S-Adenosyl methionine

S-Adenosyl methionine
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
Identifiers
CAS number 29908-03-0
PubChem 34755
MeSH S-Adenosylmethionine
Properties
Molecular formula C15H22N6O5S+
Molar mass 398.44 g/mol
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

S-Adenosyl methionine (SAM, SAMe, SAM-e) is a common co-substrate involved in methyl group transfers. SAM-e was first discovered in Italy by G. L. Cantoni in 1952.[1] It is made from adenosine triphosphate (ATP) and methionine by methionine adenosyltransferase (EC 2.5.1.6). Transmethylation, transsulfuration, and aminopropylation are the metabolic pathways that use SAM. Although these anabolic reactions occur throughout the body, most SAM is produced and consumed in the liver.[1]

The methyl group (CH3) attached to the methionine sulfur atom in SAM is chemically reactive. This allows donation of this group to an acceptor substrate in transmethylation reactions. More than 40 metabolic reactions involve the transfer of a methyl group from SAM to various substrates such as nucleic acids, proteins, and lipids.

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

Contents

Biochemistry of S-adenosyl methionine

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.[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 (EC 2.1.1.13 or EC 2.1.1.14). This methionine can then be converted back to SAM, completing the cycle.[3]

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.[4]

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 dopamine and serotonin. 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.[5][6]

Therapeutic uses

In the United States, SAM is sold as a nutritional supplement under the marketing name SAM-e (also spelled SAME or SAMe; pronounced "sam ee" or "Sammy"). SAM is also marketed under the Gumbaral, Samyr, Adomet, Heptral and Admethionine brand names as a prescription drug approved in Russia, Italy, and Germany. Some research has indicated that taking SAM on a regular basis may help fight depression,[7][8][9] liver disease, and the pain of osteoarthritis.[10] Multiple clinical trials indicate benefits for depression, some liver conditions and osteoarthritis. All other indications are not yet proven.

Therapeutic use of SAM has increased 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 for drugs of the Food and Drug Administration (FDA).

At first, a line of evidence suggested that abnormally low levels of endogenous SAM may play an important role in the development of Alzheimer's disease (AD) and that SAM may therefore have therapeutic potential in the treatment of AD. However, further research has indicated this effect is likely due to vitamin B12 deficiencies, which cause neurologic defects through one carbon transfers with folate. Severely low levels of SAM have been found in the cerebrospinal fluid[11] and in all brain regions of AD patients examined.[12] Preliminary research suggests SAM may have therapeutic potential in treating AD patients [13] and a recent study using a mouse model of AD found that supplementary SAM prevented oxidative damage and cognitive impairment.[14]

Oral forms, usage and adverse effects

Oral forms

Oral SAMe achieves peak plasma concentrations 3 to 5 hours after ingestion of an enteric-coated tablet (400–1000 mg). The half-life is about 100 minutes.[15] It may require up to one month for it to reach full effectiveness in treating osteoarthritis.[15] 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.[16]

With the advent of FDA-mandated Good Manufacturing Practices (GMPs) in 2008, manufacturers are required to confirm that 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 SAMe has a shelf life in excess of three years, however most manufacturers label for a two-year shelf life.

Claims that the SAMe butanedisulfonate salt is more stable or better absorbed are not supported by the references that are usually cited as evidence. Different salts have successfully been used in clinical trials, but there is no published head-to-head comparison.[16][17][18]

Usage

SAMe is best absorbed on an empty stomach.[19] Enteric-coated tablets packaged in foil or foil blister packs increase stability and improve absorption. SAMe should be stored in a cool, dry place to prevent deterioration.[16]

Possible side effects

Once SAM-e 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-e's main co-factors), will eventually be converted back into methionine, SAM-e, or cysteine, glutathione, and other useful substances. However, if adequate amounts of these vitamins are not present, SAM-e may not break down properly. As a consequence, the full benefits of SAM-e will not be obtained, and homocysteine may increase to unsafe levels. Small studies have not shown a consistent effect of SAM-e on homocysteine levels, but more research is needed.[20][21]

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-e. These vitamins help metabolize the homocysteine into other useful compounds.[22]

Another reported side effect of SAMe is insomnia, therefore the supplement is often taken in the morning.[19] 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. Some users report increased anxiety with as little as 50 mg/day.[23]

Therapeutic doses range from 400 mg/day to 1600 mg/day, although higher doses are used in some cases.[15][24] Some physicians recommend even lower doses ranging from 50 to 200 mg/day to treat mild depression without triggering negative side effects.[23]

Adverse effects

Gastrointestinal disorder, diarrhea, dyspepsia, anxiety, headache, psychiatric, insomnia, allergy, and rashes.[15] Long-term effects are unknown. SAMe is a weak DNA-alkylating agent, and may thus act as a weak carcinogen[25].

Serotonin syndrome

There is concern and one report of the potentially fatal serotonin syndrome in association of SAMe with other medications.[26]

Induction of mania

In an extensive MEDLINE search on SAMe, Kagan found induction of mania in one patient out of fifteen treated with parenteral SAMe. In the same review, Lipinski found the apparent induction of mania in two patients with bipolar disorder (total of nine depressed patients studied).[27] Both depression and mania can be life-threatening conditions that may cause cognitive dysfunction even after remission.[28] There is concern that antidepressants in general can induce hypomania, mania, or both.[29]

See also

References

  1. ↑ 1.0 1.1 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-February 2000). "Molecular biology of 5,10-methylenetetrahydrofolate reductase". J Nephrol 13 (1): 20–33. PMID 10720211. 
  4. ↑ 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. 
  5. ↑ 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. 
  6. ↑ 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. 
  7. ↑ "Investigating SAM-e". Geriatric Times. 2001. http://www.geriatrictimes.com/g010923.html. Retrieved 2006-12-08. 
  8. ↑ 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. PMID 2183633. http://www.ajp.psychiatryonline.org/cgi/content/abstract/147/5/591. Retrieved 2007-02-16. 
  9. ↑ 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. 
  10. ↑ S-Adenosyl-L-Methionine for Treatment of Depression, Osteoarthritis, and Liver Disease, Agency for Healthcare Research and Quality (Department of Health and Human Services)
  11. ↑ 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. PMID 2292704. 
  12. ↑ 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. 
  13. ↑ Bottiglieri T. (1997). "Ademetionine (S-adenosylmethionine) neuropharmacology: implications for drug therapies in psychiatric and neurological disorders". Expert Opin Investig Drugs. 6 (4): 417–26.. doi:10.1517/13543784.6.4.417. PMID 15989609. 
  14. ↑ Tchantchou F, Graves M, Ortiz D, Chan A, Rogers E, Shea TB. (2006). "S-adenosyl methionine: A connection between nutritional and genetic risk factors for neurodegeneration in Alzheimer's disease" (PDF). J Nutr Health Aging. 10 (6): 541–4. PMID 17183426. http://greengene.uml.edu/publish/publications/SAMLink.pdf. 
  15. ↑ 15.0 15.1 15.2 15.3 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. PMID 15102339. PMC 387830. http://www.biomedcentral.com/1471-2474/5/6. 
  16. ↑ 16.0 16.1 16.2 "S-Adenosylmethionine (SAMe)". University of Maryland Medical Center. 2004. http://www.umm.edu/altmed/articles/s-adenosylmethionine-000324.htm. Retrieved 2009-11-09. 
  17. ↑ "Product Review: SAMe". ConsumerLab. 2003-11-18. http://www.consumerlab.com/results/same.asp. Retrieved 2006-12-19. 
  18. ↑ "What Is SAMe". Newsweek. July 1999. http://www.newsweek.com/1999/07/04/what-is-same.html. Retrieved 2010-08-30. 
  19. ↑ 19.0 19.1 "SAMe (S-adenosylmethionine)". About.com. http://www.wholehealthmd.com/ME2/dirmod.asp?nm=Reference+Library&type=AWHN_Supplements&id=E5789DDA2807440687228DC727CDF39C&tier=2. Retrieved 2006-12-07. 
  20. ↑ drweil.com. "Dr. Weil: Can SAM-e hurt my heart?". http://www.drweil.com/drw/u/QAA400465/Can-SAMe-Hurt-My-Heart.html. 
  21. ↑ PMID 19422296
  22. ↑ "SAM-e & homocysteine". www.nutraseal.com. http://www.nutraseal.com/index.asp?PageAction=Custom&ID=56#function. Retrieved 2007-06-04. 
  23. ↑ 23.0 23.1 Ray Sahelian, M.D. (2009-05-05). ""SAM-e supplement benefits for depression and side effects by Ray Sahelian, M.D., mood, liver, and arthritis, dosage 100mg, 200mg"". http://www.raysahelian.com/sam-e.html. Retrieved 2009-05-05. 
  24. ↑ 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. http://www.ajcn.org/cgi/reprint/76/5/1158S.pdf. Retrieved 2006-12-07. 
  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. PMID 7188181. 
  26. ↑ "Drug Interactions: SSRIs". iHerb.Com. http://healthlibrary.epnet.com/GetContent.aspx?token=e0498803-7f62-4563-8d47-5fe33da65dd4&chunkiid=21620. Retrieved 2007-04-11. 
  27. ↑ 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. 
  28. ↑ Jamison, Kay (Updated January 21, 2004). "Brain Damage in Depression and Bipolar Disorder". McMan's Depression and Bipolar Web. http://www.mcmanweb.com/article-161.htm. 
  29. ↑ "Antidepressants in Bipolar Disorder: The Controversies". PsychEducation.org. November 2006. http://www.psycheducation.org/bipolar/controversy.htm. Retrieved 2007-04-10. 

External links

Enzyme cofactors
Active forms

vitamins: TPP / ThDP (B1) · FMN, FAD (B2) · NAD+, NADH, NADP+, NADPH (B3) · Coenzyme A (B5) · PLP / P5P (B6) · Biotin (B7) · THFA / H4FA, DHFA / H2FA, MTHF (B9) · AdoCbl, MeCbl (B12) · Ascorbic Acid (C) · Phylloquinone (K1, Menaquinone (K2) · Coenzyme F420
non-vitamins: ATP · CTP · SAMe · PAPS · GSH · Coenzyme B · Coenzyme F430 · Coenzyme M · Coenzyme Q · Heme / Haem (A, B, C, O) · Lipoic Acid · Methanofuran · Molybdopterin · PQQ · THB / BH4 · THMPT / H4MPT

minerals: Ca2+ · Cu2+ · Fe2+, Fe3+ · Mg2+ · Mn2+ · Mo · Ni2+ · Se · Zn2+
Base forms
vitamins: Thiamine (B1) · Riboflavin (B2) · Niacin, Niacinamide (B3) · Pantothenic Acid (B5) · Pyridoxine, Pyridoxamine, Pyridoxal (B6) · Cyanocobalamin, Hydroxocobalamin (B12)

: NUT

cof, enz,

noco, nuvi, sysi/, met

drug(A8/11/12)
Amino acid metabolism metabolic intermediates
K→acetyl-CoA
Saccharopine · Allysine · α-Aminoadipic acid · α-Aminoadipate · Glutaryl-CoA · Glutaconyl-CoA · Crotonyl-CoA · β-Hydroxybutyryl-CoA
α-Ketoisocaproic acid · Isovaleryl-CoA · 3-Methylcrotonyl-CoA · 3-Methylglutaconyl-CoA · HMG-CoA
N'-Formylkynurenine · Kynurenine · Anthranilic acid · 3-Hydroxykynurenine · 3-Hydroxyanthranilic acid · 2-Amino-3-carboxymuconic semialdehyde · 2-Aminomuconic semialdehyde · 2-Aminomuconic acid · Glutaryl-CoA
G
G→pyruvate→citrate

3-Phosphoglyceric acid

glycine→creatine: Glycocyamine · Phosphocreatine · Creatinine
G→glutamate→
α-ketoglutarate
Urocanic acid · Imidazol-4-one-5-propionic acid · Formiminoglutamic acid · Glutamate-1-semialdehyde
1-Pyrroline-5-carboxylic acid
Ornithine · Putrescine · Agmatine
other
cysteine+glutamate→glutathione: γ-Glutamylcysteine
G→propionyl-CoA→
succinyl-CoA
α-Ketoisovaleric acid · Isobutyryl-CoA · Methacrylyl-CoA · 3-Hydroxyisobutyryl-CoA · 3-Hydroxyisobutyric acid · 2-Methyl-3-oxopropanoic acid
2,3-Dihydroxy-3-methylpentanoic acid · 2-Methylbutyryl-CoA · Tiglyl-CoA · 2-Methylacetoacetyl-CoA

generation of homocysteine: S-Adenosyl methionine · S-Adenosyl-L-homocysteine · Homocysteine

conversion to cysteine: Cystathionine · alpha-Ketobutyric acid+Cysteine
α-Ketobutyric acid
propionyl-CoA→
Methylmalonyl-CoA
4-Hydroxyphenylpyruvic acid · Homogentisic acid · 4-Maleylacetoacetate
G→oxaloacetate
see urea cycle
Other
Cysteine metabolism
Cysteine sulfinic acid

: MET

mt, r//c/p/i/y, f/s/l/o, a/u, n, h

rgcp//y, f/s/l/o, au, n, h,

m(A16, C10),i(//c//i/y, /s/o, a/u,n, h)