S-adenosylmethionine in Liver Health, Injury, and Cancer

Abstract

S-adenosylmethionine (AdoMet, also known as SAM and SAMe) is the principal biological methyl donor synthesized in all mammalian cells but most abundantly in the liver. Biosynthesis of AdoMet requires the enzyme methionine adenosyltransferase (MAT). In mammals, two genes, MAT1A that is largely expressed by normal liver and MAT2A that is expressed by all extrahepatic tissues, encode MAT. Patients with chronic liver disease have reduced MAT activity and AdoMet levels. Mice lacking Mat1a have reduced hepatic AdoMet levels and develop oxidative stress, steatohepatitis, and hepatocellular carcinoma (HCC). In these mice, several signaling pathways are abnormal that can contribute to HCC formation. However, injury and HCC also occur if hepatic AdoMet level is excessive chronically. This can result from inactive mutation of the enzyme glycine N-methyltransferase (GNMT). Children with GNMT mutation have elevated liver transaminases, and Gnmt knockout mice develop liver injury, fibrosis, and HCC. Thus a normal hepatic AdoMet level is necessary to maintain liver health and prevent injury and HCC. AdoMet is effective in cholestasis of pregnancy, and its role in other human liver diseases remains to be better defined. In experimental models, it is effective as a chemopreventive agent in HCC and perhaps other forms of cancer as well.

AMD1 mRNA employs ribosome stalling as a mechanism for molecular memory formation

“…SAM is an important metabolite as it serves as a major donor of methyl groups in numerous reactions involving methylation of DNA, RNA, proteins and metabolites [4][5][6] . Thus, in addition to its essential role in polyamine synthesis, AdoMetDC may also influence methylation reactions by affecting SAM availability.…”

Human METTL20 Is a Mitochondrial Lysine Methyltransferase That Targets the β Subunit of Electron Transfer Flavoprotein (ETFβ) and Modulates Its Activity

“…Thus, the interesting possibility exists that the interaction of these enzymes with ETF is more sensitive to ETF␤ methylation status than what is the case for the enzymes tested here. Recent studies have indicated that cellular SAM levels are subject to tight regulation, and the one-carbon units generated by DMGDH and SARDH can actually be used for replenishment of the cellular SAM pool (33). Thus, the interesting, though speculative, possibility exists that METTL20 acts as SAM sensor, which in a SAM-dependent manner regulates the flow of electrons from DMGDH and/or SARDH to ETF, thereby regulating the level of one-carbon units available for SAM synthesis.…”

Crystallography captures catalytic steps in human methionine adenosyltransferase enzymes

“…methionine adenosyltransferase | cell growth | liver cancer | X-ray crystallography | methylation T ransmethylation, the transfer of a methyl group from one molecule to another, is a fundamental chemical reaction that plays a central role in important biological processes such as gene expression, cell growth, and apoptosis (1). The highly conserved methionine adenosyltransferase (MAT) enzymes synthesize the main source of methyl groups in all living organisms in the form of S-adenosylmethionine (SAMe) (2).…”

“…For example, mutations involving the MAT1A gene have links with hepatic MAT deficiency which leads to hypermethioninemia (6,7). Expression of MATα2 confers a growth advantage in cells and is important for differentiation and apoptosis (1) in diseases such as human hepatocellular carcinoma (5), colon cancer (8), and leukemia (9).…”