Page 119 - 82_02
P. 119
The new levels of redox regulation of S-adenosylmethionine synthesis
growth retardation was detected in rats fed methionine-free adenosine can be utilized by adenosine deaminase (ADA;
diets (25). Hence, this amino acid must be obtained from EC 3.5.4.4) or adenosine kinase (ADK; EC 2.7.1.20) to
the diet, and after absorption, needs to be distributed to the produce inosine or AMP, respectively (26). All these
whole organism, where requirements of each organ are not reactions connect the methionine cycle with multiple
equal, as mentioned previously. Once into the cell the use pathways in which regulators of the former are generated,
of this amino acid is shared between protein synthesis and hence creating a series of feedback loops whose
the methionine cycle, and part of the methionine consumed complexity is not totally understood. Moreover, all the
in these pathways can be recycled. Mammalian cells can reactions described above do not show identical
recover part of the methionine used in the methionine importance in every tissue, due to differences in gene
cycle by homocysteine (Hcy) remethylation and also by expression patterns, and hence, on the enzymes or
the methionine salvage pathway, which has a minor role. isoenzymes encountered in each cell type.
Hcy remethylation requires additional methyl donors to
synthesize methionine, being those mainly 5-methyl Main players in the regulation of the hepatic
tetrahydrofolate (MTHF), but also betaine and S- methionine cycle are metabolites, from the same or related
methylmethionine (vitamin U). These remethylation pathways, hormones and nutrients, some of their key
reactions are catalyzed by a vitamin B12-dependent effects being summarized below. Among the metabolites,
methionine synthase (MTR; EC 2.1.1.13), betaine SAM deserves a special consideration, since its role
homocysteine methyltransferase (BHMT; EC 2.1.1.5) and includes the activation or inhibition of several enzymes
BHMT2 (EC 2.1.1.10), respectively (26,27). The Hcy such as MATs, CBS and CTH, as well as the inhibition of
required for this purpose is generated as an intermediate in BHMT expression (29,31,32). SAM further contributes to
the trans-sulfuration pathway that converts methionine into the inter-regulation between pathways by inhibiting
cysteine, and in which SAM synthesis by MATs is the first methylene tetrahydrofolate reductase (MTHFR; EC
step. Transmethylations then use the methyl donor 1.5.1.20) of the folate cycle and regulating AMP kinase
rendering the methylated products together with (AMPK; EC 2.7.11.31) phosphorylation (33,34). Nutrients
demethylated SAM, named S-adenosylhomocysteine such as vitamins of the B group, or their derivatives, also
(SAH). Three methyltransferases in charged of the have a relevant role as cofactors or substrates for MTR,
synthesis of small compounds are the main consumers of CBS and CTH, but also as inhibitors of GNMT in the form
hepatic SAM. Namely, glycine N-methyltransferase of MTHF (35-38). Moreover, methionine levels have been
(GNMT; EC 2.1.1.20), phosphatidylethanolamine N- shown to regulate expression of MAT genes (39), and
methyltransferase (PEMT; EC 2.1.1.17) and hormones seem to exert their role preferentially at the
guanidinoacetate N-methyltransferase (GANMT; EC expression level, as occurs with glucocorticoids and MAT
2.1.1.2) which synthesize sarcosine, phosphatidylcholine genes (40). Redox regulation is exerted by glutathione, and
and creatine, respectively (13). the ratio of its reduced (GSH) and oxidized (GSSG) forms
(41-43), nitric oxide (44), hydroxyl radicals (45), NADP+
The byproduct of transmethylations, SAH, is a potent (46), copper (20,47), etc. on MATs and SAHH.
inhibitor of most methyltransferases and its hydrolysis is Additionally, oxidative stress inhibits MTR and activates
carried out by SAH hydrolase (SAHH or AHCY; EC CBS through changes in the redox status of their cofactors,
3.3.1.1) in the only reversible reaction of the methionine vitamin B12 and the heme group, respectively (48).
cycle, which renders adenosine and Hcy (9). Elimination
of SAH is key in order to maintain an appropriate 3. METHIONINE ADENOSYLTRANSFERASES
methylation level that depends on the SAM/SAH ratio,
also known as the methylation index. Calculations carried MATs are a family of enzymes highly conserved
out in several tissues have established that the optimal between Bacteria and Eukaryota. This conservation
hepatic ratio is approximately 4, although this number is expands from the amino acid sequence to the protein
higher for other tissues such as the lung, where the structure, facts that allowed us to propose MATs as a good
preferred methylation index is around 9 (28). Preservation phylogenetic marker back in 2004 (49). Moreover, MATs
of these optimal SAM/SAH ratios depends on an efficient from Archaea despite their low sequence conservation
removal of Hcy, adenosine or both.
(~18%) still preserve the amino acid residues involved in
Hcy levels depend on its catabolism through the catalysis (50), suggesting that the mechanism for SAM
remaining reactions of the trans-sulfuration pathway synthesis has been maintained throughout evolution (5).
leading to cystathionine and cysteine, its elimination into This family of enzymes uses methionine and ATP as
the blood or, when methionine levels become low, its substrates in a reaction that requires Mg2+ and K+ ions and
remethylation. The metabolic branch point represented by which takes place in two steps: 1) the transfer of the
Hcy favors its use for cysteine synthesis through the adenosyl moiety of ATP to the sulfur atom of methionine,
generating SAM and triphosphate; and 2) the hydrolysis of
consecutive activities of cystathione ß-synthase (CBS; EC the triphosphate originating pyrophosphate and inorganic
4.2.1.22) and cystathionase (CTH; EC 4.4.1.1). These two phosphate and allowing SAM liberation from the active
enzymes exhibit higher Km values for Hcy than site (4,5).
remethylating proteins, are activated by high levels of
SAM and require vitamin B6 (26,29,30). In parallel, There are three MAT genes in mammals, named
MAT1A, MAT2A and MAT2B, which encode two types of
@Real Academia Nacional de Farmacia. Spain 233
