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''S''-Adenosyl methionine (SAM), also known under the commercial names of SAMe, SAM-e, or AdoMet, is a common
cosubstrate A cofactor is a non- protein chemical compound or metallic ion that is required for an enzyme's role as a catalyst (a catalyst is a substance that increases the rate of a chemical reaction). Cofactors can be considered "helper molecules" that as ...
involved in methyl group transfers, transsulfuration, and aminopropylation. Although these
anabolic Anabolism () is the set of metabolic pathways that construct molecules from smaller units. These reactions require energy, known also as an endergonic process. Anabolism is the building-up aspect of metabolism, whereas catabolism is the breakin ...
reactions occur throughout the body, most SAM is produced and consumed in the liver. More than 40 methyl transfers from SAM are known, to various substrates such as nucleic acids,
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
s,
lipid Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids in ...
s and secondary metabolites. It is made from
adenosine triphosphate Adenosine triphosphate (ATP) is an organic compound that provides energy to drive many processes in living cells, such as muscle contraction, nerve impulse propagation, condensate dissolution, and chemical synthesis. Found in all known forms ...
(ATP) and methionine by methionine adenosyltransferase. SAM was first discovered by
Giulio Cantoni Giulio Leonardo Cantoni (29 September 1915 – 25 July 2005) was the director of the United States' National Institutes of Health's Laboratory of Cellular Pharmacology, later renamed the Laboratory of General and Comparative Biochemistry. Early l ...
in 1952. In
bacteria Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were am ...
, SAM is bound by the
SAM riboswitch The SAM riboswitch (also known as the S-box leader and the SAM-I riboswitch) is found upstream of a number of genes which code for proteins involved in methionine or cysteine biosynthesis in Gram-positive bacteria. Two SAM riboswitches in ''B ...
, which regulates
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
s involved in methionine or cysteine biosynthesis. In
eukaryotic Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...
cells, SAM serves as a regulator of a variety of processes including DNA,
tRNA Transfer RNA (abbreviated tRNA and formerly referred to as sRNA, for soluble RNA) is an adaptor molecule composed of RNA, typically 76 to 90 nucleotides in length (in eukaryotes), that serves as the physical link between the mRNA and the amino ...
, and
rRNA Ribosomal ribonucleic acid (rRNA) is a type of non-coding RNA which is the primary component of ribosomes, essential to all cells. rRNA is a ribozyme which carries out protein synthesis in ribosomes. Ribosomal RNA is transcribed from ribos ...
methylation;
immune response An immune response is a reaction which occurs within an organism for the purpose of defending against foreign invaders. These invaders include a wide variety of different microorganisms including viruses, bacteria, parasites, and fungi which coul ...
; amino acid metabolism; transsulfuration; and more. In plants, SAM is crucial to the biosynthesis of
ethylene Ethylene (IUPAC name: ethene) is a hydrocarbon which has the formula or . It is a colourless, flammable gas with a faint "sweet and musky" odour when pure. It is the simplest alkene (a hydrocarbon with carbon-carbon double bonds). Ethylene ...
, an important plant hormone and signaling molecule.


Structure

''S''-Adenosyl methionine consists of the adenosyl cation attached to the sulfur of methionine. It is synthesized from ATP and methionine by ''S''-Adenosylmethionine synthetase enzyme through the following reaction: : ATP + L-methionine + \rightleftharpoons
phosphate In chemistry, a phosphate is an anion, salt, functional group or ester derived from a phosphoric acid. It most commonly means orthophosphate, a derivative of orthophosphoric acid . The phosphate or orthophosphate ion is derived from phosph ...
+ diphosphate + ''S''-adenosyl-L-methionine The
sulfonium In organic chemistry, a sulfonium ion, also known as sulphonium ion or sulfanium ion, is a positively-charged ion (a "cation") featuring three organic substituents attached to sulfur. These organosulfur compounds have the formula . Together wi ...
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: *adenosyl radical, which converts to deoxyadenosine (AdO): classic rSAM reaction, also cogenerates methionine * ''S''-adenosyl homocysteine, releasing methyl radical * methylthioadenosine (SMT), homoalanine radical


Biochemistry


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. ''S''-Adenosyl homocysteine is a strong negative regulator of nearly all SAM-dependent methylases despite their biological diversity. This is hydrolysed to homocysteine and adenosine by ''S''-adenosylhomocysteine hydrolasebr>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 (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. In the rate-limiting step of the SAM cycle, MTHFR (methylenetetrahydrofolate reductase) irreversibly reduces 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate.


Radical SAM enzymes

A large number of enzymes cleave SAM reductively to produce radicals: 5′-deoxyadenosyl 5′-radical, methyl radical, and others. These enzymes are called radical SAMs. They all feature
iron-sulfur cluster Iron–sulfur proteins (or iron–sulphur proteins in British spelling) are proteins characterized by the presence of iron–sulfur clusters containing sulfide-linked di-, tri-, and tetrairon centers in variable oxidation states. Iron–sulfur c ...
at their active sites. 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 include
spore photoproduct lyase Spore photoproduct lyase (''SP lyase'', ''SPL'', ''SplB'', ''SplG'') is a radical SAM enzyme that repairs DNA cross linking of thymine bases caused by UV-radiation. There are several types of thymine cross linking, but SPL specifically targets ...
, activases of pyruvate formate lyase and anaerobic sulfatases, lysine 2,3-aminomutase, and various enzymes of cofactor biosynthesis, peptide modification, metalloprotein cluster formation,
tRNA Transfer RNA (abbreviated tRNA and formerly referred to as sRNA, for soluble RNA) is an adaptor molecule composed of RNA, typically 76 to 90 nucleotides in length (in eukaryotes), that serves as the physical link between the mRNA and the amino ...
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.


Polyamine biosynthesis

Another major role of SAM is in polyamine biosynthesis. Here, SAM is decarboxylated by
adenosylmethionine decarboxylase The enzyme adenosylmethionine decarboxylase () catalyzes the conversion of ''S''-adenosyl methionine to ''S''-adenosylmethioninamine. Polyamines such as spermidine and spermine are essential for cellular growth under most conditions, being im ...

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 Spermidine is a polyamine compound () found in ribosomes and living tissues and having various metabolic functions within organisms. It was originally isolated from semen. Function Spermidine is an aliphatic polyamine. Spermidine synthase (SPDS ...
and
spermine Spermine is a polyamine involved in cellular metabolism that is found in all eukaryotic cells. The precursor for synthesis of spermine is the amino acid ornithine. It is an essential growth factor in some bacteria as well. It is found as a ...
from
putrescine Putrescine is an organic compound with the formula (CH2)4(NH2)2. It is a colorless solid that melts near room temperature. It is classified as a diamine. Together with cadaverine, it is largely responsible for the foul odor of putrefying flesh ...
. 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.
Methyltransferase Methyltransferases are a large group of enzymes that all Methylation, methylate their substrates but can be split into several subclasses based on their structural features. The most common class of methyltransferases is class I, all of which co ...
s are also responsible for the addition of methyl groups to the 2′ hydroxyls of the first and second
nucleotide Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecu ...
s next to the 5′ cap in messenger RNA.


Therapeutic uses

As of 2012, the evidence was inconclusive as to whether SAM can mitigate the pain of
osteoarthritis Osteoarthritis (OA) is a type of degenerative joint disease that results from breakdown of joint cartilage and underlying bone which affects 1 in 7 adults in the United States. It is believed to be the fourth leading cause of disability in the ...
; clinical trials that had been conducted were too small from which to generalize. 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. 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.


Depression

A 2016 Cochrane review concluded that for
major depressive disorder Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive low mood, low self-esteem, and loss of interest or pleasure in normally enjoyable activities. Intro ...
, "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." A 2020 systematic review found that it performed significantly better than placebo, and had similar outcomes to other commonly used antidepressants (imipramine or escitalopram).


Anti-cancer treatment

SAM has recently been shown to play a role in
epigenetic In biology, epigenetics is the study of stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are ...
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. Because of this impact on epigenetic regulation, SAM has been tested as an anti-cancer treatment. Cancer cell proliferation is dependent on having low levels of DNA methylation. In vitro addition has been shown to remethylate promoter sequences and decrease the production of proto-oncogenes.


Pharmacokinetics

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.


Availability in different countries

In Canada, the UK, and the United States, SAM is sold as a dietary supplement under the marketing name SAM-e (also spelled SAME or SAMe, pronounced "Sammy"). It was introduced in the US in 1999, after the
Dietary Supplement Health and Education Act The Dietary Supplement Health and Education Act of 1994 ("DSHEA"), is a 1994 statute of United States Federal legislation which defines and regulates dietary supplements. Under the act, supplements are regulated by the FDA for Good Manufacturing P ...
was passed in 1994. It was introduced as a prescription drug in Italy in 1979, in Spain in 1985, and in Germany in 1989. As of 2012, it was sold as a prescription drug in Russia, India, China, Italy, Germany, Vietnam, and Mexico.


Adverse effects

Gastrointestinal disorder, dyspepsia and
anxiety Anxiety is an emotion which is characterized by an unpleasant state of inner turmoil and includes feelings of dread over anticipated events. Anxiety is different than fear in that the former is defined as the anticipation of a future threat wh ...
can occur with SAM consumption. Long-term effects are unknown. SAM is a weak DNA-
alkylating Alkylation is the transfer of an alkyl group from one molecule to another. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion, or a carbene (or their equivalents). Alkylating agents are reagents for effectin ...
agent. Another reported side effect of SAM is
insomnia Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy, ...
; 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.


Interactions and contraindications

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. These drugs include
dextromethorphan Dextromethorphan (DXM) is a medication most often used as a cough suppressant in over-the-counter cold and cough medicines. It is sold in syrup, tablet, spray, and lozenge forms. In 2022, the FDA approved a formulation of it combined with b ...
(Robitussin), meperidine (Demerol),
pentazocine Pentazocine, sold under the brand name Talwin among others, is a painkiller used to treat moderate to severe pain. It is believed to work by activating (agonizing) κ-opioid receptors (KOR) and μ-opioid receptors (MOR). As such it is called an ...
(Talwin), and
tramadol Tramadol, sold under the brand name Ultram among others, is an opioid pain medication used to treat moderate to moderately severe pain. When taken by mouth in an immediate-release formulation, the onset of pain relief usually begins within an ...
(Ultram). SAM may also interact with antidepressant medications — including tryptophan and '' Hypericum perforatum'' (St. John’s wort) — increasing the potential for serotonin syndrome or other side effects, and may reduce the effectiveness of levodopa for Parkinson's disease. People who have
bipolar disorder Bipolar disorder, previously known as manic depression, is a mental disorder characterized by periods of Depression (mood), depression and periods of abnormally elevated Mood (psychology), mood that last from days to weeks each. If the elevat ...
should not use SAM because it increases the risk of manic episodes.


Toxicity

A 2022 study concluded that SAMe could be toxic. Jean-Michel Fustin of Manchester University said that the researchers found that excess SAMe breaks down into toxic substances
adenine Adenine () ( symbol A or Ade) is a nucleobase (a purine derivative). It is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The three others are guanine, cytosine and thymine. Its deriv ...
and methylthioadenosine in the body, both producing the
paradoxical effect A paradoxical reaction (or paradoxical effect) is an effect of a chemical substance, such as a medical drug, that is opposite to what would usually be expected. An example of a paradoxical reaction is pain caused by a pain relief medication. Parad ...
of inhibiting methylation. This was found in laboratory mice, causing harm to health, and in ''
in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called " test-tube experiments", these studies in biology a ...
'' tests on human cells. Deficiencies in radical SAM enzymes have been associated with a variety of diseases including congenital heart disease, amyotrophic lateral sclerosis, and increased viral susceptibility.


See also

* DNA methyltransferase * SAM-I riboswitch * SAM-II riboswitch * SAM-III riboswitch *
SAM-IV riboswitch SAM-IV riboswitches are a kind of riboswitch that specifically binds S-adenosylmethionine (SAM), a cofactor used in many methylation reactions. Originally identified by bioinformatics, SAM-IV riboswitches are largely confined to the Actinomycet ...
*
SAM-V riboswitch SAM-V riboswitch is the fifth known riboswitch to bind S-adenosyl methionine (SAM). It was first discovered in the marine bacterium '' Candidatus Pelagibacter ubique'' and can also be found in marine metagenomes. SAM-V features a similar consensu ...
*
SAM-VI riboswitch SAM-VI is a member of the riboswitch family. It is predominantly found in ''Bifidobacterium'' and exhibits some similarities to the SAM-III ( Smk box) riboswitch class, but lacks most of the highly conserved nucleotides of SAM-III class. SAM-VI apt ...
* List of investigational antidepressants


References


External links

* * {{DEFAULTSORT:Adenosyl Methionine, S- Coenzymes Dietary supplements Biology of bipolar disorder Psychopharmacology Sulfonium compounds