S-Adenosyl methionine
S-Adenosyl methionine (SAM), also known under the commercial names of SAMe, SAM-e, or AdoMet, is a common cosubstrate involved in methyl group transfers, transsulfuration, and aminopropylation. Although these anabolic 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 as nucleic acids, proteins, lipids and secondary metabolites. It is made from adenosine triphosphate (ATP) and methionine by methionine adenosyltransferase. SAM was first discovered by Giulio Cantoni in 1952.[1]
In bacteria, SAM is bound by the SAM riboswitch, which regulates genes involved in methionine or cysteine biosynthesis. In eukaryotic cells, SAM serves as a regulator of a variety of processes including DNA, tRNA, and rRNA methylation; immune response;[2] amino acid metabolism; transsulfuration; and more. In plants, SAM is crucial to the biosynthesis of ethylene, an important plant hormone and signaling molecule.[3]
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 by S-Adenosylmethionine synthetase enzyme through the following reaction:
The sulfonium functional group present in S-adenosyl methionine is the center of its peculiar reactivity. Depending on the enzyme, S-adenosyl methionine can be converted into one of three products:
Therapeutic uses[edit]
Osteoarthrtitis pain[edit]
As of 2012, the evidence was inconclusive as to whether SAM can mitigate the pain of osteoarthritis; clinical trials that had been conducted were too small from which to generalize.[12]
Liver disease[edit]
The SAM cycle has been closely tied to the liver since 1947 because people with alcoholic cirrhosis of the liver would accumulate large amounts of methionine in their blood.[13] While multiple lines of evidence from laboratory tests on cells and animal models suggest that SAM might be useful to treat various liver 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.[14][15]
Depression[edit]
A 2016 Cochrane review concluded that for major 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."[16]
A 2020 systematic review found that it performed significantly better than placebo, and had similar outcomes to other commonly used antidepressants (imipramine and escitalopram).[17]
Anti-cancer treatment[edit]
SAM has recently been shown to play a role in epigenetic 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.[18] 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.[19] 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.[20]
Availability in different countries[edit]
In Canada, the UK,[22] and the United States, SAM is sold as a dietary supplement under the marketing name SAM-e (also spelled SAME or SAMe).[23] It was introduced in the US in 1999, after the Dietary Supplement Health and Education Act was passed in 1994.[24]
It was introduced as a prescription drug in Italy in 1979, in Spain in 1985, and in Germany in 1989.[24] As of 2012, it was sold as a prescription drug in Russia, India, China, Italy, Germany, Vietnam, and Mexico.[15]