S-Adenosyl methionine

S-Adenosyl methionine

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"S"-Adenosyl methionine (SAM) is a coenzyme involved in methyl group transfers. SAM was first discovered in Italy by G. L. Cantoni in 1952.cite journal | title=The Nature of the Active Methyl Donor Formed Enzymatically from L-Methionine and Adenosinetriphosphate | last=Cantoni | first = GL | journal=J Am Chem Soc | volume=74 | issue=11 | pages=2942–2943 | year=1952 | doi=10.1021/ja01131a519 ] It is made from adenosine triphosphate (ATP) and methionine by methionine adenosyltransferase [http://www.expasy.org/enzyme/ EC] . 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.

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.

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. [cite journal |author=Finkelstein J, Martin J |title=Homocysteine |journal=Int J Biochem Cell Biol |volume=32 |issue=4 |pages=385–9 |year=2000 |pmid=10762063 |doi=10.1016/S1357-2725(99)00138-7] This is hydrolysed to homocysteine and adenosine by S-adenosylhomocysteine hydrolase [http://www.expasy.org/enzyme/ EC] 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 [http://www.expasy.org/enzyme/ EC] or [http://www.expasy.org/enzyme/ EC] . This methionine can then be converted back to SAM, completing the cycle. [cite journal |author=Födinger M, Hörl W, Sunder-Plassmann G |title=Molecular biology of 5,10-methylenetetrahydrofolate reductase |journal=J Nephrol |volume=13 |issue=1 |pages=20–33 |year= |pmid=10720211]

Polyamine biosynthesis

Another major role of SAM is in polyamine biosynthesis. Here, SAM is decarboxylated by Adenosylmethionine decarboxylase [http://www.expasy.org/enzyme/ EC] to form S-adenosyl-5'-3-methylpropylamine. This compound then donates its n-propylamine group in the biosynthesis of polyamines such as spermidine and spermine from putrescine. [cite journal |author=Roje S |title=S-Adenosyl-L-methionine: beyond the universal methyl group donor |journal=Phytochemistry |volume=67 |issue=15 |pages=1686–98 |year=2006 |pmid=16766004 |doi=10.1016/j.phytochem.2006.04.019]

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. [cite journal |author=Loenen W |title=S-adenosylmethionine: jack of all trades and master of everything? |journal=Biochem Soc Trans |volume=34 |issue=Pt 2 |pages=330–3 |year=2006 |pmid=16545107 |doi=10.1042/BST20060330] [cite journal |author=Chiang P, Gordon R, Tal J, Zeng G, Doctor B, Pardhasaradhi K, McCann P |title=S-Adenosylmethionine and methylation |journal=FASEB J |volume=10 |issue=4 |pages=471–80 |year=1996 |pmid=8647346]

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"). SAM is also marketed under the Gumbaral, Samyr, Adomet and Admethionine brand names. Some research has indicated that taking SAM on a regular basis may help fight depression,cite web
title = Investigating SAM-e
publisher = Geriatric Times
year = 2001
url = http://www.geriatrictimes.com/g010923.html
accessdate = 2006-12-08
] cite journal
title = Oral S-adenosylmethionine in depression: a randomized, double-blind, placebo-controlled trial
last=Kagan | first=BL | coauthors=Sultzer, DL; Rosenlicht, N; Gerner, RH
journal = Am J Psychiatry
year = 1990
volume = 147
pages = 591–595
pmid = 2183633
url = http://www.ajp.psychiatryonline.org/cgi/content/abstract/147/5/591
accessdate = 2007-02-16
] cite journal
title = The antidepressant potential of oral S-adenosyl-l-methionine
last=Rosenbaum | first=JF | coauthors=Fava, M; Falk, WE; Pollack, MH; Cohen, LS; Cohen, BM; Zubenko, GS
journal = Acta Psychiatrica Scandinavica
year = 1990 | month = May
volume = 81 | issue = 5
pages = 432–436
pmid = 2113347
accessdate = 2007-02-16
doi = 10.1111/j.1600-0447.1990.tb05476.x
] liver disease, and the pain of osteoarthritis. An authoritative report on SAMe is from the Agency for Healthcare Research and Quality (Dept Health and Human Services) at: http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=hstat1a.chapter.2159. 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 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 (further research indicates 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 cite journal | author = Bottiglieri T, Godfrey P, Flynn T, Carney MW, Toone BK, Reynolds EH. | title = Cerebrospinal fluid S-adenosylmethionine in depression and dementia: effects of treatment with parenteral and oral S-adenosylmethionine | journal = J Neurol Neurosurg Psychiatry| volume = 53 | issue = 12| pages = 1096–8| year = 1990| pmid = 2292704] and in all brain regions of AD patients examined.cite journal | author = Morrison LD, Smith DD, Kish SJ. | title = Brain S-adenosylmethionine levels are severely decreased in Alzheimer's disease | journal = J Neurochem. | volume = 67 | issue = 3| pages = 1328–31| year = 1996| pmid = 8752143] Preliminary research suggests SAM may have therapeutic potential in treating AD patients cite journal | author = Bottiglieri T. | title = Ademetionine (S-adenosylmethionine) neuropharmacology: implications for drug therapies in psychiatric and neurological disorders| journal = Expert Opin Investig Drugs. | volume = 6 | issue =4 | pages = 417–26.| year = 1997 | pmid = 15989609 | doi = 10.1517/13543784.6.4.417] and a recent study using a mouse model of AD found that supplementary SAM prevented oxidative damage and cognitive impairment.cite journal | author = Tchantchou F, Graves M, Ortiz D, Chan A, Rogers E, Shea TB.
title = S-adenosyl methionine: A connection between nutritional and genetic risk factors for neurodegeneration in Alzheimer's disease| journal = J Nutr Health Aging. | volume = 10| issue = 6| pages = 541–4| year = 2006| pmid = 17183426
] In that study ( [http://www.uml.edu/Dept/Biology/tshea/SAMlink.pdf available online] ), Tchantchou "et al" also explain the biomechanics that in addition to the above findings make low SAM a likely causal component of AD pathology.

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.cite journal
title = S-Adenosyl methionine (SAMe) versus celecoxib for the treatment of osteoarthritis symptoms: A double-blind cross-over trial
last=Najm | first=WI | coauthors=Reinsch, S; Hoehler, F; Tobis, JS; Harvey, PW
journal = BMC Musculoskeletal Disorders
volume = 5 | issue = 6
date = 26 February 2004
doi = 10.1186/1471-2474-5-6
accessdate = 2006-12-07 | pages = 6
] It may require up to one month for it to reach full effectiveness in treating osteoarthritis. 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.cite web
title = S-Adenosylmethionine (SAMe)
publisher = University of Maryland Medical Center
year = 2004
url = http://www.umm.edu/altmed/ConsSupplements/SAdenosylmethionineSAMecs.html
accessdate = 2006-12-07

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. Subscribers to Consumer Labs have access to a comparative report on SAMe content of various supplements.cite web
title = Product Review: SAMe
publisher = ConsumerLab
date = 2003-11-18
url = http://www.consumerlab.com/results/same.asp
accessdate = 2006-12-19

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. [cite web
title = What Is SAMe
publisher = Newsweek
month = July | year = 1999
url = http://www.biopsychiatry.com/sameart.html
accessdate = 2006-12-07


SAMe is best absorbed on an empty stomach. 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.cite web
title = SAMe (S-adenosylmethionine)
publisher = About.com
date =
url = http://www.wholehealthmd.com/ME2/dirmod.asp?nm=Reference+Library&type=AWHN_Supplements&id=E5789DDA2807440687228DC727CDF39C&tier=2
accessdate = 2006-12-07

Possible side effects

SAM-e & Homocysteine: Once SAM-e donates its methyl group to choline, 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, 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 will not break down properly. As a consequence, the full benefits of SAM-e will not be obtained, and homocysteine may increase to unsafe levels. 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. [http://www.nutraseal.com/index.asp?PageAction=Custom&ID=56#function] cite web
title = SAM-e & homocysteine
publisher = www.nutraseal.com
url = http://www.nutraseal.com/index.asp?PageAction=Custom&ID=56#function
accessdate = 2007-06-04

Another reported side effect of SAMe 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.cite journal
title = Role of S-adenosyl-L-methionine in the treatment of depression: a review of the evidence
last=Mischoulon | first=D | coauthors=Fava, M
journal = Am J Clin Nutr
year = 2002 | month=November
volume = 76 | issue=5
pages = 1158S–1161S
url = http://www.ajcn.org/cgi/reprint/76/5/1158S.pdf
accessdate = 2006-12-07 |format=PDF
] Consult with your physician before and during use.

Adverse effects

Gastrointestinal disorder, diarrhea, dyspepsia, anxiety, headache, psychiatric, insomnia, allergy, and rashes. Long-term effects are unknown.

erotonin syndrome

There is concern and one report of the potentially fatal serotonin syndrome in association of SAMe with other medications.cite web
title = Drug Interactions: SSRIs
publisher = iHerb.Com
date =
url = http://healthlibrary.epnet.com/GetContent.aspx?token=e0498803-7f62-4563-8d47-5fe33da65dd4&chunkiid=21620
accessdate = 2007-04-11

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). [cite journal |author=Janicak PG, Lipinski J, Davis JM, Altman E, Sharma RP |title=Parenteral S-adenosyl-methionine (SAMe) in depression: literature review and preliminary data |journal=Psychopharmacology bulletin |volume=25 |issue=2 |pages=238–42 |year=1989 |pmid=2690166] Both depression and mania can be life-threatening conditions that may cause cognitive dysfunction even after remission. [cite web
last = Jamison
first = Kay
title = Brain Damage in Depression and Bipolar Disorder
work = McMan's Depression and Bipolar Web
date = Updated January 21, 2004
url = http://www.mcmanweb.com/article-161.htm
] There is concern that antidepressants in general can induce hypomania, mania, or both.cite web
title = Antidepressants in Bipolar Disorder: The Controversies
publisher = PsychEducation.org
date = 11/2006
url = http://www.psycheducation.org/bipolar/controversy.htm
accessdate = 2007-04-10


See also

* DNA methyltransferase

External links

* [http://www.biomedcentral.com/1471-244X/4/38 S-adenosylmethionine (SAM-e) for the treatment of depression in people living with HIV/AIDS] at biomedcentral.com
* [http://arthritis.about.com/od/same/ About.com SAM-e Resource Index] at About.com
* [http://www.umm.edu/altmed/articles/s-adenosylmethionine-000324.htm list of known SAM-e drug interactions and precautions in use] at University of Maryland Medical Centers

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