# S-Adenosylmethionine, a Promising Antitumor Agent in Oral and Laryngeal Cancer
## 2 Structural, Metabolic and Regulatory Aspects  
AdoMet, together with its decarboxylated product S-adenosyl-(5\({}^{\prime}\))-3-methylthio-propilammine, is the only sulfonium compound found in mammalian tissues. The study of the biochemistry of AdoMet can be traced back to the experiments of [PERSON] [13], who first synthesized this compound allowing further successful characterization. The positively charged sulfonium center makes AdoMet a chemically versatile molecule and the second most widely used enzyme substrate after ATP [13]. The chiral sulfur center of AdoMet exists in two enantiomeric forms, making AdoMet a diastereomer (Figure 1). The (S,S) configuration represents the only biosynthesized form and also the biologically active form for almost all AdoMet-dependent methyltransferases [14]. Under physiological conditions or normal storage conditions, the absolute configuration (S,S) racemizes to the enzymatically inactive (R,S)-AdoMet with a racemization rate of 8 \(\times\) 10\({}^{-6}\) S\({}^{-1}\) at 37 \({}^{\circ}\)C pH 7.5 [15]. Figure 1: Conformations of S-adenosyl-L-methionine. AdoMet biosynthesis occurs mainly in the liver, where most of the methylation reactions take place [16; 17; 18], and is carried out by methionine adenosyltransferase (MAT) (EC 2.5.1.6), also known as AdoMet synthetase. This enzyme catalyzes the transfer of the adenosyl moiety of ATP to the sulfur atom of methionine in a two-step reaction requiring Mg\({}^{2+}\) and K\({}^{+}\) ions following a S\({}_{N}\)2 mechanism [16; 17; 18]. Notably in this reaction, ATP plays an unusual role, undergoing complete dephosphorylation to provide energy for the removal of the reaction product from the enzyme active site. The biosynthesis of AdoMet is a process essential for life, as demonstrated by findings indicating that the gene encoding MAT protein represents one of the 482 genes necessary for the survival of all organisms and that its expression occurs in all cells except for some parasites and infectious agents which acquire AdoMet from their hosts [16; 17; 18; 19; 20]. AdoMet is a ubiquitous sulfurnucleoside widely known as the principal biological methyl donor for the majority of methyltransferases. Recently, AdoMet has been well-explored as a therapeutic compound for its antiproliferation and proapoptotic effects in many types of human tumors [10; 21; 22; 23; 24; 25]. Several multiple isoforms of MAT with different kinetic, regulatory, and physical properties have been characterized in mammalian tissues [17; 18]. Recently, the presence of MAT in the nucleus has been demonstrated [26] and it has been hypothesized that this MAT activity might be involved in providing a source of nuclear AdoMet necessary for DNA or histone methylation. In mammals, three isoforms of AdoMet synthetase have been isolated and characterized, encoded by two different genes: _MAT1A_ and _MAT2A_. _MAT1A_ is mostly expressed in the adult liver and encodes the \(\alpha\)1 subunit, present in two isoforms: MAT III (dimer of \(\alpha\)1 subunit) and MAT I (tetramer of \(\alpha\)1 subunit). _MAT2A_ instead encodes for the \(\alpha\)2 catalytic subunit found in the MAT II isoenzyme, which is widely distributed and active in all cells with a marked predominance in the fetal liver, where it will be progressively replaced during development by the _MAT1A_ gene product [17; 18]. The _MAT2B_ gene encodes a regulatory \(\beta\) subunit existing in two distinct splicing variants: V1 and V2 that differ in NH2-terminal amino acid sequence of the protein. Both splicing variants of the \(\beta\) regulatory subunit can be associated with MAT II [17; 18] and regulate its catalytic activity. The expression of the _MAT2B_ gene was observed only in mammals, especially in all examined extrahepatic tissues, and at low levels in the adult liver.