# S-Adenosylmethionine, a Promising Antitumor Agent in Oral and Laryngeal Cancer
## 2 Structural, Metabolic and Regulatory Aspects
Over the past five decades, several studies have unequivocally established the significant role of AdoMet in the cellular metabolism of all living organisms, highlighting the importance of maintaining its physiological level in cells [27; 28; 29]. Notably, cells expressing the _MAT1A_ gene show greater intracellular concentration of AdoMet than cells expressing _MAT2A_. Recent studies have shown that in the adult liver, the reduction in _MAT1A_ expression and the concomitant overexpression of _MAT2A_, known as \"_MAT1A/MAT2A_ switch\", cause a chronic depletion of hepatic AdoMet levels, predisposing the liver to developing steatohepatitisitis, cirrhosis, and hepatocellular carcinoma [29]. The synthesis of AdoMet is part of the so-called one-carbon cycle that involves three interrelated biochemical pathways: the methionine cycle, the folate cycle, and the trans-sulfuration pathway. After transferring its methyl group to a large variety of acceptor substrates, AdoMet is converted to S-adenosyl/homocysteine (AdoHcy or SAH), a strong competitive inhibitor of AdoMet-dependent methyltransferases, by the enzyme AdoHcy hydrolase (EC 3.3.1.1. ), leading to the formation of adenosine and homocysteine (Hcy) through a hydrolytic reaction [30; 31]. Hcy, in turn, will either be converted to cystathionine and then to glutathione (GSH) by trans-sulfuration, or will be remethylated to methionine by vitamin B12-dependent homocysteine methyltransferase through the transfer of a methyl group from the methyltetrahydrofolate, completing the methionine cycle (Figure 2) [30; 31; 32]. Modulation of the metabolic flux through the competing remethylation and trans-sulfuration pathways occurs at several levels. In the presence of low levels of AdoMet, Hcy metabolism is shifted towards remethylation to preserve methionine and AdoMet synthesis. On the other hand, high AdoMet levels and methionine excess trigger the trans-sulfurationpathway. In this light, AdoMet is able to control methionine metabolism in response to impairments of physiological conditions. AdoMet exerts a primary role in cellular metabolism through a variety of well-documented biological functions. The reactivity of AdoMet is based on the high-energy sulfonium ion that makes the molecule an efficient methyl-, aminopropyl-, and adenosyl-group donor [9; 12; 30; 31; 32], as well as a key player in three important metabolic pathways, such as transmethylation, trans-sulfuration, and polyamine biosynthesis. The first known and well-studied metabolic reaction from the elucidation of the AdoMet structure is the transmethylation pathway, in which the sulfonium compound donates its methyl group to a large variety of acceptor molecules in reactions catalyzed by methyltransferases [31]. Epigenetic modification is the most important effect obtained by the methylation reaction, and represents one of the most studied processes in cancer. Experimental evidence has been reported, showing that AdoMet, through an epigenetic mechanism, is able to regulate the expression of genes playing a crucial role in cell migration, invasion, and metastasis [33; 34; 35; 36]. In recent decades, many in vitro and in vivo studies have shown the involvement of AdoMet in various cellular processes, including proliferation, differentiation, cell cycle regulation, and apoptosis, demonstrating that the sulfonium compound exerts pleiotropic effects on signal transduction in different cell types and that it is able to halt the progression of many human tumors [21; 22; 23; 24; 25; 26; 27; 28; 29; 33; 34; 35; 36]. In addition to its well-known functions as a methyl donor and precursor of GSH and polyamine biosynthesis, the sulfonium compound serves as a source of 5'-deoxyadenosyl radicals in anaerobic organisms [37]. Radical AdoMet enzymes are found in all domains of life. These enzymes share a CX3 CX2C motif forming a characteristic [4 Fe-4S] cluster that binds AdoMet and catalyzes its reductive cleavage to generate [4 Fe-4S]-methionine and a 5'-deoxyadenosyl 5'-radicals.