S-Adenosyl methionine (SAM-e, SAMe, SAM, S-Adenosyl-L-methionine, AdoMet, ademetionine) is a common cosubstrate involved in methyl group transfers. SAM was first discovered in Italy by G. L. Cantoni in 1952.[1] It is made from adenosine triphosphate (ATP) and methionine by methionine adenosyltransferase. 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.[1]
The methyl group (CH3) attached to the methionine sulfur atom in SAM is chemically reactive. This allows donation of this group to an acceptor substrate in transmethylation reactions. More than 40 metabolic reactions involve the transfer of a methyl group from SAM to various substrates, such as nucleic acids, proteins, lipids and secondary metabolites.
In bacteria, SAM is bound by the SAM riboswitch, which regulates genes involved in methionine or cysteine biosynthesis.
Biochemistry of S-adenosyl methionine[edit]
SAM cycle[edit]
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.[2] 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 from5-methyltetrahydrofolate, by one of the two classes of methionine synthases (i.e. cobalamin-dependent (EC 2.1.1.13) or cobalamin-independent (EC 2.1.1.14)). This methionine can then be converted back to SAM, completing the cycle.[3] In the rate-limiting step of the SAM cycle, MTHFR (methylenetetrahydrofolate reductase) irreversibly reduces 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate.
Radical SAM enzymes[edit]
A large number of iron-sulfur cluster-containing enzymes cleave SAM reductively to produce a 5′-deoxyadenosyl 5′-radical as an intermediate, and are called radical SAMenzymes.[4] Most enzymes with this capability share a region of sequence homology that includes the motif CxxxCxxC or a close variant. The radical intermediate allows enzymes to perform a wide variety of unusual chemical reactions. Examples of radical SAM enzymes include spore photoproduct lyase, activases of pyruvate formate lyase and anaerobic sulfatases, lysine 2,3-aminomutase, and various enzymes of cofactor biosynthesis, peptide modification, metalloprotein cluster formation, tRNA modification, lipid metabolism, etc. Some radical SAM enzymes use a second SAM as a methyl donor. Radical SAM enzymes are much more abundant in anaerobic bacteria than in aerobic organisms.
Polyamine biosynthesis[edit]
Another major role of SAM is in polyamine biosynthesis. Here, SAM is decarboxylated by adenosylmethionine decarboxylase (EC 4.1.1.50) to form S-adenosylmethioninamine. This compound then donates its n-propylamine group in the biosynthesis of polyamines such as spermidine and spermine from putrescine.[5]
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.Methyltransferases 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.[6][7]
Therapeutic uses[edit]
In the United States and Canada, SAM is sold as a nutritional supplement under the marketing name SAM-e (also spelled SAME or SAMe; pronounced "sam ee" or "Sammy"). SAM is also marketed under the Gumbaral, Samyr, Adomet, Heptral, Agotan, Donamet, Isimet and Admethionine brand names as a prescription drug approved in Russia, Italy, and several countries of the European Union. In India, SAM is also marketed as Nusam under dietary supplement category. In Serbia, the drug is marketed as "Tensilen".[8]Some research, including multiple clinical trials, has indicated taking SAM on a regular basis may help fight depression,[9][10][11][12][13] liver disease,[14][15] and the pain ofosteoarthritis.[16] All other indications are not yet well-evidenced.
Therapeutic use of SAM has increased in the US, as dietary supplements have gained in popularity, especially after the Dietary Supplement Health and Education Act was passed in 1994. This law allowed the distribution of SAM as a dietary supplement, and therefore allowed it to bypass the regulatory requirements for drugs of the Food and Drug Administration (FDA).
At first, a line of evidence suggested abnormally low levels of endogenous SAM may play an important role in the development of Alzheimer's disease, and that SAM may therefore have therapeutic potential in the treatment of Alzheimer's disease. However, further research has indicated this effect is likely due to vitamin B12 deficiencies, which result in neurologic defects due to the inability to conduct one carbon transfers (with folate) in the absence of B12. Severely low levels of SAM have been found in thecerebrospinal fluid[17] and in all brain regions of Alzheimer's disease patients examined.[18]
SAMe has been studied in the treatment of osteoarthritis, wherein the substance reduces the pain associated with the disease. Although an optimal dose has yet to be determined, SAMe appears as effective as the non-steroidal anti-inflammatory drugs. Additional study is warranted to confirm these findings.[19]
Applications in drug discovery and development[edit]
Recent work has revealed the methyltransferases involved in methylation of naturally-occurring anticancer agents to use SAM analogs that carry alternative alkyl groups as a replacement for methyl. The development of the facile chemoenzymatic platform to generate and utilize differentially alkylated SAM analogs in the context of drug discovery anddrug development is known as alkylrandomization.[20]
Forms, usage and adverse effects[edit]
Oral forms[edit]
Oral SAM achieves peak plasma concentrations three to five hours after ingestion of an enteric-coated tablet (400–1000 mg). The half-life is about 100 minutes.[21] It may require up to one month for it to reach full effectiveness in treating osteoarthritis.[21] Because of structural instability, stable salt forms of SAM are required for its use as an oral drug. The University of Maryland lists the commonly used salts: tosylate, butanedisulfonate, disulfate tosylate, disulfate ditosylate, and disulfate monotosylate.[22]
With the advent of FDA-mandated good manufacturing practices (GMPs) in 2008, manufacturers are required to confirm their products contain what is listed on the label through the end of shelf life. Whether they achieve this goal or not has been questioned. This testing has shown that properly produced and packaged SAM has a shelf life in excess of three years; however, most manufacturers label for a two-year shelf life.
Claims that the SAM butanedisulfonate salt is more stable or better absorbed are not supported by the references usually cited as evidence. Different salts have successfully been used in clinical trials, but there is no published head-to-head comparison.[22][23][24]
Injectable forms[edit]
Injectable SAMe (marketed as Heptral by Abbott) is available in Russia. Bioavailability of intramuscular injected SAMe is 96% (compared to 5% of oral form) [25]
Usage[edit]
SAM is best absorbed on an empty stomach. Enteric-coated tablets packaged in foil or foil blister packs increase stability and improve absorption. SAM should be stored in a cool, dry place to prevent decomposition.[22]
Adverse effects[edit]
Gastrointestinal disorder, dyspepsia and anxiety can occur with SAM consumption.[21] Long-term effects are unknown. SAM is a weak DNA-alkylating agent.[26]
Possible side effects[edit]
Once SAM donates its methyl group to choline, in the formation of creatine, carnitine, DNA, tRNA, norepinephrine, and other compounds, it is transformed into S-adenosyl-homocysteine, (SAH). Under normal circumstances, homocysteine, in the presence of vitamin B6, vitamin B12, and folic acid (SAM's main cofactors), will eventually be converted back into methionine, SAM, or cysteine, glutathione, and other useful substances. However, if adequate amounts of these vitamins are not present, SAM may not break down properly. As a consequence, its full benefits will not be obtained, and homocysteine may increase to unsafe levels. Small studies have not shown a consistent effect of SAM on homocysteine levels, but more research is needed.[27][28]
High levels of homocysteine have been associated with atherosclerosis (hardening and narrowing of the arteries), as well as an increased risk of heart attacks, strokes, liver damage, and possibly Alzheimer's disease. Therefore, vitamin B supplements are often taken along with SAM. These vitamins help metabolize the homocysteine into other useful compounds.[29]
Another reported side effect of SAM is insomnia; therefore, the supplement is often taken in the morning. Other reports of mild side effects include lack of appetite, constipation, nausea, dry mouth, sweating, and anxiety/nervousness, but in placebo-controlled studies, these side effects occur at about the same incidence in the placebo groups.
Therapeutic doses range from 400 mg/day to 1600 mg/day, although higher doses are used in some cases.[21][30]
Induction of mania[edit]
In an extensive MEDLINE search on SAM, Kagan found induction of mania in one patient out of 15 treated with parenteral SAM. In the same review, Lipinski found the apparent induction of mania in two patients with bipolar disorder (total of nine depressed patients studied).[31] Both depression and mania can be life-threatening conditions that may causecognitive dysfunction even after remission.[32] There is concern that antidepressants in general can induce mania or hypomania in bipolar persons.[33]
Interactions and contraindications[edit]
Taking SAM at the same time as some drugs may increase the risk of serotonin syndrome, a potentially dangerous condition caused by having too much serotonin.[34] These drugs include dextromethorphan (Robitussin), meperidine (Demerol), pentazocine (Talwin), and tramadol (Ultram).[34] SAM may also interact with antidepressant medications increasing the potential for their side effects and reduce the effectiveness of levodopa for Parkinson's disease.
