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| Names | |
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| Systematic IUPAC name (2S)-2-Amino-4-[(S)-{[(2S,3S,4R,5R)-5-(4-amino-9H-purin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl}methylsulfaniumyl]butanoate | |
| Other names S-Adenosyl-L-methionine; SAM-e; SAMe,AdoMet, Heparab (India), ademethionine | |
| Identifiers | |
3D model (JSmol) | |
| ChEMBL | |
| ChemSpider |
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| ECHA InfoCard | 100.045.391 |
| KEGG |
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| MeSH | S-Adenosylmethionine |
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| Properties | |
| C15H22N6O5S | |
| Molar mass | 398.44 g·mol−1 |
| Pharmacology | |
| A16AA02 (WHO) | |
Except where otherwise noted, data are given for materials in theirstandard state (at 25 °C [77 °F], 100 kPa). | |
S-Adenosyl methionine (SAM), also known under the commercial names ofSAMe,SAM-e, orAdoMet, is a commoncosubstrate involved inmethyl group transfers,transsulfuration, and aminopropylation. Although theseanabolic reactions occur throughout the body, most SAM is produced and consumed in the liver.[1] More than 40 methyl transfers from SAM are known, to various substrates such asnucleic acids,proteins,lipids andsecondary metabolites. It is made fromadenosine triphosphate (ATP) andmethionine bymethionine adenosyltransferase. SAM was first discovered byGiulio Cantoni in 1952.[1]
Inbacteria, SAM is bound by theSAM riboswitch, which regulatesgenes involved in methionine orcysteine biosynthesis. Ineukaryotic cells, SAM serves as a regulator of a variety of processes includingDNA,tRNA, andrRNAmethylation;immune response;[2] amino acid metabolism;transsulfuration; and more. In plants, SAM is crucial to the biosynthesis ofethylene, an importantplant hormone and signaling molecule.[3]
SAMe has been studied fordepression,osteoarthritis, andliver diseases with inconclusive results, and while generally considered safe short-term, its long-term safety, use duringpregnancy, and risks for people withbipolar disorder or compromisedimmune systems remain unclear.[4]
S-Adenosyl methionine consists of the adenosyl group attached to the sulfur of methionine, providing it with a positive charge. It is synthesized from ATP and methionine byS-Adenosylmethionine synthetase enzyme through the following reaction:
Thesulfonium functional group present inS-adenosyl methionine is the center of its peculiar reactivity. Depending on the enzyme,S-adenosyl methionine can be converted into one of three products:
The reactions that produce, consume, and regenerate SAM are called the SAM cycle. In the first step of this cycle, the SAM-dependentmethylases (EC 2.1.1) that use SAM as a substrate produceS-adenosyl homocysteine as a product.[5]S-Adenosyl homocysteine is a strong negative regulator of nearly all SAM-dependent methylases despite their biological diversity. This is hydrolysed tohomocysteine andadenosine byS-adenosylhomocysteine hydrolaseEC 3.3.1.1Archived 2011-06-22 at theWayback Machine and the homocysteine recycled back tomethionine through transfer of a methyl group from5-methyltetrahydrofolate, by one of the two classes ofmethionine synthases (i.e.cobalamin-dependent (EC 2.1.1.13Archived 2011-06-22 at theWayback Machine) or cobalamin-independent (EC 2.1.1.14Archived 2011-06-22 at theWayback Machine)). This methionine can then be converted back to SAM, completing the cycle.[6] In the rate-limiting step of the SAM cycle, MTHFR (methylenetetrahydrofolate reductase) irreversibly reduces 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate.[7]
A large number of enzymes cleave SAM reductively to produce radicals:5′-deoxyadenosyl 5′-radical, methyl radical, and others. These enzymes are calledradical SAMs. They all featureiron-sulfur cluster at their active sites.[8] Most enzymes with this capability share a region of sequence homology that includes the motif CxxxCxxC or a close variant. This sequence provides three cysteinyl thiolate ligands that bind to three of the four metals in the 4Fe-4S cluster. The fourth Fe binds the SAM.
The radical intermediates generated by these enzymes perform a wide variety of unusual chemical reactions. Examples of radical SAM enzymes includespore photoproduct lyase, activates ofpyruvate 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. They can be found in all domains of life and are largely unexplored. A recent bioinformatics study concluded that this family of enzymes includes at least 114,000 sequences including 65 unique reactions.[9]
Deficiencies in radical SAM enzymes have been associated with a variety of diseases includingcongenital heart disease,amyotrophic lateral sclerosis, and increased viral susceptibility.[9]
Another major role of SAM is inpolyamine biosynthesis. Here, SAM is decarboxylated byadenosylmethionine decarboxylase (EC 4.1.1.50Archived 2011-06-22 at theWayback Machine) to formS-adenosylmethioninamine. This compound then donates itsn-propylamine group in the biosynthesis of polyamines such asspermidine andspermine fromputrescine.[10]
SAM is required for cellular growth and repair. It is also involved in the biosynthesis of several hormones and neurotransmitters that affect mood, such asepinephrine.Methyltransferases are also responsible for the addition of methyl groups to the 2′ hydroxyls of the first and secondnucleotides next to the 5′ cap inmessenger RNA.[11][12]
SAMe has been studied fordepression,osteoarthritis, andliver diseases with inconclusive results, and while generally considered safe short-term, its long-term safety, use duringpregnancy, and risks for people withbipolar disorder or compromisedimmune systems remain unclear.[4]
As of 2012, the evidence was inconclusive as to whether SAM can mitigate the pain ofosteoarthritis; clinical trials that had been conducted were too small from which to generalize.[13]
The SAM cycle has been closely tied to the liver since 1947 because people withalcoholic cirrhosis of the liver would accumulate large amounts of methionine in their blood.[14] While multiple lines of evidence from laboratory tests on cells andanimal models suggest that SAM might be useful to treat variousliver diseases, as of 2012 SAM had not been studied in any large randomized placebo-controlled clinical trials that would allow an assessment of its efficacy and safety.[15][16]
A 2016 Cochrane review concluded that formajor depressive disorder, "Given the absence of high quality evidence and the inability to draw firm conclusions based on that evidence, the use of SAMe for the treatment of depression in adults should be investigated further."[17]
A 2020 systematic review found that it performed significantly better than placebo, and had similar outcomes to other commonly used antidepressants (imipramine andescitalopram).[18]
SAM has recently been shown to play a role inepigenetic regulation. DNA methylation is a key regulator in epigenetic modification during mammalian cell development and differentiation. In mouse models, excess levels of SAM have been implicated in erroneous methylation patterns associated with diabetic neuropathy. SAM serves as the methyl donor in cytosine methylation, which is a key epigenetic regulatory process.[19] Because of this impact on epigenetic regulation, SAM has been tested as an anti-cancer treatment. In many cancers, proliferation is dependent on having low levels of DNA methylation. In vitro addition in such cancers has been shown to remethylate oncogene promoter sequences and decrease the production of proto-oncogenes.[20] In cancers such as colorectal cancer, aberrant global hypermethylation can inhibit promoter regions of tumor-suppressing genes. Contrary to the former information, colorectal cancers (CRCs) are characterized by global hypomethylation and promoter-specific DNA methylation.[21]
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.[22]
In Canada, the UK,[23] and the United States, SAM is sold as adietary supplement under the marketing name SAM-e (also spelled SAME or SAMe).[24] It was introduced in the US in 1999, after theDietary Supplement Health and Education Act was passed in 1994.[25]
It was introduced as aprescription drug in Italy in 1979, in Spain in 1985, and in Germany in 1989.[25] As of 2012, it was sold as a prescription drug in Russia, India, China, Italy, Germany, Vietnam, and Mexico.[16]
Gastrointestinal disorder,dyspepsia andanxiety can occur with SAM consumption.[22] Long-term effects are unknown. SAM is a weak DNA-alkylating agent.[26]
Another reported side effect of SAM isinsomnia; 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.[medical citation needed]
Taking SAM at the same time as some drugs may increase the risk ofserotonin syndrome, a potentially dangerous condition caused by having too much serotonin. These drugs include, but are certainly not limited to,dextromethorphan (Robitussin),meperidine (Demerol),pentazocine (Talwin), andtramadol (Ultram).[27]
SAM can also interact with many antidepressant medications — includingtryptophan and the herbal medicineHypericum perforatum (St. John's wort) — increasing the potential for serotonin syndrome or other side effects, and may reduce the effectiveness oflevodopa for Parkinson's disease.[4] SAM can increase the risk of manic episodes in people who havebipolar disorder.[4]
A 2022 study concluded that SAMe could be toxic. Jean-Michel Fustin ofManchester University said that the researchers found that excess SAMe breaks down intoadenine andmethylthioadenosine in the body, both producing theparadoxical effect of inhibiting methylation. This was found inlaboratory mice, causing harm to health, and inin vitro tests on human cells.[28][23]
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