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Undid revision 769535276 by Okjamil (talk) review from 1990 - 27 years ago, is not useful for supporting content about what has happened "thus far". other refs are primary
Okjamil (talk | contribs)
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Added a variety of details including a section on the role SAM-e plays in epigenetics and how that has been used to show positive and adverse effects on human health. Added info regarding eukaryotic and plant functions of SAM-e. +Some other minor edits.
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'''''S''-Adenosyl methionine'''<ref group="alternative names">'''SAM-e''', '''SAMe''', '''SAM''', '''S-Adenosyl-L-methionine''', '''AdoMet''', '''ademetionine'''</ref> 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.<ref name=cantoni1952/> More than 40 methyl transfers from SAM-e are known, to various substrates such as [[nucleic acid]]s, [[protein]]s, [[lipid]]s and [[secondary metabolite]]s. 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]). SAM was first discovered by [[Giulio 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=2942–3 | year=1952 | doi=10.1021/ja01131a519 }}</ref>
'''''S''-Adenosyl methionine'''<ref group="alternative names">'''SAM-e''', '''SAMe''', '''SAM''', '''S-Adenosyl-L-methionine''', '''AdoMet''', '''ademetionine'''</ref> 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.<ref name=cantoni1952/> More than 40 methyl transfers from SAM-e are known, to various substrates such as [[nucleic acid]]s, [[protein]]s, [[lipid]]s and [[secondary metabolite]]s. 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]). SAM was first discovered by [[Giulio 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=2942–3 | year=1952 | doi=10.1021/ja01131a519 }}</ref>


In bacteria, SAM-e is bound by the [[SAM riboswitch (S box leader)|SAM riboswitch]], which regulates genes involved in [[methionine]] or [[cysteine]] biosynthesis. In eukaryotic cells, SAM-e serves as a regulator of a variety of processes including DNA, tRNA, and rRNA methylation; immune response<sup><ref>{{Cite journal|last=Ding|first=Wei|last2=Smulan|first2=Lorissa J.|last3=Hou|first3=Nicole S.|last4=Taubert|first4=Stefan|last5=Watts|first5=Jennifer L.|last6=Walker|first6=Amy K.|date=2015-10-06|title=s-Adenosylmethionine Levels Govern Innate Immunity through Distinct Methylation-Dependent Pathways|url=http://www.sciencedirect.com/science/article/pii/S1550413115003423|journal=Cell Metabolism|volume=22|issue=4|pages=633–645|doi=10.1016/j.cmet.2015.07.013|pmc=PMC4598287|pmid=26321661}}</ref></sup>; amino acid metabolism; transsulfuration; and more. In plants, SAM-e is crucial to the biosynthesis of ethylene, an important plant hormone and signaling molecule.<ref>{{Cite journal|last=Wang|first=X.|last2=Oh|first2=M. W.|last3=Komatsu|first3=S.|date=2016-06-01|title=Characterization of S-adenosylmethionine synthetases in soybean under flooding and drought stresses|url=https://link.springer.com/article/10.1007/s10535-016-0586-6|journal=Biologia Plantarum|language=en|volume=60|issue=2|pages=269–278|doi=10.1007/s10535-016-0586-6|issn=0006-3134}}</ref>
In bacteria, SAM-e is bound by the [[SAM riboswitch (S box leader)|SAM riboswitch]], which regulates genes involved in [[methionine]] or [[cysteine]] biosynthesis.


== Biochemistry ==
== Biochemistry ==
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=== SAM-e cycle ===
=== 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 [[methylase]]s (EC 2.1.1) that use SAM-e as a substrate produce [[S-adenosyl homocysteine]] as a product.<ref>{{cite journal |vauthors=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 [[Adenosylhomocysteinase|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 (i.e. [[cobalamin]]-dependent ([http://www.expasy.org/enzyme/2.1.1.13 EC 2.1.1.13]) or cobalamin-independent ([http://www.expasy.org/enzyme/2.1.1.14 EC 2.1.1.14])). This methionine can then be converted back to SAM-e, completing the cycle.<ref>{{cite journal |vauthors=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 |date=Jan{{ndash}}Feb 2000 |pmid=10720211}}</ref> In the rate-limiting step of the SAM cycle, MTHFR (methylenetetrahydrofolate reductase) irreversibly reduces 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate.<ref>{{Cite journal|last=Goyette|first=P.|last2=Sumner|first2=J. S.|last3=Milos|first3=R.|last4=Duncan|first4=A. M.|last5=Rosenblatt|first5=D. S.|last6=Matthews|first6=R. G.|last7=Rozen|first7=R.|date=1994-06-01|title=Human methylenetetrahydrofolate reductase: isolation of cDNA, mapping and mutation identification|url=https://www.ncbi.nlm.nih.gov/pubmed/7920641|journal=Nature Genetics|volume=7|issue=2|pages=195–200|doi=10.1038/ng0694-195|issn=1061-4036|pmid=7920641}}</ref>
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 [[methylase]]s (EC 2.1.1) that use SAM-e as a substrate produce [[S-adenosyl homocysteine]] as a product.<ref>{{cite journal |vauthors=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> S-adenosyl homocysteine is a strong negative regulator of nearly all SAM-dependent methylases despite their biological diversity. This is hydrolysed to [[homocysteine]] and [[adenosine]] by [[Adenosylhomocysteinase|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 (i.e. [[cobalamin]]-dependent ([http://www.expasy.org/enzyme/2.1.1.13 EC 2.1.1.13]) or cobalamin-independent ([http://www.expasy.org/enzyme/2.1.1.14 EC 2.1.1.14])). This methionine can then be converted back to SAM-e, completing the cycle.<ref>{{cite journal |vauthors=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 |date=Jan{{ndash}}Feb 2000 |pmid=10720211}}</ref> In the rate-limiting step of the SAM cycle, MTHFR (methylenetetrahydrofolate reductase) irreversibly reduces 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate.<ref>{{Cite journal|last=Goyette|first=P.|last2=Sumner|first2=J. S.|last3=Milos|first3=R.|last4=Duncan|first4=A. M.|last5=Rosenblatt|first5=D. S.|last6=Matthews|first6=R. G.|last7=Rozen|first7=R.|date=1994-06-01|title=Human methylenetetrahydrofolate reductase: isolation of cDNA, mapping and mutation identification|url=https://www.ncbi.nlm.nih.gov/pubmed/7920641|journal=Nature Genetics|volume=7|issue=2|pages=195–200|doi=10.1038/ng0694-195|issn=1061-4036|pmid=7920641}}</ref>


[[File:Summary of S-Adenosyl Methionine Regeneration Cycle.png|alt=SAM-e Cycle|thumb|center|1000x1000px|Summary of the S-Adenosyl Methionine cycle with donated methyl group highlighted in red throughout.]]
[[File:Summary of S-Adenosyl Methionine Regeneration Cycle.png|alt=SAM-e Cycle|thumb|center|1000x1000px|Summary of the S-Adenosyl Methionine cycle with donated methyl group highlighted in red throughout.]]
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=== Radical SAM-e enzymes ===
=== 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.<ref>{{Cite journal | pmid = 21152342 | year = 2010 | last1 = Booker | first1 = SJ | last2 = Grove | first2 = TL | title = Mechanistic and functional versatility of radical SAM enzymes | volume = 2 | page = 52 | doi = 10.3410/B2-52 | pmc = 2996862 | journal = F1000 biology reports}}</ref> 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.
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.<ref>{{Cite journal | pmid = 21152342 | year = 2010 | last1 = Booker | first1 = SJ | last2 = Grove | first2 = TL | title = Mechanistic and functional versatility of radical SAM enzymes | volume = 2 | page = 52 | doi = 10.3410/B2-52 | pmc = 2996862 | journal = F1000 biology reports}}</ref> 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. They can be found in all domains of life and are largely unexplored. A recent bioinformatics study concluded that this family of enzymes includes at least 114,000 sequences including 65 unique reactions.<ref name=":0">{{Cite web|url=http://www.annualreviews.org/doi/10.1146/annurev-biochem-060713-035504|title=Radical S-Adenosylmethionine Enzymes in Human Health and Disease|last=Landgraf|first=Bradley J.|last2=McCarthy|first2=Erin L.|date=2016-06-13|website=http://dx.doi.org/10.1146/annurev-biochem-060713-035504|language=en|doi=10.1146/annurev-biochem-060713-035504|access-date=2017-03-10|last3=Booker|first3=Squire J.}}</ref>


=== Polyamine biosynthesis ===
=== Polyamine biosynthesis ===
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Some research, including multiple clinical trials, has indicated taking SAM on a regular basis may help fight [[Clinical depression|depression]],<ref name=Papakostas>{{cite journal|last=Papakostas|first=GI|title=Role of S-adenosyl-L-methionine in the treatment of depression: a review of the evidence|journal=Am J Clin Nutr.|date=Nov 2002|volume=76(5)|pages=1158S-61S|pmid=19909689|doi=10.4088/JCP.8157su1c.04}}</ref><ref name=Bressa>{{cite journal|last=Bressa|first=GM|title=S-adenosyl-l-methionine (SAMe) as antidepressant: meta-analysis of clinical studies|journal=Acta Neurol Scand Suppl.|year=1994|volume=154|pages=7–14|pmid=7941964}}</ref> [[liver disease]],<ref>{{cite journal|last1=Anstee|first1=Quentin M.|last2=Day|first2=Christopher P.|title=S-adenosylmethionine (SAMe) therapy in liver disease: A review of current evidence and clinical utility|journal=Journal of hepatology|date=2012|volume=57|issue=5|pages=1097–1109|doi=10.1016/j.jhep.2012.04.041|url=http://emergency.doctorsonly.co.il/wp-content/uploads/2011/03/SAMe-therapy-in-liver-disease-J-HEP-11.12.pdf|accessdate=18 June 2014}}</ref><ref>{{cite journal|last1=Mato|first1=José M.|title=Role of S‐adenosyl‐L‐methionine in liver health and injury|journal=Hepatology|date=2007|volume=45|issue=5|pages=1306–1312|doi=10.1002/hep.21650}}</ref> and the pain of [[arthritis|osteoarthritis]].<ref>{{Cite report |author=Mary Hardy |author2=Ian Coulter |author3=Sally C Morton |author4=Joya Favreau |author5=Swamy Venuturupalli |author6=Francesco Chiappelli |author7=Frederico Rossi |author8=Greg Orshansky |author9=Lara K Jungvig |author10=Elizabeth A Roth |author11=Marika J Suttorp |author12=Paul Shekelle |date=October 2002 |title=S-Adenosyl-L-Methionine for Treatment of Depression, Osteoarthritis, and Liver Disease |url=https://www.ncbi.nlm.nih.gov/books/NBK36942/ |publisher=Agency for Healthcare Research and Quality|accessdate=2012-08-31}}</ref> All other indications are not yet well-evidenced.
Some research, including multiple clinical trials, has indicated taking SAM on a regular basis may help fight [[Clinical depression|depression]],<ref name=Papakostas>{{cite journal|last=Papakostas|first=GI|title=Role of S-adenosyl-L-methionine in the treatment of depression: a review of the evidence|journal=Am J Clin Nutr.|date=Nov 2002|volume=76(5)|pages=1158S-61S|pmid=19909689|doi=10.4088/JCP.8157su1c.04}}</ref><ref name=Bressa>{{cite journal|last=Bressa|first=GM|title=S-adenosyl-l-methionine (SAMe) as antidepressant: meta-analysis of clinical studies|journal=Acta Neurol Scand Suppl.|year=1994|volume=154|pages=7–14|pmid=7941964}}</ref> [[liver disease]],<ref>{{cite journal|last1=Anstee|first1=Quentin M.|last2=Day|first2=Christopher P.|title=S-adenosylmethionine (SAMe) therapy in liver disease: A review of current evidence and clinical utility|journal=Journal of hepatology|date=2012|volume=57|issue=5|pages=1097–1109|doi=10.1016/j.jhep.2012.04.041|url=http://emergency.doctorsonly.co.il/wp-content/uploads/2011/03/SAMe-therapy-in-liver-disease-J-HEP-11.12.pdf|accessdate=18 June 2014}}</ref><ref>{{cite journal|last1=Mato|first1=José M.|title=Role of S‐adenosyl‐L‐methionine in liver health and injury|journal=Hepatology|date=2007|volume=45|issue=5|pages=1306–1312|doi=10.1002/hep.21650}}</ref> and the pain of [[arthritis|osteoarthritis]].<ref>{{Cite report |author=Mary Hardy |author2=Ian Coulter |author3=Sally C Morton |author4=Joya Favreau |author5=Swamy Venuturupalli |author6=Francesco Chiappelli |author7=Frederico Rossi |author8=Greg Orshansky |author9=Lara K Jungvig |author10=Elizabeth A Roth |author11=Marika J Suttorp |author12=Paul Shekelle |date=October 2002 |title=S-Adenosyl-L-Methionine for Treatment of Depression, Osteoarthritis, and Liver Disease |url=https://www.ncbi.nlm.nih.gov/books/NBK36942/ |publisher=Agency for Healthcare Research and Quality|accessdate=2012-08-31}}</ref> All other indications are not yet well-evidenced.


The SAM-e cycle has been closely tied to the liver since 1947 because patients with alcoholic cirrhosis of the liver would accumulate large amounts of methionine in their blood.<ref>{{Cite journal|last=Mato|first=Jose M|year=1997|title=S-adenosylmethionine synthesis: Molecular mechanisms and clinical implications|url=http://www.sciencedirect.com/science/article/pii/S0163725896001970|journal=Pharmacology & Therapeutics|volume=73|pages=265-280|via=}}</ref> Further experiments showing that cirrhotic liver is associated with lower urinary sulfate levels implied that liver damage inhibits the ability of the body to break down methionine.<ref>{{Cite journal|last=Chawla|first=Rajender|year=1984|title=Plasma cysteine, cystine, and glutathione in cirrhosis|url=http://www.gastrojournal.org/article/0016-5085(84)90069-6/abstract|journal=Gastroenterology|volume=87|pages=770-776|via=}}</ref> Administration of SAM-e with ethanol substantially reduced the effects of cirrhotic damage to the liver due to alcohol. Both baboon and rat models showed that many of the key pathologies of cirrhosis and the rate of alcohol metabolism are significantly improved in subjects with regular SAM-e intake.<ref>{{Cite book|url=https://link.springer.com/chapter/10.1007/978-3-642-69132-4_34|title=Disease, Metabolism and Reproduction in the Toxic Response to Drugs and Other Chemicals|last=Padova|first=C. Di|last2=Tritapepe|first2=R.|last3=Rovagnati|first3=P.|last4=Pozzoli|first4=M.|last5=Stramentinoli|first5=G.|date=1984-01-01|publisher=Springer, Berlin, Heidelberg|pages=240–242|language=en|doi=10.1007/978-3-642-69132-4_34}}</ref><ref>{{Cite journal|last=Lieber|first=C. S.|last2=Casini|first2=A.|last3=DeCarli|first3=L. M.|last4=Kim|first4=C. I.|last5=Lowe|first5=N.|last6=Sasaki|first6=R.|last7=Leo|first7=M. A.|date=1990-02-01|title=S-adenosyl-L-methionine attenuates alcohol-induced liver injury in the baboon|url=https://www.ncbi.nlm.nih.gov/pubmed/2307395|journal=Hepatology (Baltimore, Md.)|volume=11|issue=2|pages=165–172|issn=0270-9139|pmid=2307395}}</ref>
The SAM-e cycle has been closely tied to the liver since 1947 because patients with alcoholic cirrhosis of the liver would accumulate large amounts of methionine in their blood.<ref>{{Cite journal|last=Mato|first=Jose M|year=1997|title=S-adenosylmethionine synthesis: Molecular mechanisms and clinical implications|url=http://www.sciencedirect.com/science/article/pii/S0163725896001970|journal=Pharmacology & Therapeutics|volume=73|pages=265-280|via=}}</ref> Further experiments showing that cirrhotic liver is associated with lower urinary sulfate levels implied that liver damage inhibits the ability of the body to break down methionine.<ref>{{Cite journal|last=Chawla|first=Rajender|year=1984|title=Plasma cysteine, cystine, and glutathione in cirrhosis|url=http://www.gastrojournal.org/article/0016-5085(84)90069-6/abstract|journal=Gastroenterology|volume=87|pages=770-776|via=}}</ref> Administration of SAM-e with ethanol substantially reduced the effects of cirrhotic damage to the liver due to alcohol. Both baboon and rat models showed that many of the key pathologies of cirrhosis and the rate of alcohol metabolism are significantly improved in subjects with regular SAM-e intake.<ref>{{Cite book|url=https://link.springer.com/chapter/10.1007/978-3-642-69132-4_34|title=Disease, Metabolism and Reproduction in the Toxic Response to Drugs and Other Chemicals|last=Padova|first=C. Di|last2=Tritapepe|first2=R.|last3=Rovagnati|first3=P.|last4=Pozzoli|first4=M.|last5=Stramentinoli|first5=G.|date=1984-01-01|publisher=Springer, Berlin, Heidelberg|pages=240–242|language=en|doi=10.1007/978-3-642-69132-4_34}}</ref><ref>{{Cite journal|last=Lieber|first=C. S.|last2=Casini|first2=A.|last3=DeCarli|first3=L. M.|last4=Kim|first4=C. I.|last5=Lowe|first5=N.|last6=Sasaki|first6=R.|last7=Leo|first7=M. A.|date=1990-02-01|title=S-adenosyl-L-methionine attenuates alcohol-induced liver injury in the baboon|url=https://www.ncbi.nlm.nih.gov/pubmed/2307395|journal=Hepatology (Baltimore, Md.)|volume=11|issue=2|pages=165–172|issn=0270-9139|pmid=2307395}}</ref> SAM-e has also been showed to benefit pregnant women and other patients with cholestasis. Cholestasis is a condition in which bile flow from the liver slows or stops completely, often as a result of hormone imbalances during pregnancy. This tends not to have a significant impact on a pregnant mother's health, but it may have devastating effects on fetal health. Bile flow impairment was prevented by the administration of SAM-e in pregnant mothers. It has also been shown to prevent drug-induced cholestasis.<ref>{{Cite journal|last=Zhang|first=Yang|last2=Lu|first2=Linlin|last3=Victor|first3=David W|last4=Xin|first4=Yongning|last5=Xuan|first5=Shiying|date=2016-07-01|title=Ursodeoxycholic Acid and S-adenosylmethionine for the Treatment of Intrahepatic Cholestasis of Pregnancy: A Meta-analysis|url=http://www.hepatmon.com/?page=article&article_id=38558|journal=Hepatitis Monthly|language=En|volume=16|issue=8|doi=10.5812/hepatmon.38558|issn=1735-3408|pmc=PMC5075145|pmid=27799965}}</ref>


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|vitamin B<sub>12</sub>]] deficiencies, which result in neurologic defects due to the inability to conduct one carbon transfers (with [[folate]]) in the absence of B<sub>12</sub>. {{mcn|date=December 2016}}
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|vitamin B<sub>12</sub>]] deficiencies, which result in neurologic defects due to the inability to conduct one carbon transfers (with [[folate]]) in the absence of B<sub>12</sub>. {{mcn|date=December 2016}}
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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.{{medcn|date=November 2016}}
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.{{medcn|date=November 2016}}

SAM-e has recently been shown to play a role in epigenetic regulation. DNA methylation is a key regulator in epigenetic modification during mammalian cell development and differentiation. In mouse models, excess levels of SAM-e has been implicated in erroneous methylation patterns associated with diabetic neuropathy. SAM-e serves as the methyl donor in cytosine methylation, which is a key epigenetic regulatory process.<ref>{{Cite journal|last=Varela-Rey|first=Marta|year=2014|title=S-adenosylmethionine Levels Regulate the Schwann Cell DNA Methylome|url=http://www.sciencedirect.com/science/article/pii/S0896627314000683|journal=Neuron|volume=81|pages=1024-1039|via=}}</ref> Because of this impact on epigenetic regulation, SAM-e has been tested as an anti-cancer treatment. Cancer cell proliferation is dependent on having low levels of DNA methylation. ''In Vitro'' addition of has been shown to remethylate promoter sequences and decrease the production of proto-oncogenes.<ref>{{Cite journal|last=Schmidt|first=Thomas|last2=Leha|first2=Andreas|last3=Salinas-Riester|first3=Gabriela|date=2016-12-31|title=Treatment of prostate cancer cells with S-adenosylmethionine leads to genome-wide alterations in transcription profiles|url=http://www.sciencedirect.com/science/article/pii/S0378111916307703|journal=Gene|volume=595|issue=2|pages=161–167|doi=10.1016/j.gene.2016.09.032}}</ref>

Deficiencies in radical SAM-e enzymes have been associated with a variety of diseases including congenital heart disease, amyotrophic lateral sclerosis, and increased viral susceptibility.<ref name=":0" />


===Interactions and contraindications===
===Interactions and contraindications===

Revision as of 06:17, 10 March 2017

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
3D model (JSmol)
ChEMBL
ChemSpider
ECHA InfoCard 100.045.391 Edit this at Wikidata
KEGG
MeSH S-Adenosylmethionine
  • InChI=1S/C15H22N6O5S/c1-27(3-2-7(16)15(24)25)4-8-10(22)11(23)14(26-8)21-6-20-9-12(17)18-5-19-13(9)21/h5-8,10-11,14,22-23H,2-4,16H2,1H3,(H2-,17,18,19,24,25)/p+1/t7?,8-,10-,11-,14-,27?/m1/s1 checkY
    Key: MEFKEPWMEQBLKI-YDBXVIPQSA-O checkY
  • InChI=1/C15H22N6O5S/c1-27(3-2-7(16)15(24)25)4-8-10(22)11(23)14(26-8)21-6-20-9-12(17)18-5-19-13(9)21/h5-8,10-11,14,22-23H,2-4,16H2,1H3,(H2-,17,18,19,24,25)/p+1/t7?,8-,10-,11-,14-,27?/m1/s1
    Key: MEFKEPWMEQBLKI-NNGIMXIKBF
  • O=C(O)C(N)CC[S+](C)C[C@H]3O[C@@H](n2cnc1c(ncnc12)N)[C@H](O)[C@@H]3O
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).
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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. In eukaryotic cells, SAM-e serves as a regulator of a variety of processes including DNA, tRNA, and rRNA methylation; immune response[2]; amino acid metabolism; transsulfuration; and more. In plants, SAM-e is crucial to the biosynthesis of ethylene, an important plant hormone and signaling molecule.[3]

Biochemistry

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.[4] S-adenosyl homocysteine is a strong negative regulator of nearly all SAM-dependent methylases despite their biological diversity. 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.[5] In the rate-limiting step of the SAM cycle, MTHFR (methylenetetrahydrofolate reductase) irreversibly reduces 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate.[6]

SAM-e Cycle
Summary of the S-Adenosyl Methionine cycle with donated methyl group highlighted in red throughout.

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.[7] 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. They can be found in all domains of life and are largely unexplored. A recent bioinformatics study concluded that this family of enzymes includes at least 114,000 sequences including 65 unique reactions.[8]

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.[9]

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.[10][11]

Therapeutic uses

Some research, including multiple clinical trials, has indicated taking SAM on a regular basis may help fight depression,[12][13] liver disease,[14][15] and the pain of osteoarthritis.[16] All other indications are not yet well-evidenced.

The SAM-e cycle has been closely tied to the liver since 1947 because patients with alcoholic cirrhosis of the liver would accumulate large amounts of methionine in their blood.[17] Further experiments showing that cirrhotic liver is associated with lower urinary sulfate levels implied that liver damage inhibits the ability of the body to break down methionine.[18] Administration of SAM-e with ethanol substantially reduced the effects of cirrhotic damage to the liver due to alcohol. Both baboon and rat models showed that many of the key pathologies of cirrhosis and the rate of alcohol metabolism are significantly improved in subjects with regular SAM-e intake.[19][20] SAM-e has also been showed to benefit pregnant women and other patients with cholestasis. Cholestasis is a condition in which bile flow from the liver slows or stops completely, often as a result of hormone imbalances during pregnancy. This tends not to have a significant impact on a pregnant mother's health, but it may have devastating effects on fetal health. Bile flow impairment was prevented by the administration of SAM-e in pregnant mothers. It has also been shown to prevent drug-induced cholestasis.[21]

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.

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".[22] 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

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.[23]

Adverse effects

Gastrointestinal disorder, dyspepsia and anxiety can occur with SAM consumption.[23] Long-term effects are unknown. SAM is a weak DNA-alkylating agent.[24]

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]

SAM-e has recently been shown to play a role in epigenetic regulation. DNA methylation is a key regulator in epigenetic modification during mammalian cell development and differentiation. In mouse models, excess levels of SAM-e has been implicated in erroneous methylation patterns associated with diabetic neuropathy. SAM-e serves as the methyl donor in cytosine methylation, which is a key epigenetic regulatory process.[25] Because of this impact on epigenetic regulation, SAM-e has been tested as an anti-cancer treatment. Cancer cell proliferation is dependent on having low levels of DNA methylation. In Vitro addition of has been shown to remethylate promoter sequences and decrease the production of proto-oncogenes.[26]

Deficiencies in radical SAM-e enzymes have been associated with a variety of diseases including congenital heart disease, amyotrophic lateral sclerosis, and increased viral susceptibility.[8]

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. 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.

See also

Alternative names

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

References

  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. ^ Ding, Wei; Smulan, Lorissa J.; Hou, Nicole S.; Taubert, Stefan; Watts, Jennifer L.; Walker, Amy K. (2015-10-06). "s-Adenosylmethionine Levels Govern Innate Immunity through Distinct Methylation-Dependent Pathways". Cell Metabolism. 22 (4): 633–645. doi:10.1016/j.cmet.2015.07.013. PMC 4598287. PMID 26321661. {{cite journal}}: no-break space character in |first2= at position 8 (help); no-break space character in |first3= at position 7 (help); no-break space character in |first5= at position 9 (help); no-break space character in |first6= at position 4 (help)CS1 maint: PMC format (link)
  3. ^ Wang, X.; Oh, M. W.; Komatsu, S. (2016-06-01). "Characterization of S-adenosylmethionine synthetases in soybean under flooding and drought stresses". Biologia Plantarum. 60 (2): 269–278. doi:10.1007/s10535-016-0586-6. ISSN 0006-3134.
  4. ^ 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.
  5. ^ 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.
  6. ^ Goyette, P.; Sumner, J. S.; Milos, R.; Duncan, A. M.; Rosenblatt, D. S.; Matthews, R. G.; Rozen, R. (1994-06-01). "Human methylenetetrahydrofolate reductase: isolation of cDNA, mapping and mutation identification". Nature Genetics. 7 (2): 195–200. doi:10.1038/ng0694-195. ISSN 1061-4036. PMID 7920641.
  7. ^ Booker, SJ; Grove, TL (2010). "Mechanistic and functional versatility of radical SAM enzymes". F1000 biology reports. 2: 52. doi:10.3410/B2-52. PMC 2996862. PMID 21152342.
  8. ^ a b Landgraf, Bradley J.; McCarthy, Erin L.; Booker, Squire J. (2016-06-13). "Radical S-Adenosylmethionine Enzymes in Human Health and Disease". http://dx.doi.org/10.1146/annurev-biochem-060713-035504. doi:10.1146/annurev-biochem-060713-035504. Retrieved 2017-03-10. {{cite web}}: External link in |website= (help)
  9. ^ 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.
  10. ^ 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.
  11. ^ 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.
  12. ^ 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.
  13. ^ Bressa, GM (1994). "S-adenosyl-l-methionine (SAMe) as antidepressant: meta-analysis of clinical studies". Acta Neurol Scand Suppl. 154: 7–14. PMID 7941964.
  14. ^ 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.
  15. ^ 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.
  16. ^ 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.
  17. ^ Mato, Jose M (1997). "S-adenosylmethionine synthesis: Molecular mechanisms and clinical implications". Pharmacology & Therapeutics. 73: 265–280.
  18. ^ Chawla, Rajender (1984). "Plasma cysteine, cystine, and glutathione in cirrhosis". Gastroenterology. 87: 770–776.
  19. ^ Padova, C. Di; Tritapepe, R.; Rovagnati, P.; Pozzoli, M.; Stramentinoli, G. (1984-01-01). Disease, Metabolism and Reproduction in the Toxic Response to Drugs and Other Chemicals. Springer, Berlin, Heidelberg. pp. 240–242. doi:10.1007/978-3-642-69132-4_34.
  20. ^ Lieber, C. S.; Casini, A.; DeCarli, L. M.; Kim, C. I.; Lowe, N.; Sasaki, R.; Leo, M. A. (1990-02-01). "S-adenosyl-L-methionine attenuates alcohol-induced liver injury in the baboon". Hepatology (Baltimore, Md.). 11 (2): 165–172. ISSN 0270-9139. PMID 2307395.
  21. ^ Zhang, Yang; Lu, Linlin; Victor, David W; Xin, Yongning; Xuan, Shiying (2016-07-01). "Ursodeoxycholic Acid and S-adenosylmethionine for the Treatment of Intrahepatic Cholestasis of Pregnancy: A Meta-analysis". Hepatitis Monthly. 16 (8). doi:10.5812/hepatmon.38558. ISSN 1735-3408. PMC 5075145. PMID 27799965.{{cite journal}}: CS1 maint: PMC format (link)
  22. ^ "Šta je". Tensilen. Retrieved 2014-04-28.
  23. ^ 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 387830. PMID 15102339.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  24. ^ 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 553022. PMID 7188181.
  25. ^ Varela-Rey, Marta (2014). "S-adenosylmethionine Levels Regulate the Schwann Cell DNA Methylome". Neuron. 81: 1024–1039.
  26. ^ Schmidt, Thomas; Leha, Andreas; Salinas-Riester, Gabriela (2016-12-31). "Treatment of prostate cancer cells with S-adenosylmethionine leads to genome-wide alterations in transcription profiles". Gene. 595 (2): 161–167. doi:10.1016/j.gene.2016.09.032.

External links

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