S-Adenosyl methionine
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2008-07-01T15:46:47Z
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| CASNo=29908-03-0
| PubChem=1079
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| MeSHName=S-Adenosylmethionine
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| Formula=C<sub>15</sub>H<sub>23</sub>N<sub>6</sub>O<sub>5</sub>S+
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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.<ref name="cantoni1952">{{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 }}</ref> It is made from [[adenosine triphosphate]] (ATP) and [[methionine]] by [[methionine adenosyltransferase]] [http://www.expasy.org/enzyme/2.5.1.6 EC 2.5.1.6]. Transmethylation, transsulfuration, and aminopropylation are the [[metabolic pathway]]s that use SAM. Although these [[anabolic]] reactions occur throughout the body, most SAM is produced and consumed in the liver.<ref name="cantoni1952"/>
The methyl group (CH<sub>3</sub>) 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 [[metabolism|metabolic]] reactions involve the transfer of a methyl group from SAM to various substrates such as [[nucleic acid]]s, [[protein]]s, and [[lipid]]s.
In bacteria, SAM is bound by the [[SAM riboswitch (S box leader)|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 [[methylase]]s (EC 2.1.1) that use SAM as a substrate produce [[S-adenosyl homocysteine]] as a product.<ref>{{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}}</ref> This is hydrolysed to [[homocysteine]] and [[adenosine]] by [[S-adenosylhomocysteine hydrolase]] [http://www.expasy.org/enzyme/3.3.1.1 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 synthase]]s [http://www.expasy.org/enzyme/2.1.1.13 EC 2.1.1.13] or [http://www.expasy.org/enzyme/2.1.1.14 EC 2.1.1.14]. This methionine can then be converted back to SAM, completing the cycle.<ref>{{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}}</ref>
=== Polyamine biosynthesis ===
Another major role of SAM is in [[polyamine]] biosynthesis. Here, SAM is decarboxylated by [[Adenosylmethionine decarboxylase]] [http://www.expasy.org/enzyme/4.1.1.50 EC 4.1.1.50] 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]].<ref>{{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}}</ref>
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]]. [[Methyltransferase]]s are also responsible for the addition of methyl groups to the 2' hydroxyls of the first and second [[nucleotide]]s next to the 5' cap in [[messenger RNA]].<ref>{{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}}</ref><ref>{{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}}</ref>
== Therapeutic uses ==
In the [[United States]], SAM is sold as a [[dietary supplement|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 [[Clinical depression|depression]],<ref name="Geriatric">
{{cite web
| title = Investigating SAM-e
| publisher = Geriatric Times
| date = 2001
| url = http://www.geriatrictimes.com/g010923.html
| accessdate = 2006-12-08 }}
</ref><ref name="Oral S-adenosylmethionine in depression: a randomized, double-blind, placebo-controlled trial">
{{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 }}
</ref><ref name="The antidepressant potential of oral S-adenosyl-l-methionine">
{{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 }}
</ref> [[liver disease]], and the pain of [[arthritis|osteoarthritis]]. An authorative 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]] <ref name="Bottiglieri">{{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}}</ref> and in all brain regions of AD patients examined.<ref name="Morrison">{{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}}</ref> Preliminary research suggests SAM may have therapeutic potential in treating AD patients <ref name="Bottiglieri_1997">{{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}}</ref> and a recent study using a mouse model of AD found that supplementary SAM prevented oxidative damage and cognitive impairment.<ref name="Tchantchou">{{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 }}</ref> 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.<ref name="BMC">
{{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
}}
</ref> It may require up to one month for it to reach full effectiveness in treating osteoarthritis.<ref name="BMC"/> 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]].<ref name="Maryland">{{cite web
| title = S-Adenosylmethionine (SAMe)
| publisher = University of Maryland Medical Center
| date = 2004
| url = http://www.umm.edu/altmed/ConsSupplements/SAdenosylmethionineSAMecs.html
| accessdate = 2006-12-07 }}
</ref>
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.<ref name="consumerlab">{{cite web
| title = Product Review: SAMe
| publisher = ConsumerLab
| date = 2003-11-18
| url = http://www.consumerlab.com/results/same.asp
| accessdate = 2006-12-19 }}
</ref>
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.<ref name="Maryland"/><ref name="consumerlab"/><ref>{{cite web
| title = What Is SAMe
| publisher = Newsweek
| date = July 1999
| url = http://www.biopsychiatry.com/sameart.html
| accessdate = 2006-12-07 }}
</ref>
===Usage===
SAMe is best absorbed on an empty stomach.<ref name="About"/> [[Enteric coating|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.<ref name="Maryland"/><ref name="About">
{{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 }}
</ref>
===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]<ref name="nutraseal">
{{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 }}</ref>
Another reported side effect of SAMe is [[insomnia]], therefore the supplement is often taken in the morning.<ref name="About"/> 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 [[milligram|mg]]/day to 1600 [[milligram|mg]]/day, although higher doses are used in some cases.<ref name="BMC"/><ref name="ajcn">
{{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
| pmid=12420702
| accessdate = 2006-12-07 }}
</ref> Consult with your physician before and during use.
===Adverse effects===
Gastrointestinal disorder, [[diarrhea]], [[dyspepsia]], [[anxiety]], [[headache]], psychiatric, [[insomnia]], [[allergy]], and [[rash]]es.<ref name="BMC"/> Long-term effects are unknown.
====Serotonin syndrome====
There is concern and one report of the potentially fatal [[Serotonin syndrome|serotonin syndrome]] in association of SAMe with other medications.<ref name="Interactions">
{{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 }}
</ref>
====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).<ref>{{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}}</ref> Both depression and mania can be life-threatening conditions that may cause [[cognitive dysfunction]] even after [[remission]].<ref>{{cite web
| last = Jamison
| first = Kay
| title = Brain Damage in Depression and Bipolar Disorder
| work = McMan's Depression and Bipolar Web
| date = Updated Jan 21, 2004
| url = http://www.mcmanweb.com/article-161.htm}}</ref> There is concern that antidepressants in general can induce [[hypomania]], mania, or both.<ref name="controversies">{{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}}
</ref>
== References==
{{Reflist|2}}
== See also ==
* [[DNA methyltransferase]]
== External links ==
* {{EINECSLink|249-946-8}}
* [http://www.stoneclinic.com/sam_e.htm S-Adenosyl Methionine as a food supplement: Pros and Cons] at stoneclinic.com
* [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://www.nutraseal.com/index.asp?PageAction=Custom&ID=56#science In 2002 a study done by The United States department of health and human services, entitled “S-Adenosyl-Methionine for treatment of depression, osteoarthritis, and liver disease” concluded...] at [http://www.nutraseal.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, Baltimore|University of Maryland]] Medical Centers
{{Enzyme cofactors}}
{{Amino acid metabolism intermediates}}
[[Category:Coenzymes]]
[[Category:Dietary supplements]]
[[de:S-Adenosylmethionin]]
[[fr:S-adénosyl méthionine]]
[[ja:S-アデノシルメチオニン]]
[[pt:S-Adenosilmetionina]]
[[zh:S-腺苷基蛋氨酸]]