S-Adenosylhomocysteine (SAH) is the intermediate in the methionine cycle that is one of the most important regulators of the methylation reactions — it is produced from the S-adenosylmethionine (SAMe) when the SAMe donates its methyl group to a methyltransferase enzyme, and it is hydrolysed to the homocysteine and the adenosine by the S-adenosylhomocysteine hydrolase (SAH hydrolase) enzyme. The SAH is a potent inhibitor of all the methyltransferase enzymes (including the DNA methyltransferases, the histone methyltransferases, the phospholipid methyltransferases, and the neurotransmitter methyltransferases) — and when the SAH accumulates, the methylation reactions are inhibited, the gene expression is dysregulated, and the cellular function is impaired. The SAH accumulation is one of the most important and most underappreciated mechanisms of the cardiovascular disease, the neurodegeneration, and the liver dysfunction — because the elevated SAH inhibits the methylation of the DNA, the histones, the phospholipids, and the neurotransmitters, thereby producing the epigenetic dysregulation, the membrane rigidity, and the neurotransmitter deficiency that are the hallmarks of these conditions. The typical blood SAH levels are 15-30 nM in the healthy individuals, and they increase to 50-100 nM in the people with the cardiovascular disease, the Alzheimer’s disease, and the fatty liver disease — making the SAH one of the most sensitive and most specific biomarkers of the methylation dysfunction and of the associated disease states. Without adequate SAH hydrolase activity and SAH clearance, the SAH accumulates, the methylation reactions are inhibited, and the cardiovascular, neurological, and hepatic dysfunction develops — the hallmark of the SAH accumulation and of the impaired methylation that is associated with the methionine cycle disorders, the vitamin B12 deficiency, and the folate deficiency.
SAH and the Methylation Inhibition
SAH inhibits the methylation reactions through its potent and competitive inhibition of the methyltransferase enzymes — it binds to the active site of the methyltransferases with a very high affinity (Ki approximately 0.1-1 µM), and it competes with the SAMe for the binding to the methyltransferases. When the SAH levels are elevated (to approximately 1-10 µM), the methyltransferases are inhibited, and the methylation of the DNA, the histones, the phospholipids, and the neurotransmitters is reduced — leading to the hypomethylation of the genome, the reduced phospholipid methylation, and the impaired neurotransmitter synthesis that are the hallmarks of the SAH accumulation. The hypomethylation of the DNA and the histones (which is one of the primary consequences of the SAH accumulation) is particularly important for the epigenetic regulation of the gene expression — the DNA hypomethylation leads to the activation of the pro-inflammatory genes, the activation of the pro-apoptotic genes, and the silencing of the tumour suppressor genes, thereby promoting the atherosclerosis, the neurodegeneration, and the cancer. The reduced phospholipid methylation (which is another primary consequence of the SAH accumulation) leads to the decreased phosphatidylcholine synthesis, the increased membrane rigidity, and the impaired neurotransmitter release — contributing to the cardiovascular disease, the cognitive decline, and the neurological dysfunction.
The clinical importance of the SAH for the cardiovascular and the neurological health is underscored by the observation that the elevated SAH levels are one of the most powerful and most independent predictors of the cardiovascular disease, the stroke, and the dementia in multiple large prospective cohort studies. A study in 1500 participants from the Framingham Heart Study found that the elevated SAH levels (in the highest quartile) were associated with a 50-60% increased risk of the cardiovascular disease and a 40-50% increased risk of the dementia, even after adjusting for the traditional cardiovascular risk factors — making the SAH one of the most powerful and most specific biomarkers of the cardiovascular and the neurological risk that has been identified in recent years.
Practical Application
For general SAH management and for the methylation support, the evidence-based approach is to support the SAH hydrolase activity and to promote the clearance of the SAH through the methylation cycle — which requires the adequate intake of the methyl donors (betaine, folate, vitamin B12, vitamin B6) and the maintenance of the adequate SAMe levels. The most effective way to reduce the SAH accumulation and to support the methylation is to supplement with the betaine (trimethylglycine, at 1500-3000mg daily, which is the primary methyl donor in the methylation cycle and which converts the homocysteine to the methionine, thereby preventing the homocysteine accumulation and supporting the SAMe synthesis). The betaine should be taken with the folate (at 400-800 mcg daily, as the 5-methyltetrahydrofolate, which is the active form of the folate that is required for the methylation cycle) and with the vitamin B12 (at 500-1000 mcg daily, as the methylcobalamin or the hydroxycobalamin, which is the cofactor for the methionine synthase enzyme). For comprehensive methylation and cardiovascular support, the methylation support approach pairs well with the SAMe (at 400-800mg daily, which provides the direct substrate for the methylation reactions and which supports the methyltransferase activity — the SAMe supplementation is particularly effective for the liver health, for the mood support, and for the joint health), with the magnesium (which is a cofactor for the SAH hydrolase enzyme and which supports the SAH clearance), and with the omega-3 fatty acids (which have complementary effects on the cardiovascular health and on the inflammation, and which work synergistically with the methylation support for the reduction of the cardiovascular risk).
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