S-adenosyl methionine

S-adenosyl methionine (SAM) is a biological compound involved in methyl group transfers, and is present in all living cells.

SAM was first discovered in 1952 (Cantoni). It is synthesized endogenously from adenosine triphosphate (ATP) and methionine by methionine adenosyltransferase EC 2.5.1.6. Transmethylation, transsulfuration and aminopropylation are the metabolic pathways that use SAM. Although these anabolic reactions occur throughout the body, most SAM is produced and consumed in the liver (Cantoni). The activated methyl group (CH3) in SAM allows donation of this group to an acceptor substrate in transmethylation reactions. More than 40 metabolic reactions involve the transfer of a methyl group of SAM to various substrates such as nucleic acids, proteins and lipids.

SAM cycle
The reactions that produce, consume and regenerate SAM are called the SAM cycle. In the first step of this cycle, the SAM-dependent methylases (EC 2.1.1) that use SAM as a substrate produce S-adenosyl homocysteine as a product. This is hydrolysed to homocysteine and adenosine by S-adenosylhomocysteine hydrolase EC 3.3.1.1 and the homocysteine recycled back to methionine through transfer of a methyl group from 5-methyltetrahydrofolate, by one of the two classes of methionine synthases EC 2.1.1.13 or EC 2.1.1.14. This methionine can then be converted back to SAM, completing the cycle.

Polyamine biosynthesis
Another major role of SAM is in polyamine biosynthesis. Here, SAM is decarboxylated by Adenosylmethionine decarboxylase EC 4.1.1.50 to form S-adenosyl-5'-3-methylpropylamine. This compound then donates its n-propylamine group in the biosynthesis of polyamines such as spermidine and spermine from putrescine.

SAM is required for cellular growth and repair. It is also involved in the biosynthesis of several hormones and neurotransmitters that affect mood, such as epinephrine. Methylases are also responsible for the addition of methyl groups to the 2' hydroxyls of the first and second nucleotides next to the 5' cap in messenger RNA.

Therapeutic uses of SAM
In the United States SAM is sold as a nutritional supplement under the marketing name SAM-e (also spelled SAME or SAMe; pronounced "sam ee"). SAM is also known as Gumbaral, Samyr, Adomet and Admethionine. Some research has shown that taking SAM on a regular basis can help fight depression, liver disease, and the pain of osteoarthritis.

Therapeutic use of SAM has increased as dietary supplements have gained in popularity, especially after the Dietary Supplement Health and Education Act was passed in 1999. This law allowed the distribution of SAM as an over-the-counter supplement, and therefore allowed it to bypass the regulatory requirements of the Food and Drug Administration (FDA). SAM has been suggested to have a therapeutic effect in liver disease, mood disorders and osteoporosis.

Oral forms
Oral SAMe achieves peak plasma concentrations 3 to 5 hours after ingestion of an enteric-coated tablet (400 – 1000 mg). The half-life is about 100 minutes. It may require up to one month for it to reach full effectiveness. Because of structural instability, stable salt forms of SAM are required for its use as an oral drug. Although more stable salt forms have been developed, SAM is still liable to degradation leading to distributors that may advertise a dose higher than what is actually being ingested. In 1999 two forms of SAM-e were available: sulfate-p-toluenesulfonate (also called tosylate) and butanedisulfonate. The butanedisulfonate form appears more stable. According to one study the oral bioavailability of the tosylate salt is 1%, and the oral bioavailability of the butanedisulfonate salt is 5%. (Stramentinoli G, Gualano M, Galli-Kienle M. Intestinal absorption of S-adenosyl-L-methionine. J Pharmacol Exp Ther 1979;209:323-6.) One study used the disulfate monotosylate salt. At least five salts are currently available including SAM tosylate, SAM butanedisulfonate, SAM disulfate tosylate (Nature Made), SAM disulfate ditosylate (Natrol), and SAM disulfate monotosylate (GNC). One study using SAM disulfate monotosylate (GNC) suggests a loss of potency to 49% at day 595 while kept under refrideration. The comparative stability and bioavailabilty of these various salt forms is unknown at this time.

Usage
It is important to purchase enteric-coated tablets packaged in foil or foil blister packs. The butanedisulfonate form is preferred to the tosylate salt although newer salts are available that may be more stable and more bioavailable (see above). SAMe should be stored in a cool, dry place. Tablets should be kept in the blister pack until the time of ingestion. Enteric-coated SAMe is more readily absorbed by the body and remains chemically stable for much longer (the coating protects it from exposure to air). Purchase SAMe from a reliable company whose quality standards you trust. If improperly handled, the raw material used to make SAMe can deteriorate rapidly, making these costly supplements weak or even inactive. Look for "pharmaceutical grade" products and opt for a more stable form called "butanedisulfonate" rather than "tosylate" or other newer salt forms (see above). To avoid a toxic buildup of homocysteine molecules (which are formed when SAMe breaks down) be sure to take a high-quality Vitamin B complex supplement along with SAMe. These vitamins help metabolize homocysteine, which in high concentrations poses the risk for various health problems including heart attack and stroke. SAMe is best absorbed on an empty stomach, so try to take it about one hour before or two hours after meals. If nausea or heartburn develop, take it with plenty of water.

Therapeutic doses range from 800 mg/day to 1600 mg/day, although lower and higher doses are used. Consult with your physician before and during use.

Adverse effects
Gastrointestinal disorder, diarrhea, dyspepsia, anxiety, headache, psychiatric, insomnia, allergy, rash, and loss of SAMe potency. Long term effects are unknown.

Induction of mania
People who have a history of bipolar disorder are at risk of developing manic symptoms. However, studies of Sam-E have also shown that taking oral or injected doses of the compound induces mania in a significant proportion of patients with unipolar depression, more frequently than most other antidepressants. Because mania can be a life-threatening condition that causes cognitive dysfunction even after remission, some doctors have warned their patients against Sam-E use until further research is available on this risk.