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Methylation Index, SAM/SAH

The methylation index SAM/SAH is the ratio between S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) in a biological system. Both SAM and SAH are essential molecules involved in methylation processes. Measuring the SAM/SAH methylation index is helpful for the direct and accurate assessment of methylation in the body.

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SAM is a universal methyl donor in biological systems, and it participates in numerous methylation reactions, including DNA methylation, histone methylation, and the methylation of various other molecules. On the other hand, SAH is produced as a byproduct of these methylation reactions. It acts as an inhibitor of methyltransferase enzymes, which transfer methyl groups from SAM to other molecules.

The SAM/SAH ratio is often used to indicate the cellular methylation potential. A higher SAM/SAH ratio indicates a favorable environment for methylation reactions, suggesting sufficient methyl groups are available for methylation processes. Conversely, a lower SAM/SAH ratio may indicate a decreased methylation capacity, potentially due to reduced SAM levels or increased SAH levels.

Monitoring the SAM/SAH ratio can provide insights into cellular methylation dynamics and potential alterations in methylation patterns associated with various physiological and pathological conditions, such as aging, cancer, and metabolic disorders.

Genetic or nutritional disturbances (e.g., deficiency of folate, Vitamin B12, B6, methionine, or choline) that prevent efficient product removal of homocysteine (Hcy) or adenosine will lead to S-adenosylhomocysteine (SAH) accumulation. Excess SAH and homocysteine are thought to readily cross the cell membrane into the plasma. Elevated SAH or homocysteine has been associated with an increased risk of cardiovascular diseases, colon cancers, birth defects, recurrent pregnancy loss, central nervous system demyelination, and neuropsychiatric disorders. Increased SAH leads to methyltransferase inhibition, which reduces methylation of essential molecules such as DNA, RNA, protein, neurotransmitters, etc. This means the methylation index is much reduced in many pathological processes.

Measuring methylation index SAM/SAH is also helpful when SAM is used daily as a nutritional supplement to avoid unwanted side effects (insomnia, high blood pressure, gas, nausea, vomiting, diarrhea) and ensure proper treatment dosages are taken.

S-adenosylmethionine (SAM) is an essential metabolic intermediate and the cell’s universal methyl donor for synthesizing and modifying various biomolecules, such as nucleic acids, histones, proteins, hormones, phospholipids, and biogenic amines.

SAM provides the methyl group in the production of essential biomolecules, including:

  • Acetyl-L-Carnitine: Neuronutrient and membrane-transporting agent
  • Epinephrine: Endogenous catecholamine, stress hormone and neurotransmitter
  • Phosphatidylcholine: A necessary component of biological membranes
  • Carnitine: Transporter of fatty acids into mitochondria
  • Phosphocreatine: ATP reservoir
  • Melatonin: Circadian rhythm modulator

SAM is synthesized de novo from the essential amino acid methionine (Met) by adding an adenosyl group into methionine via methionine adenosyl methyltransferase (MAT). The demethylation of SAM produces S-adenosylhomocysteine (SAH). The ratio between SAM and SAH is commonly called the “methylation index,” which reflects the methylation capacity of a cell or an organism. SAM-dependent enzymes catalyze the transfer of methyl groups into acceptor molecules via various mechanisms. At high concentrations, SAH competitively inhibits SAM-dependent methyl transferases. Thus, methylation is controlled through product inhibition and depends on the efficient hydrolytic conversion of SAH into the downstream metabolite homocysteine. Homocysteine is a crucial metabolite that connects the methionine and folate cycles and the transsulfuration pathway, and its partition between these pathways is carefully regulated. The remethylation of homocysteine to form methionine depends on methionine synthase, an enzyme that requires cobalamin (vitamin B12) and 5-methyltetrahydrofolate (vitamin B9) as cofactors. The conversion of Hcy to cystathionine and cysteine is carried out by cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE), respectively, which utilize pyridoxal phosphate (vitamin B6) as a cofactor. SAM is an activator of CBS and an inhibitor of methylenetetrahydrofolate reductase (MTHFR). The enzyme MTHFR catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. While SAM is recognized as the universal methyl donor in all living cells, this small molecule is also a source of other groups, such as amino, aminoalkyl, and ribosyl moieties.

SAM also plays a vital role in the synthesis of polyamines using the aminopropylation pathway. SAM is first decarboxylated, and the aminopropyl group is transferred to putrescine to generate spermidine and spermine, which are critical to cell growth, differentiation, and the stability of DNA and RNA.

Methylthioadenosine (MTA), the by-product of polyamine synthesis, is a potent analgesic and anti-inflammatory agent. This may be partially responsible for the clinical benefits observed in treating osteoarthritis, rheumatoid arthritis, and fibromyalgia with SAM.

The transsulfuration pathway begins with S-adenosylhomocysteine (SAH), the residual structure following the transfer of a methyl group from SAM. Hydrolysis of SAH yields homocysteine, converted to cystathionine, cysteine, and glutathione, the hepatocellular antioxidant and life-saving detoxification agent. Since dietary cysteine content is low, and up to 80% of dietary cysteine loses its sulfhydryl groups through the gastrointestinal tract, SAM is the primary source of cysteine, the building block of glutathione.

It is important to note that while the Methylation Index does not directly measure DNA methylation, the SAM/SAH ratio has been shown to correlate with DNA methylation.

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