S-Adenosyl methionine

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S-Adenosyl methionine
S-Adenosyl-L-methionin.svg
S-adenosylmethionine spacefill.png
S-adenosylmethionine.png
Names
IUPAC name
(2S)-2-Amino-4-[[(2S,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl-methylsulfonio]butanoate
Other names
S-Adenosyl-L-methionine; SAM-e; SAMe, AdoMet, ademethionine
Identifiers
29908-03-0 YesY
3D model (Jmol) Interactive image
ChEMBL ChEMBL1088977 N
ChemSpider 8041295 YesY
ECHA InfoCard 100.045.391
KEGG C00019 N
MeSH S-Adenosylmethionine
PubChem 9865604
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).
N verify (what is YesYN ?)
Infobox references

S-Adenosyl methionine[alternative names 1] is a common cosubstrate involved in methyl group transfers, transsulfuration, and aminopropylation. Although these anabolic reactions occur throughout the body, most SAM-e is produced and consumed in the liver.[1] More than 40 methyl transfers from SAM-e 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 (EC 2.5.1.6). SAM was first discovered by Giulio Cantoni in 1952.[1]

In bacteria, SAM-e is bound by the SAM riboswitch, which regulates genes involved in methionine or cysteine biosynthesis.

Biochemistry[edit]

SAM-e cycle[edit]

The reactions that produce, consume, and regenerate SAM-e are called the SAM-e cycle. In the first step of this cycle, the SAM-dependent methylases (EC 2.1.1) that use SAM-e 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 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-e, 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-e enzymes[edit]

A large number of iron-sulfur cluster-containing enzymes cleave SAM-e reductively to produce a 5′-deoxyadenosyl 5′-radical as an intermediate, and are called radical SAM enzymes.[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-e enzymes use a second SAM-e 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-e is in polyamine biosynthesis. Here, SAM-e 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-e 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]

Some research, including multiple clinical trials, has indicated taking SAM on a regular basis may help fight depression,[8][9] liver disease,[10][11] and the pain of osteoarthritis.[12] All other indications are not yet well-evidenced.

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.[medical citation needed]

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"). Approved in Russia, Italy, and several countries of the European Union, SAM is also marketed as a prescription drug under the brand names Gumbaral, Samyr, Adomet, Heptral, Agotan, Donamet, Isimet and Admethionine. In India, SAM is also marketed as Nusam under dietary supplement category. In Serbia, the drug is marketed as "Tensilen".[13] 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 of the Food and Drug Administration (FDA) for drugs.

Pharmacology[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.[14]

Adverse effects[edit]

Gastrointestinal disorder, dyspepsia and anxiety can occur with SAM consumption.[14] Long-term effects are unknown. SAM is a weak DNA-alkylating agent.[15]

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[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. These drugs include dextromethorphan (Robitussin), meperidine (Demerol), pentazocine (Talwin), and tramadol (Ultram). SAM may also interact with antidepressant medications increasing the potential for their side effects and reduce the effectiveness of levodopa for Parkinson's disease.[medical citation needed]

See also[edit]

Alternative names[edit]

  1. ^ SAM-e, SAMe, SAM, S-Adenosyl-L-methionine, AdoMet, ademetionine

References[edit]

  1. ^ a b 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. ^ Finkelstein J, Martin J (2000). "Homocysteine". Int J Biochem Cell Biol. 32 (4): 385–9. doi:10.1016/S1357-2725(99)00138-7. PMID 10762063. 
  3. ^ 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. 
  4. ^ Booker, SJ; Grove, TL (2010). "Mechanistic and functional versatility of radical SAM enzymes". F1000 biology reports. 2: 52. doi:10.3410/B2-52. PMC 2996862Freely accessible. PMID 21152342. 
  5. ^ Roje S (2006). "S-Adenosyl-L-methionine: beyond the universal methyl group donor". Phytochemistry. 67 (15): 1686–98. doi:10.1016/j.phytochem.2006.04.019. PMID 16766004. 
  6. ^ 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. 
  7. ^ 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. PMID 8647346. 
  8. ^ Papakostas, GI (Nov 2002). "Role of S-adenosyl-L-methionine in the treatment of depression: a review of the evidence". Am J Clin Nutr. 76(5): 1158S–61S. doi:10.4088/JCP.8157su1c.04. PMID 19909689. 
  9. ^ Bressa, GM (1994). "S-adenosyl-l-methionine (SAMe) as antidepressant: meta-analysis of clinical studies". Acta Neurol Scand Suppl. 154: 7–14. PMID 7941964. 
  10. ^ Anstee, Quentin M.; Day, Christopher P. (2012). "S-adenosylmethionine (SAMe) therapy in liver disease: A review of current evidence and clinical utility" (PDF). Journal of hepatology. 57 (5): 1097–1109. doi:10.1016/j.jhep.2012.04.041. Retrieved 18 June 2014. 
  11. ^ Mato, José M. (2007). "Role of S‐adenosyl‐L‐methionine in liver health and injury". Hepatology. 45 (5): 1306–1312. doi:10.1002/hep.21650. 
  12. ^ Mary Hardy; Ian Coulter; Sally C Morton; Joya Favreau; Swamy Venuturupalli; Francesco Chiappelli; Frederico Rossi; Greg Orshansky; Lara K Jungvig; Elizabeth A Roth; Marika J Suttorp; Paul Shekelle (October 2002). S-Adenosyl-L-Methionine for Treatment of Depression, Osteoarthritis, and Liver Disease (Report). Agency for Healthcare Research and Quality. Retrieved 2012-08-31. 
  13. ^ "Šta je". Tensilen. Retrieved 2014-04-28. 
  14. ^ a b 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 387830Freely accessible. PMID 15102339. 
  15. ^ 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. PMC 553022Freely accessible. PMID 7188181. 

External links[edit]