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nucleosides (3-amino carboxypropyl group), pelargonic María Ángeles Pajares
acid (amino group), polyamines, molecules involved in
bacterial signaling and ethylene (aminopropyl group). concerning other organs is becoming available (i.e. the
SAM can also be used both as cofactor or substrate by cochlea (12)). The need for increasing the existing
SAM radical proteins, which catalyze probably the last set knowledge in extrahepatic tissues has been emphasized
of reactions involving this compound that has been when impairments of the methionine cycle, and especially
identified to date (3,8). In mammals, transmethylations reductions in SAM concentrations or
consume approximately 95% of the SAM produced and hyperhomocysteinemia, have been associated with
the rest is used for SAM decarboxylation, being different pathologies. Most of the diseases in which
decarboxylated SAM the genuine aminopropyl donor for alterations of the pathway have been demonstrated concern
the synthesis of the polyamines spermidine and spermine the liver (i.e. hepatitis, cirrhosis, acute liver failure,
(4,9). hepatocellular carcinoma) (9,13), but its impairment in
cardiovascular diseases (14,15), Alzheimer (16-18),
2. THE METHIONINE CYCLE IN MAMMALS psoriasis (19), rare diseases (i.e. Wilson disease) (20-22)
and even hearing loss (12,23) has been also shown. It is
SAM synthesis is carried out by methionine not surprising that such a variety of pathological states
adenosyltransferases (MATs; EC 2.5.1.6), also known as concur with an anomalous function of the methionine
SAM synthetases, this step being the first and rate limiting cycle, given not only the large diversity of biological
of the methionine cycle (4) (Figure 1). Most of the processes involving SAM, but also the connections of this
information regarding this pathway has been obtained in pathway with additional key routes and its dependence on
liver, where a human adult processes up to 48% of the the nutrient status, as will be explained below.
ingested methionine (9-11), but slowly information

Figure 1. Mammalian methionine cycle and associated pathways. The scheme shows the main reactions involved in the methionine
cycle, polyamine synthesis, folate cycle, trans-sulfuration and glutathione synthesis. A discontinuous blue line indicates the methionine
salvage pathway. Enzymes and metabolites appear abbreviated as follows: MATs, methionine adenosyltransferases; PEMT,
phosphatidylethanolamine N-methyltransferase; GNMT, glycine N-methyltransferase; GAMT, guanidinoacetate N-methyltransferase;
MTases, methyltransferases; SAHH, S-adenosylhomocysteine hydrolase; ADK, adenosine kinase; ADA, adenosine deaminase; CBS,
cystathionine ß-synthase; CTH, cystathionase; GCS, ?-glutamylcysteine synthetase; GSS, glutathione synthetase; GSR, glutathione
reductase; BHMT, betaine homocysteine methyltransferase; BHMT2, betaine homocysteine methyltransferase 2; MTR, methionine
synthase; DHFR, dihydrofolate reductase; SHMT, serine hydroxymethyltransferase; MTHFR, methylene tetrahydrofolate reductase;
AMD, S-adenosylmethionine decarboxylase; THF, tetrahydrofolate; DHF, dihydrofolate; MTHF, 5-methyl tetrahydrofolate; MeTHF,
methylene tetrahydrofolate; MTA, methylthioadenosine; GSSG, glutathione oxidized form; GAA, guanidinoacetate; X, any methyl

acceptor.

Methionine was discovered in 1923 by Mueller (24), and found to be essential for mammals in 1937, when

232 @Real Academia Nacional de Farmacia. Spain