S-Adenosyl methionine

Last updated
S-Adenosyl methionine
S-adenosyl methionine.png
S-adenosylmethionine.png
S-adenosylmethionine spacefill.png
Names
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
ECHA InfoCard 100.045.391 OOjs UI icon edit-ltr-progressive.svg
KEGG
MeSH S-Adenosylmethionine
PubChem CID
UNII
  • InChI=1S/C15H22N6O5S/c1-27(3-2-7(16)15(24)25)4-8-10(22)11(23)14(26-8)21-6-20-9-12(17)18-5-19-13(9)21/h5-8,10-11,14,22-23H,2-4,16H2,1H3,(H2-,17,18,19,24,25)/p+1/t7?,8-,10-,11-,14-,27?/m1/s1 Yes check.svgY
    Key: MEFKEPWMEQBLKI-YDBXVIPQSA-O Yes check.svgY
  • InChI=1/C15H22N6O5S/c1-27(3-2-7(16)15(24)25)4-8-10(22)11(23)14(26-8)21-6-20-9-12(17)18-5-19-13(9)21/h5-8,10-11,14,22-23H,2-4,16H2,1H3,(H2-,17,18,19,24,25)/p+1/t7?,8-,10-,11-,14-,27?/m1/s1
    Key: MEFKEPWMEQBLKI-NNGIMXIKBF
  • O=C(O)C(N)CC[S+](C)C[C@H]3O[C@@H](n2cnc1c(ncnc12)N)[C@H](O)[C@@H]3O
Properties
C15H22N6O5S
Molar mass 398.44 g·mol−1
Pharmacology
A16AA02 ( WHO )
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

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]

Contents

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]

Structure

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:

ATP + L-methionine + H2O phosphate + diphosphate + S-adenosyl-L-methionine

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:

Biochemistry

SAM cycle

The SN2-like methyl transfer reaction. Only the SAM cofactor and cytosine base are shown for simplicity. SN2 Mechanism of Methyltransferases.png
The SN2-like methyl transfer reaction. Only the SAM cofactor and cytosine base are shown for simplicity.

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. [4] 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 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 (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. [5] In the rate-limiting step of the SAM cycle, MTHFR (methylenetetrahydrofolate reductase) irreversibly reduces 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. [6]

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 at their active sites. [7] 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, 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. 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. [8]

Deficiencies in radical SAM enzymes have been associated with a variety of diseases including congenital heart disease, amyotrophic lateral sclerosis, and increased viral susceptibility. [8]

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-adenosylmethioninamine. This compound then donates its n-propylamine group in the biosynthesis of polyamines such as spermidine and spermine from putrescine. [9]

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. [10] [11]

Therapeutic uses

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]

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

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

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]

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. [21]

Availability in different countries

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, pronounced "Sammy"). [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]

Adverse effects

Gastrointestinal disorder, dyspepsia and anxiety can occur with SAM consumption. [21] Long-term effects are unknown. SAM is a weak DNA-alkylating agent. [25]

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.[ medical citation needed ]

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 (Robitussin), meperidine (Demerol), pentazocine (Talwin), and tramadol (Ultram). [26]

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. [27]

People who have bipolar disorder should not use SAM because it increases the risk of manic episodes. [27]

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 adenine and methylthioadenosine in the body, both producing the paradoxical effect of inhibiting methylation. This was found in laboratory mice, causing harm to health, and in in vitro tests on human cells. [28] [22]

See also

Related Research Articles

<span class="mw-page-title-main">Methionine</span> Sulfur-containing amino acid

Methionine is an essential amino acid in humans.

Methylation, in the chemical sciences, is the addition of a methyl group on a substrate, or the substitution of an atom by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These terms are commonly used in chemistry, biochemistry, soil science, and biology.

<span class="mw-page-title-main">Choline</span> Chemical compound and essential nutrient

Choline ( KOH-leen) is an essential nutrient for humans and many other animals, which was formerly classified as a B vitamin (vitamin B4). It is a structural part of phospholipids and a methyl donor in metabolic one-carbon chemistry. The compound is related to trimethylglycine in the latter respect. It is a cation with the chemical formula [(CH3)3NCH2CH2OH]+. Choline forms various salts, for example choline chloride and choline bitartrate.

<span class="mw-page-title-main">Methylenetetrahydrofolate reductase</span> Rate-limiting enzyme in the methyl cycle

Methylenetetrahydrofolate reductase (MTHFR) is the rate-limiting enzyme in the methyl cycle, and it is encoded by the MTHFR gene. Methylenetetrahydrofolate reductase catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a cosubstrate for homocysteine remethylation to methionine. Natural variation in this gene is common in otherwise healthy people. Although some variants have been reported to influence susceptibility to occlusive vascular disease, neural tube defects, Alzheimer's disease and other forms of dementia, colon cancer, and acute leukemia, findings from small early studies have not been reproduced. Some mutations in this gene are associated with methylenetetrahydrofolate reductase deficiency. Complex I deficiency with recessive spastic paraparesis has also been linked to MTHFR variants. In addition, the aberrant promoter hypermethylation of this gene is associated with male infertility and recurrent spontaneous abortion.

<span class="mw-page-title-main">Methionine synthase</span> Mammalian protein found in Homo sapiens

Methionine synthase (MS, MeSe, MTR) is responsible for the regeneration of methionine from homocysteine. In humans it is encoded by the MTR gene (5-methyltetrahydrofolate-homocysteine methyltransferase). Methionine synthase forms part of the S-adenosylmethionine (SAMe) biosynthesis and regeneration cycle, and is the enzyme responsible for linking the cycle to one-carbon metabolism via the folate cycle. There are two primary forms of this enzyme, the Vitamin B12 (cobalamin)-dependent (MetH) and independent (MetE) forms, although minimal core methionine synthases that do not fit cleanly into either category have also been described in some anaerobic bacteria. The two dominant forms of the enzymes appear to be evolutionary independent and rely on considerably different chemical mechanisms. Mammals and other higher eukaryotes express only the cobalamin-dependent form. In contrast, the distribution of the two forms in Archaeplastida (plants and algae) is more complex. Plants exclusively possess the cobalamin-independent form, while algae have either one of the two, depending on species. Many different microorganisms express both the cobalamin-dependent and cobalamin-independent forms.

<span class="mw-page-title-main">Methyltransferase</span> Group of methylating enzymes

Methyltransferases are a large group of enzymes that all 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 contain a Rossmann fold for binding S-Adenosyl methionine (SAM). Class II methyltransferases contain a SET domain, which are exemplified by SET domain histone methyltransferases, and class III methyltransferases, which are membrane associated. Methyltransferases can also be grouped as different types utilizing different substrates in methyl transfer reactions. These types include protein methyltransferases, DNA/RNA methyltransferases, natural product methyltransferases, and non-SAM dependent methyltransferases. SAM is the classical methyl donor for methyltransferases, however, examples of other methyl donors are seen in nature. The general mechanism for methyl transfer is a SN2-like nucleophilic attack where the methionine sulfur serves as the leaving group and the methyl group attached to it acts as the electrophile that transfers the methyl group to the enzyme substrate. SAM is converted to S-Adenosyl homocysteine (SAH) during this process. The breaking of the SAM-methyl bond and the formation of the substrate-methyl bond happen nearly simultaneously. These enzymatic reactions are found in many pathways and are implicated in genetic diseases, cancer, and metabolic diseases. Another type of methyl transfer is the radical S-Adenosyl methionine (SAM) which is the methylation of unactivated carbon atoms in primary metabolites, proteins, lipids, and RNA.

Histone-arginine N-methyltransferase is an enzyme with systematic name S-adenosyl-L-methionine:histone-arginine Nomega-methyltransferase. This enzyme catalyses the following chemical reaction

<span class="mw-page-title-main">Magnesium protoporphyrin IX methyltransferase</span>

In enzymology, a magnesium protoporphyrin IX methyltransferase is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Phosphatidylethanolamine N-methyltransferase</span> Protein-coding gene in the species Homo sapiens

Phosphatidylethanolamine N-methyltransferase is a transferase enzyme which converts phosphatidylethanolamine (PE) to phosphatidylcholine (PC) in the liver. In humans it is encoded by the PEMT gene within the Smith–Magenis syndrome region on chromosome 17.

<span class="mw-page-title-main">Protein-glutamate O-methyltransferase</span>

In enzymology, a protein-glutamate O-methyltransferase is an enzyme that catalyzes the chemical reaction

In enzymology, a sterol 24-C-methyltransferase is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">MTRR (gene)</span> Protein-coding gene in the species Homo sapiens

Methionine synthase reductase, also known as MSR, is an enzyme that in humans is encoded by the MTRR gene.

<i>S</i>-Adenosylmethionine synthetase enzyme

S-Adenosylmethionine synthetase, also known as methionine adenosyltransferase (MAT), is an enzyme that creates S-adenosylmethionine by reacting methionine and ATP.

<span class="mw-page-title-main">Cobalamin biosynthesis</span>

Cobalamin biosynthesis is the process by which bacteria and archea make cobalamin, vitamin B12. Many steps are involved in converting aminolevulinic acid via uroporphyrinogen III and adenosylcobyric acid to the final forms in which it is used by enzymes in both the producing organisms and other species, including humans who acquire it through their diet.

Radical SAMenzymes is a superfamily of enzymes that use a [4Fe-4S]+ cluster to reductively cleave S-adenosyl-L-methionine (SAM) to generate a radical, usually a 5′-deoxyadenosyl radical (5'-dAdo), as a critical intermediate. These enzymes utilize this radical intermediate to perform diverse transformations, often to functionalize unactivated C-H bonds. Radical SAM enzymes are involved in cofactor biosynthesis, enzyme activation, peptide modification, post-transcriptional and post-translational modifications, metalloprotein cluster formation, tRNA modification, lipid metabolism, biosynthesis of antibiotics and natural products etc. The vast majority of known radical SAM enzymes belong to the radical SAM superfamily, and have a cysteine-rich motif that matches or resembles CxxxCxxC. Radical SAM enzymes comprise the largest superfamily of metal-containing enzymes.

8-hydroxyfuranocoumarin 8-O-methyltransferase is an enzyme with systematic name S-adenosyl-L-methionine:8-hydroxyfurocoumarin 8-O-methyltransferase. This enzyme catalyses the following chemical reaction

<span class="mw-page-title-main">Uroporphyrinogen-III C-methyltransferase</span> Class of enzymes

Uroporphyrinogen-III C-methyltransferase, uroporphyrinogen methyltransferase, uroporphyrinogen-III methyltransferase, adenosylmethionine-uroporphyrinogen III methyltransferase, S-adenosyl-L-methionine-dependent uroporphyrinogen III methylase, uroporphyrinogen-III methylase, SirA, CysG, CobA, uroporphyrin-III C-methyltransferase, S-adenosyl-L-methionine:uroporphyrin-III C-methyltransferase) is an enzyme with systematic name S-adenosyl-L-methionine:uroporphyrinogen-III C-methyltransferase. This enzyme catalyses the following chemical reaction

Methyl halide transferase is an enzyme with systematic name S-adenosylmethionine:iodide methyltransferase. This enzyme catalyses the following chemical reaction

23S rRNA (adenine2503-C2)-methyltransferase (EC 2.1.1.192, RlmN, YfgB, Cfr) is an enzyme with systematic name S-adenosyl-L-methionine:23S rRNA (adenine2503-C2)-methyltransferase. This enzyme catalyses the following chemical reaction

23S rRNA (adenine2503-C8)-methyltransferase (EC 2.1.1.224, Cfr (gene)) is an enzyme with systematic name S-adenosyl-L-methionine:23S rRNA (adenine2503-C8)-methyltransferase. This enzyme catalyses the following chemical reaction

References

  1. 1 2 Cantoni, GL (1952). "The Nature of the Active Methyl Donor Formed Enzymatically from L-Methionine and Adenosinetriphosphate". J Am Chem Soc. 74 (11): 2942–3. doi:10.1021/ja01131a519.
  2. ↑ Ding, Wei; Smulan, Lorissa J.; Hou, Nicole S.; Taubert, Stefan; Watts, Jennifer L.; Walker, Amy K. (2015-10-06). "S-Adenosylmethionine Levels Govern Innate Immunity through Distinct Methylation-Dependent Pathways". Cell Metabolism. 22 (4): 633–645. doi:10.1016/j.cmet.2015.07.013. PMC   4598287 . PMID   26321661.
  3. ↑ Wang, X.; Oh, M. W.; Komatsu, S. (2016-06-01). "Characterization of S-adenosylmethionine synthetases in soybean under flooding and drought stresses". Biologia Plantarum. 60 (2): 269–278. doi: 10.1007/s10535-016-0586-6 . ISSN   0006-3134. S2CID   15567646.
  4. ↑ Finkelstein J, Martin J (2000). "Homocysteine". The International Journal of Biochemistry & Cell Biology. 32 (4): 385–9. doi:10.1016/S1357-2725(99)00138-7. PMID   10762063.
  5. ↑ Födinger M, Hörl W, Sunder-Plassmann G (Jan–Feb 2000). "Molecular biology of 5,10-methylenetetrahydrofolate reductase". J Nephrol. 13 (1): 20–33. PMID   10720211.
  6. ↑ Goyette, P.; Sumner, J. S.; Milos, R.; Duncan, A. M.; Rosenblatt, D. S.; Matthews, R. G.; Rozen, R. (1994-06-01). "Human methylenetetrahydrofolate reductase: isolation of cDNA, mapping and mutation identification". Nature Genetics. 7 (2): 195–200. doi:10.1038/ng0694-195. ISSN   1061-4036. PMID   7920641. S2CID   23877329.
  7. ↑ Booker, SJ; Grove, TL (2010). "Mechanistic and functional versatility of radical SAM enzymes". F1000 Biology Reports. 2: 52. doi: 10.3410/B2-52 . PMC   2996862 . PMID   21152342.
  8. 1 2 Landgraf, Bradley J.; McCarthy, Erin L.; Booker, Squire J. (2016-06-13). "Radical S-Adenosylmethionine Enzymes in Human Health and Disease". Annual Review of Biochemistry. 85: 485–514. doi:10.1146/annurev-biochem-060713-035504. PMID   27145839.
  9. ↑ Roje S (2006). "S-Adenosyl-L-methionine: beyond the universal methyl group donor". Phytochemistry . 67 (15): 1686–98. Bibcode:2006PChem..67.1686R. doi:10.1016/j.phytochem.2006.04.019. PMID   16766004.
  10. ↑ Loenen W (2006). "S-Adenosylmethionine: jack of all trades and master of everything?". Biochem Soc Trans. 34 (Pt 2): 330–3. doi:10.1042/BST20060330. PMID   16545107.
  11. ↑ Chiang P, Gordon R, Tal J, Zeng G, Doctor B, Pardhasaradhi K, McCann P (1996). "S-Adenosylmethionine and methylation". FASEB J. 10 (4): 471–80. doi: 10.1096/fasebj.10.4.8647346 . PMID   8647346. S2CID   11214528.
  12. ↑ Rutjes, AW; Nüesch, E; Reichenbach, S; Jüni, P (7 October 2009). "S-Adenosylmethionine for osteoarthritis of the knee or hip" (PDF). The Cochrane Database of Systematic Reviews. 2009 (4): CD007321. doi:10.1002/14651858.CD007321.pub2. PMC   7061276 . PMID   19821403.
  13. ↑ Mato, Jose M (1997). "S-adenosylmethionine synthesis: Molecular mechanisms and clinical implications". Pharmacology & Therapeutics. 73 (3): 265–280. doi:10.1016/s0163-7258(96)00197-0. hdl: 10261/79246 . PMID   9175157.
  14. ↑ Anstee, QM; Day, CP (November 2012). "S-Adenosylmethionine (SAMe) therapy in liver disease: a review of current evidence and clinical utility". Journal of Hepatology. 57 (5): 1097–109. doi: 10.1016/j.jhep.2012.04.041 . PMID   22659519.
  15. 1 2 Lu, SC; Mato, JM (October 2012). "S-Adenosylmethionine in liver health, injury, and cancer". Physiological Reviews. 92 (4): 1515–42. doi:10.1152/physrev.00047.2011. PMC   3698976 . PMID   23073625.
  16. ↑ Galizia, I; Oldani, L; Macritchie, K; Amari, E; Dougall, D; Jones, TN; Lam, RW; Massei, GJ; Yatham, LN; Young, AH (10 October 2016). "S-Adenosyl methionine (SAMe) for depression in adults". The Cochrane Database of Systematic Reviews. 2016 (10): CD011286. doi:10.1002/14651858.CD011286.pub2. PMC   6457972 . PMID   27727432.
  17. ↑ Cuomo, Alessandro; Beccarini Crescenzi, Bruno; Bolognesi, Simone; Goracci, Arianna; Koukouna, Despoina; Rossi, Rodolfo; Fagiolini, Andrea (2020-09-05). "S-Adenosylmethionine (SAMe) in major depressive disorder (MDD): a clinician-oriented systematic review". Annals of General Psychiatry. 19 (1). Springer Science and Business Media LLC: 50. doi: 10.1186/s12991-020-00298-z . ISSN   1744-859X. PMC   7487540 . PMID   32939220.
  18. ↑ Varela-Rey, Marta (2014). "S-Adenosylmethionine Levels Regulate the Schwann Cell DNA Methylome". Neuron. 81 (5): 1024–1039. doi:10.1016/j.neuron.2014.01.037. PMC   3960855 . PMID   24607226.
  19. ↑ Schmidt, Thomas; Leha, Andreas; Salinas-Riester, Gabriela (2016-12-31). "Treatment of prostate cancer cells with S-adenosylmethionine leads to genome-wide alterations in transcription profiles". Gene. 595 (2): 161–167. doi:10.1016/j.gene.2016.09.032. PMID   27688072.
  20. ↑ Tse, Janson (September 12, 2017). "Aberrant DNA Methylation in Colorectal Cancer: What Should We Target?". National Library of Medicine. 3 (10): 698–712. doi:10.1016/j.trecan.2017.08.003. PMID   28958388.
  21. 1 2 Najm WI, Reinsch S, Hoehler F, Tobis JS, Harvey PW (February 2004). "S-Adenosyl methionine (SAMe) versus celecoxib for the treatment of osteoarthritis symptoms: A double-blind cross-over trial. ISRCTN36233495". BMC Musculoskelet Disord. 5: 6. doi: 10.1186/1471-2474-5-6 . PMC   387830 . PMID   15102339.
  22. 1 2 McKie, Robin (10 April 2022). "Biologists warn against toxic SAMe 'health' supplement". The Observer.
  23. ↑ Woolston, Chris (31 December 2020). "What is SAM-e?". HealthDay.
  24. 1 2 Bottiglieri, T (November 2002). "S-Adenosyl-L-methionine (SAMe): from the bench to the bedside--molecular basis of a pleiotrophic molecule". The American Journal of Clinical Nutrition. 76 (5): 1151S–1157S. doi: 10.1093/ajcn/76.5.1151S . PMID   12418493.
  25. ↑ Rydberg B, Lindahl T (1982). "Nonenzymatic methylation of DNA by the intracellular methyl group donor S-adenosyl-L-methionine is a potentially mutagenic reaction". EMBO J. 1 (2): 211–6. doi:10.1002/j.1460-2075.1982.tb01149.x. PMC   553022 . PMID   7188181.
  26. ↑ "SAMe - Mayo Clinic". Mayo Clinic .
  27. 1 2 "S-Adenosyl-L-Methionine (SAMe): In Depth". National Center for Complementary and Integrative Health (NCCIH). January 11, 2017.
  28. ↑ Fukumoto, Kazuki; Ito, Kakeru; Saer, Benjamin; Taylor, George; Ye, Shiqi; Yamano, Mayu; Toriba, Yuki; Hayes, Andrew; Okamura, Hitoshi; Fustin, Jean-Michel (5 April 2022). "Excess S-adenosylmethionine inhibits methylation via catabolism to adenine". Communications Biology . 5 (1). Nature Publishing Group: 313. doi: 10.1038/s42003-022-03280-5 . hdl: 2433/269415 . ISSN   2399-3642. PMC   8983724 . PMID   35383287.
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