S-adenosylmethionine (SAM) is the primary methyl donor in the human body and is the substrate for over 100 different methyltransferase enzymes that methylate DNA, RNA, proteins, lipids, neurotransmitters, and a vast array of other substrates. SAM is synthesised from methionine and ATP by the enzyme methionine adenosyltransferase (MAT), and it is the universal methyl donor for virtually all methylation reactions in the body. After donating its methyl group, SAM becomes S-adenosylhomocysteine (SAH), which is hydrolysed to homocysteine. The methylation cycle — the network of reactions that generates SAM, uses SAM for methylation, and recycles SAH back to methionine — is the foundation of all methyl group metabolism in the body, and its dysfunction is implicated in some of the most common chronic diseases of modern civilisation, including cardiovascular disease, neurodegenerative disease, depression, and cancer.
SAM and DNA Methylation
DNA methylation is the most important epigenetic mechanism for the regulation of gene expression — it involves the addition of a methyl group to the cytosine residues in CpG dinucleotides, generating 5-methylcytosine, which is a stable epigenetic mark that is associated with gene silencing. The DNA methyltransferases (DNMTs) that catalyse DNA methylation require SAM as the methyl donor, and the availability of SAM is one of the primary determinants of the DNA methylation status of the genome. When SAM levels are high (as after a diet rich in methionine, folate, and other methyl donor nutrients), DNA methylation is increased at specific genomic regions, and the expression of the genes that are regulated by these methylation events is correspondingly altered. When SAM levels are low (as in folate deficiency, in vitamin B12 deficiency, or in the conditions that are associated with elevated homocysteine), the DNA methylation status of the genome is altered in ways that are associated with the genomic instability, the aberrant gene expression, and the cellular dysfunction that characterise cancer and other chronic diseases.
The clinical importance of SAM for DNA methylation is most clearly seen in the association between low SAM levels and cancer. In many cancers, the global DNA methylation pattern is altered — there is a paradoxical increase in DNA methylation at specific genomic regions (particularly in the promoters of tumour suppressor genes, where DNA methylation silences tumour suppressor gene expression) combined with a global decrease in DNA methylation (particularly in the repetitive DNA sequences, where hypomethylation is associated with genomic instability). This altered DNA methylation pattern is one of the most consistent epigenetic findings in cancer, and it is thought to contribute to both the silencing of tumour suppressor genes and to the genomic instability that drives cancer progression.
SAM and Neurotransmitter Synthesis
SAM is also the methyl donor for the synthesis of the neurotransmitters adrenaline and noradrenaline, for the methylation of phosphatidylethanolamine to phosphatidylcholine (the most abundant phospholipid in the cell membrane), and for the methylation of the myelin basic protein that is essential for the integrity of the myelin sheath. The synthesis of adrenaline from noradrenaline requires SAM as the methyl donor, catalysed by phenylethanolamine N-methyltransferase (PNMT), which is expressed primarily in the adrenal medulla. The methylation of phosphatidylethanolamine to phosphatidylcholine (catalysed by phosphatidylethanolamine N-methyltransferase, PEMT) is one of the primary mechanisms by which the phospholipid composition of the cell membrane is regulated, and it is particularly important in the liver, where the PEMT reaction is highly active and where phosphatidylcholine is required for the assembly and secretion of very-low-density lipoprotein (VLDL).
Practical Application
For general SAM supplementation (as a methylation support strategy), the evidence-based approach is to supplement with SAM at 200-400mg daily, taken in the morning on an empty stomach for optimal absorption. SAM is generally well-tolerated with no significant adverse effects at therapeutic doses, though very high doses can produce mild GI upset and insomnia. SAM is most commonly used for depression (it has been studied in over 30 RCTs for its antidepressant effects, with a effect size that is comparable to that of the tricyclic antidepressants), for osteoarthritis (SAM has been shown in multiple RCTs to reduce pain and improve function in knee and hip osteoarthritis, possibly through its effects on cartilage metabolism), and for liver disease (SAM supports liver methylation reactions and has been shown to improve liver function in alcoholic liver disease and in cholestasis). For comprehensive methylation support, SAM pairs well with the B-complex vitamins (particularly folate, B12, and B6, which are required for the methylation cycle and for the clearance of homocysteine), with trimethylglycine (TMG, which provides additional methyl groups for the methylation cycle), with NAC (which supports glutathione synthesis and the transsulfuration pathway), and with the omega-3 fatty acids (which have anti-inflammatory effects and which are required for the synthesis and the function of cell membranes).
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