP-Activated Protein Kinases; D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D049109:Cell Proliferation; D004195:Disease Models, Animal; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000473:pathology / Q000503:physiopathology; D008715:Methionine / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009097:Multienzyme Complexes / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D000954:Antigens, Surface; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D009097:Multienzyme Complexes; D016601:RNA-Binding Proteins; D012436:S-Adenosylmethionine; D008715:Methionine; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases