S-Adenosylmethionine (SAM)

One of the essential metabolic functions of the body is active methyl donation (cycle A). The active methylation donor is S-adenosylmethionine (SAM), which is produced from methionine by the addition of ATP (adenosine triphosphate). After the methyl group has been donated (reaction 3), homocysteine remains. Because homocysteine has pro-oxidant properties (elevated levels are associated with cardiovascular disease), it must be detoxified. Two separate mechanisms exist, both of which are serine dependent. In the first (reaction 1), homocysteine is re-methylated by methyltetrahydrofolate (Me-THF, or “activated” folic acid) back to methionine, and the SAM cycle is closed. Under most circumstances, this should be the dominant pathway. In the second mechanism (reaction 2), homocysteine is combined with serine to form cystathionine which is split back apart (slightly differently) to yield cysteine and homoserine. This reaction depends on the enzyme cystathionine beta-synthase which opens up the SAM cycle and results in loss of methionine (and accumulation of cysteine).

The restoration of the SAM cycle is not solely dependent on increasing serine levels. The folate cycle (cycle B) is essential to close the SAM cycle and keep methionine available for producing SAM.

The folate cycle not only requires folic acid, but also vitamins B-6 and B-12, and NADH (a vitamin B-3-containing reducing agent). NADH is now available as a dietary supplement in the US.