Dimers of cMAT (1FUG) and rlMAT I/III (1QM4) are shown in the figure. Each subunit appears in a different color; subunit A (palecyan) and subunit B (light pink). The P-loop sequence of subunit A appears in black, whereas the active site phenylalanine residue appears in red for cMAT (F230) and aquamarine for rlMAT I/III (F251). The white bar shows the distance between both areas in each active site.

The upper part of the figure shows the distribution along the sequence of the segments composing each domain of the monomer. Moreover, schematic representations of two of the truncated forms derived from mutations detected in the human MAT1A gene are also included (351X and 185X). Finally, the lower part includes cartoons for the wild type (wt) and putative 351X truncated dimers detected in patients with hypermethioninemia and demyelination. An arrow indicates the area that differs between the wild type and 351X structures.

In vitro folding studies using rlMAT I/III revealed three intermediates: one monomeric equilibrium intermediate (I); and two kinetic intermediates (I_k¹ and I_k²). I_k¹ is proposed to be a dimer, whereas I_k² is predicted to be a monomer. All these species can be detected under reducing conditions, and interconversion among tetramers and dimers is observed in a concentration dependent equilibrium. However, under oxidative conditions (i.e. GSH/GSSG = 10) this association/dissociation process is blocked by production of the C35-C61 intrasubunit disulfide.

The figure shows a scheme of the hepatic methionine cycle and some of the related pathways mentioned in this review. Methionine is converted to S-adenosylmethionine (AdoMet) by methionine adenosyltransferases (MAT; EC 2.5.1.6); this compound can be used by a multitude of enzymes such as methyltransferases (MTases; EC 2.1.1.X), SAM radical proteins (EC 2.8.1.6 for biotin synthesis) and AdoMet decarboxylase (AdoMetDC; EC 4.1.1.50). Polyamine synthesis occurs with methylthioadenosine (MTA) production, a compound that can be reused for methionine synthesis by the methionine salvage pathway. On the other hand, the action of MTases renders methylated products and S-adenosylhomocysteine (AdoHcy) that can be hydrolyzed by AdoHcy hydrolase (SAHH, EC 3.3.1.1) to adenosine and homocysteine (Hcy). This reaction is reversible and favors AdoHcy synthesis. Hcy can be metabolized through the trans-sulfuration pathway by the consecutive action of cystathionine β synthase (CBS; EC 4.2.1.22) and cystathionine γ lyase (CγL; EC 4.4.1.1) rendering cysteine for glutathione synthesis, among other purposes. In addition, Hcy can also serve in resynthesis of methionine by two reactions catalyzed by methionine synthase (MS; EC 2.1.1.13) and betaine homocysteine methyltransferase (BHMT; EC 2.1.1.5). Some of these steps can be modulated by metabolites synthesized in these pathways and dashed lines indicate the most relevant.