S-Adenosyl methionine

S-Adenosyl methionine
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 of S-adenosyl methionine

SAM-e cycle

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

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

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

Some research, including multiple clinical trials, has indicated taking SAM on a regular basis may help fight depression,[8][9][10][11][12] liver disease,[13][14] and the pain of osteoarthritis.[15] 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. Severely low levels of SAM have been found in the cerebrospinal fluid[16] and in all brain regions of Alzheimer's disease patients examined.[17]

SAMe has been studied in the treatment of osteoarthritis, wherein the substance reduces the pain associated with the disease. Although an optimal dose has yet to be determined, SAMe appears as effective as the non-steroidal anti-inflammatory drugs. Additional study is warranted to confirm these findings.[18]

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".[19] 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.

Applications in drug discovery and development

Recent work has revealed the methyltransferases involved in methylation of naturally-occurring anticancer agents to use SAM analogs that carry alternative alkyl groups as a replacement for methyl. The development of the facile chemoenzymatic platform to generate and utilize differentially alkylated SAM analogs in the context of drug discovery and drug development is known as alkylrandomization.[20]

Forms, usage and adverse effects

Oral forms

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] It may require up to one month for it to reach full effectiveness in treating osteoarthritis.[21] Because of structural instability, stable salt forms of SAM are required for its use as an oral drug. The University of Maryland lists the commonly used salts: tosylate, butanedisulfonate, disulfate tosylate, disulfate ditosylate, and disulfate monotosylate.[22]

With the advent of FDA-mandated good manufacturing practices (GMPs) in 2008, manufacturers are required to confirm their products contain what is listed on the label through the end of shelf life. Whether they achieve this goal or not has been questioned. This testing has shown that properly produced and packaged SAM has a shelf life in excess of three years; however, most manufacturers label for a two-year shelf life.

Claims that the SAM butanedisulfonate salt is more stable or better absorbed are not supported by the references usually cited as evidence. Different salts have successfully been used in clinical trials, but there is no published head-to-head comparison.[22][23][24]

Injectable forms

Injectable SAMe (marketed as Heptral by Abbott) is available in Russia. Bioavailability of intramuscular injected SAMe is 96% (compared to 5% of oral form) [25]

Usage

SAM is best absorbed on an empty stomach. Enteric-coated tablets packaged in foil or foil blister packs increase stability and improve absorption. SAM should be stored in a cool, dry place to prevent decomposition.[22]

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.[26]

Possible side effects

Once SAM donates its methyl group to choline, in the formation of creatine, carnitine, DNA, tRNA, norepinephrine, and other compounds, it is transformed into S-adenosyl-homocysteine, (SAH). Under normal circumstances, homocysteine, in the presence of vitamin B6, vitamin B12, and folic acid (SAM's main cofactors), will eventually be converted back into methionine, SAM, or cysteine, glutathione, and other useful substances. However, if adequate amounts of these vitamins are not present, SAM may not break down properly. As a consequence, its full benefits will not be obtained, and homocysteine may increase to unsafe levels. Small studies have not shown a consistent effect of SAM on homocysteine levels, but more research is needed.[27][28]

High levels of homocysteine have been associated with atherosclerosis (hardening and narrowing of the arteries), as well as an increased risk of heart attacks, strokes, liver damage, and possibly Alzheimer's disease. Therefore, vitamin B supplements are often taken along with SAM. These vitamins help metabolize the homocysteine into other useful compounds.[29]

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.

Therapeutic doses range from 400 mg/day to 1600 mg/day, although higher doses are used in some cases.[21][30]

Induction of mania

In an extensive MEDLINE search on SAM, Kagan found induction of mania in one patient out of 15 treated with parenteral SAM.[11] In the same review, Lipinski found the apparent induction of mania in two patients with bipolar disorder (total of nine depressed patients studied).[31] Both depression and mania can be life-threatening conditions that may cause cognitive dysfunction even after remission.[32] There is concern that antidepressants in general can induce mania or hypomania in bipolar persons.[33]

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.[34] These drugs include dextromethorphan (Robitussin), meperidine (Demerol), pentazocine (Talwin), and tramadol (Ultram).[34] SAM may also interact with antidepressant medications increasing the potential for their side effects and reduce the effectiveness of levodopa for Parkinson's disease.[34]

See also

Alternative names

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

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. ↑ 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. ↑ "Investigating SAM-e". Geriatric Times. 2001. Retrieved 2006-12-08.
  11. 1 2 Kagan, BL; Sultzer, DL; Rosenlicht, N; Gerner, RH (May 1, 1990). "Oral S-adenosylmethionine in depression: a randomized, double-blind, placebo-controlled trial". Am J Psychiatry. 147 (5): 591–5. doi:10.1176/ajp.147.5.591. PMID 2183633. Retrieved 2007-02-16.
  12. ↑ Rosenbaum, JF; Fava, M; Falk, WE; Pollack, MH; Cohen, LS; Cohen, BM; Zubenko, GS (May 1990). "The antidepressant potential of oral S-adenosyl-l-methionine". Acta Psychiatrica Scandinavica. 81 (5): 432–6. doi:10.1111/j.1600-0447.1990.tb05476.x. PMID 2113347.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ Bottiglieri T, Godfrey P, Flynn T, Carney MW, Toone BK, Reynolds EH (1990). "Cerebrospinal fluid S-adenosylmethionine in depression and dementia: effects of treatment with parenteral and oral S-adenosylmethionine". J Neurol Neurosurg Psychiatry. 53 (12): 1096–8. doi:10.1136/jnnp.53.12.1096. PMC 488323Freely accessible. PMID 2292704.
  17. ↑ Morrison LD, Smith DD, Kish SJ (1996). "Brain S-adenosylmethionine levels are severely decreased in Alzheimer's disease". J Neurochem. 67 (3): 1328–31. doi:10.1046/j.1471-4159.1996.67031328.x. PMID 8752143.
  18. ↑ "SAMe". mayoclinic.
  19. ↑ "Šta je". Tensilen. Retrieved 2014-04-28.
  20. ↑ Singh, S; Zhang, J; Huber, TD; Sunkara, M; Hurley, K; Goff, RD; Wang, G; Zhang, W; Liu, C; Rohr, J; Van Lanen, SG; Morris, AJ; Thorson, JS (7 April 2014). "Facile chemoenzymatic strategies for the synthesis and utilization of S-adenosyl-(L)-methionine analogues.". Angewandte Chemie International Edition in English. 53 (15): 3965–9. doi:10.1002/anie.201308272. PMID 24616228.
  21. 1 2 3 4 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.
  22. 1 2 3 "S-Adenosylmethionine (SAMe)". University of Maryland Medical Center. 2004. Retrieved 2009-11-09.
  23. ↑ "Product Review: SAMe". ConsumerLab. 2003-11-18. Retrieved 2006-12-19.
  24. ↑ "What Is SAMe". Newsweek. July 1999. Retrieved 2010-08-30.
  25. ↑ Russian: Vidal drug catalog: Heptral
  26. ↑ 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.
  27. ↑ drweil.com. "Dr. Weil: Can SAM-e hurt my heart?".
  28. ↑ Thompson MA, Bauer BA, Loehrer LL, et al. (May 2009). "Dietary supplement S-adenosyl-L-methionine (AdoMet) effects on plasma homocysteine levels in healthy human subjects: a double-blind, placebo-controlled, randomized clinical trial". J Altern Complement Med. 15 (5): 523–9. doi:10.1089/acm.2008.0402. PMC 2875864Freely accessible. PMID 19422296.
  29. ↑ "SAM-e & homocysteine". www.nutraseal.com. Archived from the original on 2007-09-28. Retrieved 2007-06-04.
  30. ↑ Mischoulon, D; Fava, M (November 2002). "Role of S-adenosyl-L-methionine in the treatment of depression: a review of the evidence" (PDF). Am J Clin Nutr. 76 (5): 1158S–61S. PMID 12420702. Retrieved 2006-12-07.
  31. ↑ Janicak PG, Lipinski J, Davis JM, Altman E, Sharma RP (1989). "Parenteral S-adenosyl-methionine (SAMe) in depression: literature review and preliminary data". Psychopharmacology bulletin. 25 (2): 238–42. PMID 2690166.
  32. ↑ Jamison, Kay (January 21, 2004). "Brain Damage in Depression and Bipolar Disorder". McMan's Depression and Bipolar Web. Archived from the original on 2006-06-17.
  33. ↑ "Antidepressants in Bipolar Disorder: The Controversies". PsychEducation.org. November 2006. Retrieved 2007-04-10.
  34. 1 2 3 S-adenosylmethionine, University of Maryland Medical Center
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