Trimethylglycine: Difference between revisions
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| IUPACName=(Trimethylammonio)acetate |
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| OtherNames= {{unbulleted list|Betaine|TMG|glycine betaine|''N'',''N'',''N''-trimethylglycine|Cystadane|Amversio}} |
| OtherNames= {{unbulleted list|Betaine|TMG|glycine betaine|''N'',''N'',''N''-trimethylglycine|Cystadane|Amversio}} |
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| MeltingPt_ref = <ref>{{cite journal|last1=Acheson|first1=R. M.|last2=Bond|first2=G. J. F.|title=52. Addition reactions of heterocyclic compounds. Part II. Phenanthridine and methyl acetylenedicarboxylate in methanol|journal=J. Chem. Soc.|date=1956|volume=1956|page=246|doi=10.1039/JR9560000246}}</ref> |
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| Legal_CA_comment = <ref>{{cite web | title=Notice of Amendment: Betaine removed from the Prescription Drug List (PDL) | website=[[Health Canada]] | date=6 January 2023 | url=https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/prescription-drug-list/notices-changes/amendment-betaine-removed.html | access-date=3 January 2024}}</ref> |
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'''Trimethylglycine''' is an [[amino acid]] derivative |
'''Trimethylglycine''' is an [[amino acid]] derivative with the formula {{chem2|(CH3)3N+CH2CO2-}}. A colorless, water-soluble solid, it occurs in plants.<ref name=Ashraf>{{cite journal |doi=10.1016/j.envexpbot.2005.12.006 |title=Roles of glycine betaine and proline in improving plant abiotic stress resistance |date=2007 |last1=Ashraf |first1=M. |last2=Foolad |first2=M.R. |journal=Environmental and Experimental Botany |volume=59 |issue=2 |pages=206–216 }}</ref> Trimethylglycine is a [[zwitterion]]: the molecule contains both a [[quaternary ammonium cation|quaternary ammonium]] group and a carboxylate group. Trimethylglycine was the first [[betaine]] discovered; originally it was simply called '''betaine''' because it was discovered in [[sugar beet]]s (''Beta vulgaris'' subsp. ''vulgaris'').<ref name=Ullmann>{{Ullmann|first1=Hubert|last1=Schiweck|first2=Margaret|last2=Clarke|first3=Günter|last3=Pollach|title=Sugar|doi=10.1002/14356007.a25_345.pub2}}</ref> Several other betaines are now known. |
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== Medical uses == |
== Medical uses == |
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Betaine, sold under the brand name '''Cystadane''' |
Betaine, sold under the brand name '''Cystadane''' is [[indicated]] for the adjunctive treatment of homocystinuria, involving deficiencies or defects in cystathionine beta-synthase (CBS), 5,10-methylene-tetrahydrofolate reductase (MTHFR), or cobalamin cofactor metabolism (cbl).<ref name="Cystadane FDA label" /><ref name="Cystadane EPAR" /><ref name="Amversio EPAR" /><ref>{{Cite journal |last1=Arumugam |first1=Madan Kumar |last2=Paal |first2=Matthew C. |last3=Donohue |first3=Terrence M. |last4=Ganesan |first4=Murali |last5=Osna |first5=Natalia A. |last6=Kharbanda |first6=Kusum K. |date=2021-05-22 |title=Beneficial Effects of Betaine: A Comprehensive Review |journal=Biology |language=en |volume=10 |issue=6 |pages=456 |doi=10.3390/biology10060456 |doi-access=free |pmid=34067313 |pmc=8224793 |issn=2079-7737 }}</ref> |
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The most common side effect is elevated levels of methionine in the blood.<ref name="Cystadane EPAR" /> |
The most common side effect is elevated levels of [[methionine]] in the blood.<ref name="Cystadane EPAR" /> |
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The EU has authorized the health claim that betaine "contributes to normal [[homocysteine]] metabolism.".<ref name="efsa2014">{{cite book |author1=K.K. Tiihonen |author2=K. Riihinen |author3=M. Lyyra |author4=E. Sarkkinen |author5=S.A.S. Craig |author6=P. Tenning |editor1-last=Sadler |editor1-first=M.J. |title=Foods, Nutrients and Food Ingredients with Authorised EU Health Claims |date=2014 |publisher=Woodhead Publishing |isbn=978-0-85709-842-9 |pages=251–273 |url=https://www.sciencedirect.com/book/9780857098429/foods-nutrients-and-food-ingredients-with-authorised-eu-health-claims |access-date=19 February 2024 |chapter=12 - Authorised EU health claims for betaine |quote=The European Food Safety Authority (EFSA) agreed that there is sufficient substantiation of the health claim for betaine concerning its contribution to normal homocysteine metabolism (EFSA, 2011a).}}</ref> |
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== Structure and reactions == |
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{{unreferenced section|date=July 2022}} |
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Trimethylglycine is an ''N''-methylated amino acid. It is a [[zwitterion]] as the molecule contains both a [[quaternary ammonium cation|quaternary ammonium]] group and a carboxyl group. The carboxyl group will be partially protonated in aqueous solution below pH 4, that is, approximately below pH equal to (p''K''<sub>a</sub> + 2). |
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:{{chem2|(CH3)3N+CH2CO2-}} (aq) + {{chem2|H+}} {{eqm}} {{chem2|(CH3)3N+CH2CO2H}} (aq) |
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[[Demethylation]] of trimethylglycine gives [[dimethylglycine]]. |
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==Production and biochemical processes== |
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=== Biosynthesis === |
=== Biosynthesis === |
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In most organisms, glycine betaine is biosynthesized by oxidation of [[choline]] |
In most organisms, glycine betaine is biosynthesized by oxidation of [[choline]]. The intermediate, [[betaine aldehyde]], is generated by the action of the enzyme mitochondrial choline oxidase ([[choline dehydrogenase]], EC 1.1.99.1). In mice, betaine aldehyde is further oxidised in the [[mitochondria]] by the enzyme [[betaine-aldehyde dehydrogenase]] (EC 1.2.1.8).<ref name=Kempf>{{cite journal | last1 = Kempf | first1 = B. | last2 = Bremer | first2 = E. | s2cid = 8045279 | year = 1998 | title = Uptake and synthesis of compatible solutes as microbial stress responses to high-osmolality environments | journal = Arch. Microbiol. | volume = 170 | issue = 5| pages = 319–330 | pmid = 9818351 | doi=10.1007/s002030050649| bibcode = 1998ArMic.170..319K }}</ref><ref>{{cite web |url=http://www.brenda-enzymes.org/enzyme.php?ecno=1.2.1.8 |title=BRENDA – Information on EC 1.2.1.8 – betaine-aldehyde dehydrogenase |website=Brenda-enzymes.org |access-date=7 July 2016 |archive-date=29 June 2016 |archive-url=https://web.archive.org/web/20160629164045/http://www.brenda-enzymes.org/enzyme.php?ecno=1.2.1.8 |url-status=live }}</ref> In humans betaine aldehyde activity is performed by a nonspecific [[Aldehyde dehydrogenase (NAD+)|cystosolic aldehyde dehydrogenase]] enzyme (EC 1.2.1.3) <ref>{{cite journal | last1 = Chern | first1 = M. K. | last2 = Pietruszko | first2 = R. | year = 1999 | title = Evidence for mitochondrial localization of betaine aldehyde dehydrogenase in rat liver: purification, characterization, and comparison with human cytoplasmic E3 isoenzyme | journal = Biochemistry and Cell Biology | volume = 77 | issue = 3| pages = 179–187 | pmid = 10505788 | doi=10.1139/o99-030}}</ref> |
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⚫ | Trimethylglycine is an |
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⚫ | Trimethylglycine is produced by some [[cyanobacteria]], as established by [[Carbon-13 nuclear magnetic resonance|{{sup|13}}C nuclear magnetic resonance]]. It is proposed to protect for some [[enzyme inhibition|enzymes, against inhibition]] by [[NaCl]] and [[KCl]].<ref name="Rhodes-Hanson-1993">{{cite journal | last1=Rhodes | first1=D. | last2=Hanson | first2=A. D. | title=Quaternary Ammonium and Tertiary Sulfonium Compounds in Higher Plants | journal=[[Annual Review of Plant Physiology and Plant Molecular Biology]] | publisher=[[Annual Reviews (publisher)|Annual Reviews]] | volume=44 | issue=1 | year=1993 | issn=1040-2519 | doi=10.1146/annurev.pp.44.060193.002041 | pages=357–384}}</ref> |
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Trimethylglycine is an important [[Cofactor (biochemistry)|cofactor]] in [[methylation]], a process that occurs in every mammalian cell donating [[methyl group]]s (–CH<sub>3</sub>) for other processes in the body. These processes include the synthesis of [[neurotransmitter]]s such as [[dopamine]] and [[serotonin]]. Methylation is also required for the biosynthesis of [[melatonin]] and the [[electron transport chain]] constituent [[coenzyme Q10|coenzyme Q<sub>10</sub>]], as well as the methylation of DNA for epigenetics. |
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====Osmolyte==== |
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⚫ | Trimethylglycine is an [[osmolyte]], a water-soluble salt-like substance. Sugar beet was cultivated from [[sea beet]], which requires osmolytes in order to survive the salty soils of coastal areas. Trimethylglycine also occurs in high concentrations (~10 mM) in many marine invertebrates, such as [[crustacean]]s and [[mollusc]]s. It serves as a appetitive attractant to generalist carnivores such as the predatory [[sea slug]] ''[[Pleurobranchaea californica]]''.<ref>{{cite journal | pmid = 10737805 | volume=97 | issue=7 | title=Cost-benefit analysis potential in feeding behavior of a predatory snail by integration of hunger, taste, and pain | pmc=16283 |date=March 2000 | journal=Proc. Natl. Acad. Sci. USA | pages=3585–3590 |last1=Gillette |first1=R. |last2=Huang |first2=R. C. |last3=Hatcher |first3=N. |last4=Moroz |first4=L. L. | doi=10.1073/pnas.97.7.3585| bibcode=2000PNAS...97.3585G | doi-access=free | title-link=doi }}</ref> |
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====Methyl donor==== |
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⚫ | Trimethylglycine is produced by some [[cyanobacteria]] |
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⚫ | Trimethylglycine is a [[Cofactor (biochemistry)|cofactor]] in [[methylation]], a process that occurs in all mammals. These processes include the synthesis of [[neurotransmitter]]s such as [[dopamine]] and [[serotonin]]. Methylation is also required for the biosynthesis of [[melatonin]] and the [[electron transport chain]] constituent [[coenzyme Q10|coenzyme Q<sub>10</sub>]], as well as the methylation of DNA for epigenetics. One step in the methylation cycle is the [[remethylation]] of [[homocysteine]], a compound which is naturally generated during demethylation of the essential amino acid [[methionine]]. Despite its natural formation, homocysteine has been linked to inflammation, depression, specific forms of dementia, and various types of vascular disease. The remethylation process that detoxifies homocysteine and converts it back to methionine can occur via either of two pathways. The pathway present in virtually all cells involves the enzyme [[methionine synthase]] (MS), which requires [[Vitamin B12|vitamin B<sub>12</sub>]] as a cofactor, and also depends indirectly on [[folate]] and other [[B vitamins]]. The second pathway (restricted to liver and kidney in most mammals) involves [[betaine-homocysteine methyltransferase|betaine-homocysteine methyltransferase (BHMT)]] and requires trimethylglycine as a cofactor. During normal physiological conditions, the two pathways contribute equally to removal of homocysteine in the body.<ref>{{Cite journal|last=Finkelstein|first=J. D.|date=24 March 1998|title=The metabolism of homocysteine: pathways and regulation|journal=European Journal of Pediatrics|language=en|volume=157|issue=S2|pages=S40–S44|doi=10.1007/pl00014300|pmid=9587024|s2cid=38134977|issn=0340-6199}}</ref> Further degradation of betaine, via the enzyme [[dimethylglycine dehydrogenase]] produces folate, thus contributing back to methionine synthase. Betaine is thus involved in the synthesis of many biologically important molecules, and may be even more important in situations where the major pathway for the regeneration of methionine from homocysteine has been compromised by genetic polymorphisms such as mutations in the MS gene. |
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==Agriculture and aquaculture== |
==Agriculture and aquaculture== |
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⚫ | Trimethylglycine is used as a supplement for both animals and plants.<ref name=Ashraf/> [[Food processing|Processing]] [[sucrose]] from sugar beets yields glycine betaine as a [[byproduct]]. The economic significance of trimethylglycine is comparable to that of sugar in sugar beets.<ref name=Makela/> |
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[[Factory farming|Factory farms]] supplement [[fodder]] with trimethylglycine and [[lysine]] to increase livestock's [[muscle mass]] (and, therefore, "carcass yield", the amount of usable meat). |
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[[Salmon farm]]s apply trimethylglycine to relieve the osmotic pressure on the fishes' cells when workers transfer the fish from freshwater to saltwater.<ref name="Makela">{{cite journal|first=P.|last=Mäkelä|s2cid=25219649|title=Agro-industrial uses of glycinebetaine|journal=Sugar Tech.|date=2004|volume=6|issue=4|pages=207–212|doi=10.1007/BF02942500|hdl=10138/312331|hdl-access=free | title-link=doi }}</ref><ref name="Xue">{{cite journal|last1=Xue|first1=M.|last2=Xie|first2=S.|last3=Cui|first3=Y.|date=2004|title=Effect of a feeding stimulant on feeding adaptation of gibel carp ''Carassius auratus gibelio'' (Bloch), fed diets with replacement of fish meal by meat and bone meal|journal=Aquaculture Research|volume=35|issue=5|pages=473–482|doi=10.1111/j.1365-2109.2004.01041.x|s2cid=84304519 |doi-access=free}}</ref> |
[[Salmon farm]]s apply trimethylglycine to relieve the osmotic pressure on the fishes' cells when workers transfer the fish from freshwater to saltwater.<ref name="Makela">{{cite journal|first=P.|last=Mäkelä|s2cid=25219649|title=Agro-industrial uses of glycinebetaine|journal=Sugar Tech.|date=2004|volume=6|issue=4|pages=207–212|doi=10.1007/BF02942500|hdl=10138/312331|hdl-access=free | title-link=doi }}</ref><ref name="Xue">{{cite journal|last1=Xue|first1=M.|last2=Xie|first2=S.|last3=Cui|first3=Y.|date=2004|title=Effect of a feeding stimulant on feeding adaptation of gibel carp ''Carassius auratus gibelio'' (Bloch), fed diets with replacement of fish meal by meat and bone meal|journal=Aquaculture Research|volume=35|issue=5|pages=473–482|doi=10.1111/j.1365-2109.2004.01041.x|s2cid=84304519 |doi-access=free}}</ref> |
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== Nutrition == |
== Nutrition == |
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Nutritionally, betaine is not needed when sufficient dietary choline is present for synthesis |
Nutritionally, betaine is not needed when sufficient dietary choline is present for synthesis.<ref name=ze>{{Cite book|title=Handbook of vitamins |url=https://archive.org/details/handbookvitamins00jzem |url-access=limited |vauthors= Rucker RB, Zempleni J, Suttie JW, McCormick DB |publisher=Taylor & Francis |year=2007 |isbn=978-0-8493-4022-2 |edition=4th |pages=[https://archive.org/details/handbookvitamins00jzem/page/n471 459]–477 }}</ref> When insufficient betaine is available, elevated homocysteine levels and decreased SAM levels in blood occur. Supplementation of betaine in this situation would resolve these blood marker issues, but not compensate for other functions of choline.<ref name=eu>{{Cite journal|date=2016|title=Dietary reference values for choline|journal=EFSA Journal|volume=14|issue=8|doi=10.2903/j.efsa.2016.4484|doi-access=free}}</ref> |
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{| class="wikitable" |
{| class="wikitable" |
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|+ Betaine in foods<ref name="usda-choline">{{Cite |
|+ Betaine in foods<ref name="usda-choline">{{Cite journal |date=1 November 2019 |title=USDA Database for the Choline Content of Common Foods, Release 2 (2008) |url=https://data.nal.usda.gov/dataset/usda-database-choline-content-common-foods-release-2-2008 |access-date=2 February 2021 |website=[[United States Department of Agriculture]] |doi=10.15482/USDA.ADC/1178141 |archive-date=30 July 2022 |archive-url=https://web.archive.org/web/20220730040040/https://data.nal.usda.gov/dataset/usda-database-choline-content-common-foods-release-2-2008 |url-status=live |last1=Patterson |first1=Kristine Y. |last2=Bhagwat |first2=Seema A. |last3=Williams |first3=Juhi R. |last4=Howe |first4=Juliette C. |last5=Holden |first5=Joanne M. |last6=Zeisel |first6=Steven H. |last7=Dacosta |first7=Kerry A. |last8=Mar |first8=Mei-Heng }}</ref> |
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! Food |
! Food |
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! Betaine (mg/100 g) |
! Betaine (mg/100 g) |
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| [[Wheat germ]], toasted<ref name="zeisel2003">{{cite journal |author1=Steven H Zeisel |author2=Mei-Heng Mar |author3=Juliette C Howe |author4=Joanne M Holden |title=Concentrations of choline-containing compounds and betaine in common foods |journal=The Journal of Nutrition |date=May 2003 |volume=133 |issue=5 |pages=1302–7 |doi=10.1093/jn/133.5.1302 |pmid=12730414 |doi-access=free }}</ref> |
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| [[Quinoa]] |
| [[Quinoa]] |
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=== Dietary supplement === |
=== Dietary supplement === |
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Although trimethylglycine supplementation decreases the amount of [[adipose tissue]] in pigs, research on human subjects has shown no effect on body weight, body composition, or resting energy expenditure when used in conjunction with a low calorie diet.<ref name="pmid12399266"/> The US [[Food and Drug Administration]] (FDA) approved betaine trimethylglycine (also known by the brand name Cystadane) for the treatment of [[homocystinuria]], a disease caused by abnormally high [[homocysteine]] levels at birth.<ref name="homocysteine">{{cite journal | pmid = 15550695 | doi=10.1161/01.ATV.0000151283.33976.e6 | volume=25 | issue=2 | title=Betaine and folate status as cooperative determinants of plasma homocysteine in humans |date=February 2005 | journal=Arterioscler. Thromb. Vasc. Biol. | pages=379–385 |last1=Holm |first1=P. I. |last2=Ueland |first2=P. M. |last3=Vollset |first3=S. E. |display-authors=etal |doi-access=free | title-link=doi }}</ref> Trimethylglycine is also used as the [[hydrochloride]] [[salt (chemistry)|salt]] (marketed as betaine hydrochloride or betaine HCl). Betaine hydrochloride was |
Although trimethylglycine supplementation decreases the amount of [[adipose tissue]] in pigs, research on human subjects has shown no effect on body weight, body composition, or resting energy expenditure when used in conjunction with a low calorie diet.<ref name="pmid12399266"/> The US [[Food and Drug Administration]] (FDA) approved betaine trimethylglycine (also known by the brand name Cystadane) for the treatment of [[homocystinuria]], a disease caused by abnormally high [[homocysteine]] levels at birth.<ref name="homocysteine">{{cite journal | pmid = 15550695 | doi=10.1161/01.ATV.0000151283.33976.e6 | volume=25 | issue=2 | title=Betaine and folate status as cooperative determinants of plasma homocysteine in humans |date=February 2005 | journal=Arterioscler. Thromb. Vasc. Biol. | pages=379–385 |last1=Holm |first1=P. I. |last2=Ueland |first2=P. M. |last3=Vollset |first3=S. E. |display-authors=etal |doi-access=free | title-link=doi }}</ref> Trimethylglycine is also used as the [[hydrochloride]] [[salt (chemistry)|salt]] (marketed as betaine hydrochloride or betaine HCl). Betaine hydrochloride was sold [[Over-the-counter drug|over-the-counter (OTC)]] as a purported gastric aid in the United States. US Code of Federal Regulations, Title 21, Section 310.540, which became effective in November 1993, banned the marketing of betaine hydrochloride as a digestive aid due to insufficient evidence to classify it as "generally recognized as safe and effective" for that specified use.<ref>{{Cite web|url=https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=310.545&SearchTerm=betaine%20hydrochloride|title=CFR - Code of Federal Regulations Title 21|website=U.S. Food & Drug Administration|access-date=4 September 2018|archive-date=27 July 2020|archive-url=https://web.archive.org/web/20200727002957/https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=310.545&SearchTerm=betaine+hydrochloride|url-status=live}}</ref> |
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==== Side effects ==== |
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Trimethylglycine supplementation may cause [[diarrhea]], bloating, cramps, [[dyspepsia]], [[nausea]] or vomiting.<ref name=":0">{{Citation |title=Betaine |date=2012 |url=http://www.ncbi.nlm.nih.gov/books/NBK548774/ |work=LiverTox: Clinical and Research Information on Drug-Induced Liver Injury |access-date=2023-07-14 |place=Bethesda (MD) |publisher=National Institute of Diabetes and Digestive and Kidney Diseases |pmid=31644082}}</ref> Although rare, it can also causes excessive increases in serum methionine concentrations in the brain, which may lead to [[cerebral edema]], a life-threatening condition.<ref name=":0" /> |
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⚫ | Trimethylglycine supplementation lowers homocysteine but also raises [[LDL-cholesterol]] in obese individuals and renal patients.<ref>{{cite journal |vauthors=Olthof MR, van Vliet T, Verhoef P, Zock PL, Katan MB |title=Effect of homocysteine-lowering nutrients on blood lipids: results from four randomised, placebo-controlled studies in healthy humans |journal=PLOS Med. |volume=2 |issue=5 |pages=e135 |year=2005 |pmid=15916468 |pmc=1140947 |doi=10.1371/journal.pmed.0020135 |doi-access=free }}</ref> |
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== Other uses == |
== Other uses == |
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=== Polymerase chain reaction === |
=== Polymerase chain reaction ===seems highly specialized |
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Trimethylglycine can act as an [[adjuvant]] of the [[polymerase chain reaction]] (PCR) process, and other [[DNA polymerase]]-based assays such as [[DNA sequencing]]. By an unknown mechanism, it aids in the prevention of secondary structures in the DNA molecules, and prevents problems associated with the amplification and sequencing of GC-rich regions. Trimethylglycine makes [[guanosine]] and [[cytidine]] (strong binders) behave with thermodynamics similar to those of [[thymidine]] and [[adenosine]] (weak binders). It has been determined under experiment that it is best used at a final concentration of 1 M.<ref name="pmid9380524">{{cite journal |last1=Henke |first1=W. |last2=Herdel |first2=K. |last3=Jung |first3=K. |last4=Schnorr |first4=D. |last5=Loening |first5=S. A. |title=Betaine improves the PCR amplification of GC-rich DNA sequences. |journal=Nucleic Acids Res. |volume=25 |issue=19 |pages=3957–3958 |date=October 1997 |pmid=9380524 |doi=10.1093/nar/25.19.3957 |url=http://www.pubmed.com/9380524 |archive-url=https://archive.today/20130731191555/http://www.pubmed.com/9380524 |url-status=dead |archive-date=31 July 2013 |pmc=146979 }}</ref> |
Trimethylglycine can act as an [[adjuvant]] of the [[polymerase chain reaction]] (PCR) process, and other [[DNA polymerase]]-based assays such as [[DNA sequencing]]. By an unknown mechanism, it aids in the prevention of secondary structures in the DNA molecules, and prevents problems associated with the amplification and sequencing of GC-rich regions. Trimethylglycine makes [[guanosine]] and [[cytidine]] (strong binders) behave with thermodynamics similar to those of [[thymidine]] and [[adenosine]] (weak binders). It has been determined under experiment that it is best used at a final concentration of 1 M.<ref name="pmid9380524">{{cite journal |last1=Henke |first1=W. |last2=Herdel |first2=K. |last3=Jung |first3=K. |last4=Schnorr |first4=D. |last5=Loening |first5=S. A. |title=Betaine improves the PCR amplification of GC-rich DNA sequences. |journal=Nucleic Acids Res. |volume=25 |issue=19 |pages=3957–3958 |date=October 1997 |pmid=9380524 |doi=10.1093/nar/25.19.3957 |url=http://www.pubmed.com/9380524 |archive-url=https://archive.today/20130731191555/http://www.pubmed.com/9380524 |url-status=dead |archive-date=31 July 2013 |pmc=146979 }}</ref>--> |
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=== Medical research ===<!--for lack of a better term--> |
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Laboratory studies and two clinical trials have indicated that trimethylglycine is a potential treatment of non-alcoholic [[steatohepatitis]].<ref>{{cite journal |
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|last1=Angulo |first1=P. |last2=Lindor |first2=K. D. | title = Treatment of nonalcoholic fatty liver: present and emerging therapies |
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| journal =Semin. Liver Dis. |
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| volume =21 |
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| issue =1 |
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| pages =81–88 |
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| year =2001 |
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| doi = 10.1055/s-2001-12931 |
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| pmid = 11296699}}</ref><ref>{{cite journal |last1=Abdelmalek |first1=M. F. |last2=Sanderson |first2=S. O. |last3=Angulo |first3=P. |display-authors=etal |title=Betaine for nonalcoholic fatty liver disease: results of a randomized placebo-controlled trial |journal=Hepatology |volume=50 |issue=6 |pages=1818–26 |date=December 2009 |pmid=19824078 |doi=10.1002/hep.23239 |s2cid=42163052 |doi-access=free | title-link=doi }}</ref><ref>{{cite journal |last1=Miglio |first1=F. |last2=Rovati |first2=L. C. |last3=Santoro |first3=A. |last4=Setnikar |first4=I. |title=Efficacy and safety of oral betaine glucuronate in non-alcoholic steatohepatitis. A double-blind, randomized, parallel-group, placebo-controlled prospective clinical study |journal=Arzneimittelforschung |volume=50 |issue=8 |pages=722–7 |date=August 2000 |pmid=10994156 |doi= 10.1055/s-0031-1300279|s2cid=1121418 }}</ref> |
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Trimethylglycine has been proposed as a treatment for depression. In theory, it would increase [[S-adenosylmethionine|''S''-adenosylmethionine]] (SAMe) by remethylating homocysteine. The same homocysteine-to-methionine result could be achieved by supplementing with folic acid and vitamin B12, methionine then serving as a precursor to synthesis of SAMe. SAMe as a dietary supplement has been shown to work as a nonspecific antidepressant.<ref>{{cite journal |vauthors=Mischoulon D, Fava M |title=Role of S-adenosyl-L-methionine in the treatment of depression: a review of the evidence |journal=Am. J. Clin. Nutr. |volume=76 |issue=5 |pages=1158S–61S |year=2002 |pmid=12420702 |doi= 10.1093/ajcn/76.5.1158s |doi-access=free | title-link=doi }}</ref> |
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== References == |
== References == |
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== External links == |
== External links == |
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* {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/betaine | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Betaine }} |
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* [http://www.ars.usda.gov/SP2UserFiles/Place/12354500/Data/Choline/Choln02.pdf USDA Database for the Choline Content of Common Foods] – including the data on choline metabolites, such as betaine, in 434 food items. |
* [http://www.ars.usda.gov/SP2UserFiles/Place/12354500/Data/Choline/Choln02.pdf USDA Database for the Choline Content of Common Foods] – including the data on choline metabolites, such as betaine, in 434 food items. |
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{{Other alimentary tract and metabolism products |
{{Other alimentary tract and metabolism products}} |
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{{Portal bar | Medicine}} |
{{Portal bar | Medicine}} |
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[[Category:Amino acid derivatives]] |
[[Category:Amino acid derivatives]] |
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[[Category:Amino acids]] |
[[Category:Alpha-Amino acids]] |
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[[Category:Food additives]] |
[[Category:Food additives]] |
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[[Category:Orphan drugs]] |
[[Category:Orphan drugs]] |
Latest revision as of 14:31, 19 December 2024
Names | |
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IUPAC name
(Trimethylammonio)acetate
| |
Other names
| |
Identifiers | |
3D model (JSmol)
|
|
3537113 | |
ChEBI | |
ChEMBL | |
ChemSpider | |
DrugBank | |
ECHA InfoCard | 100.003.174 |
EC Number |
|
26434 | |
KEGG | |
MeSH | Betaine |
PubChem CID
|
|
UNII | |
CompTox Dashboard (EPA)
|
|
| |
| |
Properties | |
C5H11NO2 | |
Molar mass | 117.146 |
Appearance | White solid |
Melting point | 180 °C (356 °F; 453 K) (decomposes) |
Soluble | |
Solubility | Methanol |
Acidity (pKa) | 1.84 |
Pharmacology | |
A16AA06 (WHO) | |
License data | |
By mouth | |
Legal status | |
Hazards | |
GHS labelling: | |
Warning | |
H315, H319 | |
P264, P280, P302+P352, P305+P351+P338, P321, P332+P313, P337+P313, P362 | |
Related compounds | |
Related amino acids
|
Glycine Methylglycine Dimethylglycine |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
|
Trimethylglycine is an amino acid derivative with the formula (CH3)3N+CH2CO−2. A colorless, water-soluble solid, it occurs in plants.[5] Trimethylglycine is a zwitterion: the molecule contains both a quaternary ammonium group and a carboxylate group. Trimethylglycine was the first betaine discovered; originally it was simply called betaine because it was discovered in sugar beets (Beta vulgaris subsp. vulgaris).[6] Several other betaines are now known.
Medical uses
[edit]Betaine, sold under the brand name Cystadane is indicated for the adjunctive treatment of homocystinuria, involving deficiencies or defects in cystathionine beta-synthase (CBS), 5,10-methylene-tetrahydrofolate reductase (MTHFR), or cobalamin cofactor metabolism (cbl).[2][3][4][7]
The most common side effect is elevated levels of methionine in the blood.[3]
The EU has authorized the health claim that betaine "contributes to normal homocysteine metabolism.".[8]
Biological function
[edit]Biosynthesis
[edit]In most organisms, glycine betaine is biosynthesized by oxidation of choline. The intermediate, betaine aldehyde, is generated by the action of the enzyme mitochondrial choline oxidase (choline dehydrogenase, EC 1.1.99.1). In mice, betaine aldehyde is further oxidised in the mitochondria by the enzyme betaine-aldehyde dehydrogenase (EC 1.2.1.8).[9][10] In humans betaine aldehyde activity is performed by a nonspecific cystosolic aldehyde dehydrogenase enzyme (EC 1.2.1.3) [11]
Trimethylglycine is produced by some cyanobacteria, as established by 13C nuclear magnetic resonance. It is proposed to protect for some enzymes, against inhibition by NaCl and KCl.[12]
Osmolyte
[edit]Trimethylglycine is an osmolyte, a water-soluble salt-like substance. Sugar beet was cultivated from sea beet, which requires osmolytes in order to survive the salty soils of coastal areas. Trimethylglycine also occurs in high concentrations (~10 mM) in many marine invertebrates, such as crustaceans and molluscs. It serves as a appetitive attractant to generalist carnivores such as the predatory sea slug Pleurobranchaea californica.[13]
Methyl donor
[edit]Trimethylglycine is a cofactor in methylation, a process that occurs in all mammals. These processes include the synthesis of neurotransmitters such as dopamine and serotonin. Methylation is also required for the biosynthesis of melatonin and the electron transport chain constituent coenzyme Q10, as well as the methylation of DNA for epigenetics. One step in the methylation cycle is the remethylation of homocysteine, a compound which is naturally generated during demethylation of the essential amino acid methionine. Despite its natural formation, homocysteine has been linked to inflammation, depression, specific forms of dementia, and various types of vascular disease. The remethylation process that detoxifies homocysteine and converts it back to methionine can occur via either of two pathways. The pathway present in virtually all cells involves the enzyme methionine synthase (MS), which requires vitamin B12 as a cofactor, and also depends indirectly on folate and other B vitamins. The second pathway (restricted to liver and kidney in most mammals) involves betaine-homocysteine methyltransferase (BHMT) and requires trimethylglycine as a cofactor. During normal physiological conditions, the two pathways contribute equally to removal of homocysteine in the body.[14] Further degradation of betaine, via the enzyme dimethylglycine dehydrogenase produces folate, thus contributing back to methionine synthase. Betaine is thus involved in the synthesis of many biologically important molecules, and may be even more important in situations where the major pathway for the regeneration of methionine from homocysteine has been compromised by genetic polymorphisms such as mutations in the MS gene.
Agriculture and aquaculture
[edit]Trimethylglycine is used as a supplement for both animals and plants.[5] Processing sucrose from sugar beets yields glycine betaine as a byproduct. The economic significance of trimethylglycine is comparable to that of sugar in sugar beets.[15]
Salmon farms apply trimethylglycine to relieve the osmotic pressure on the fishes' cells when workers transfer the fish from freshwater to saltwater.[15][16]
Trimethylglycine supplementation decreases the amount of adipose tissue in pigs; however, research in human subjects has shown no effect on body weight, body composition, or resting energy expenditure.[17]
Nutrition
[edit]Nutritionally, betaine is not needed when sufficient dietary choline is present for synthesis.[18] When insufficient betaine is available, elevated homocysteine levels and decreased SAM levels in blood occur. Supplementation of betaine in this situation would resolve these blood marker issues, but not compensate for other functions of choline.[19]
Food | Betaine (mg/100 g) |
---|---|
Wheat germ, toasted[21] | 1240 |
Quinoa | 630 |
Wheat germ | 410 |
Lamb's quarters | 330 |
Wheat bran | 320 |
Canned Beetroot | 260 |
Dark Rye flour | 150 |
Spinach | 110-130 |
Dietary supplement
[edit]Although trimethylglycine supplementation decreases the amount of adipose tissue in pigs, research on human subjects has shown no effect on body weight, body composition, or resting energy expenditure when used in conjunction with a low calorie diet.[17] The US Food and Drug Administration (FDA) approved betaine trimethylglycine (also known by the brand name Cystadane) for the treatment of homocystinuria, a disease caused by abnormally high homocysteine levels at birth.[22] Trimethylglycine is also used as the hydrochloride salt (marketed as betaine hydrochloride or betaine HCl). Betaine hydrochloride was sold over-the-counter (OTC) as a purported gastric aid in the United States. US Code of Federal Regulations, Title 21, Section 310.540, which became effective in November 1993, banned the marketing of betaine hydrochloride as a digestive aid due to insufficient evidence to classify it as "generally recognized as safe and effective" for that specified use.[23]
Side effects
[edit]Trimethylglycine supplementation may cause diarrhea, bloating, cramps, dyspepsia, nausea or vomiting.[24] Although rare, it can also causes excessive increases in serum methionine concentrations in the brain, which may lead to cerebral edema, a life-threatening condition.[24]
Trimethylglycine supplementation lowers homocysteine but also raises LDL-cholesterol in obese individuals and renal patients.[25]
References
[edit]- ^ "Notice of Amendment: Betaine removed from the Prescription Drug List (PDL)". Health Canada. 6 January 2023. Retrieved 3 January 2024.
- ^ a b "Cystadane- betaine powder, for solution". DailyMed. 3 October 2019. Archived from the original on 4 August 2021. Retrieved 29 July 2022.
- ^ a b c "Cystadane EPAR". European Medicines Agency. 17 September 2018. Archived from the original on 1 July 2022. Retrieved 29 July 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
- ^ a b "Amversio EPAR". European Medicines Agency. 21 February 2022. Archived from the original on 30 July 2022. Retrieved 29 July 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
- ^ a b Ashraf M, Foolad M (2007). "Roles of glycine betaine and proline in improving plant abiotic stress resistance". Environmental and Experimental Botany. 59 (2): 206–216. doi:10.1016/j.envexpbot.2005.12.006.
- ^ Schiweck H, Clarke M, Pollach G. "Sugar". Ullmann's Encyclopedia of Industrial Chemistry. Weinheim: Wiley-VCH. doi:10.1002/14356007.a25_345.pub2. ISBN 978-3527306732.
- ^ Arumugam MK, Paal MC, Donohue TM, Ganesan M, Osna NA, Kharbanda KK (22 May 2021). "Beneficial Effects of Betaine: A Comprehensive Review". Biology. 10 (6): 456. doi:10.3390/biology10060456. ISSN 2079-7737. PMC 8224793. PMID 34067313.
- ^ K.K. Tiihonen, K. Riihinen, M. Lyyra, E. Sarkkinen, S.A.S. Craig, P. Tenning (2014). "12 - Authorised EU health claims for betaine". In Sadler M (ed.). Foods, Nutrients and Food Ingredients with Authorised EU Health Claims. Woodhead Publishing. pp. 251–273. ISBN 978-0-85709-842-9. Retrieved 19 February 2024.
The European Food Safety Authority (EFSA) agreed that there is sufficient substantiation of the health claim for betaine concerning its contribution to normal homocysteine metabolism (EFSA, 2011a).
- ^ Kempf B, Bremer E (1998). "Uptake and synthesis of compatible solutes as microbial stress responses to high-osmolality environments". Arch. Microbiol. 170 (5): 319–330. Bibcode:1998ArMic.170..319K. doi:10.1007/s002030050649. PMID 9818351. S2CID 8045279.
- ^ "BRENDA – Information on EC 1.2.1.8 – betaine-aldehyde dehydrogenase". Brenda-enzymes.org. Archived from the original on 29 June 2016. Retrieved 7 July 2016.
- ^ Chern MK, Pietruszko R (1999). "Evidence for mitochondrial localization of betaine aldehyde dehydrogenase in rat liver: purification, characterization, and comparison with human cytoplasmic E3 isoenzyme". Biochemistry and Cell Biology. 77 (3): 179–187. doi:10.1139/o99-030. PMID 10505788.
- ^ Rhodes D, Hanson AD (1993). "Quaternary Ammonium and Tertiary Sulfonium Compounds in Higher Plants". Annual Review of Plant Physiology and Plant Molecular Biology. 44 (1). Annual Reviews: 357–384. doi:10.1146/annurev.pp.44.060193.002041. ISSN 1040-2519.
- ^ Gillette R, Huang RC, Hatcher N, Moroz LL (March 2000). "Cost-benefit analysis potential in feeding behavior of a predatory snail by integration of hunger, taste, and pain". Proc. Natl. Acad. Sci. USA. 97 (7): 3585–3590. Bibcode:2000PNAS...97.3585G. doi:10.1073/pnas.97.7.3585. PMC 16283. PMID 10737805.
- ^ Finkelstein JD (24 March 1998). "The metabolism of homocysteine: pathways and regulation". European Journal of Pediatrics. 157 (S2): S40–S44. doi:10.1007/pl00014300. ISSN 0340-6199. PMID 9587024. S2CID 38134977.
- ^ a b Mäkelä P (2004). "Agro-industrial uses of glycinebetaine". Sugar Tech. 6 (4): 207–212. doi:10.1007/BF02942500. hdl:10138/312331. S2CID 25219649.
- ^ Xue M, Xie S, Cui Y (2004). "Effect of a feeding stimulant on feeding adaptation of gibel carp Carassius auratus gibelio (Bloch), fed diets with replacement of fish meal by meat and bone meal". Aquaculture Research. 35 (5): 473–482. doi:10.1111/j.1365-2109.2004.01041.x. S2CID 84304519.
- ^ a b Schwab U, Törrönen A, Toppinen L, et al. (November 2002). "Betaine supplementation decreases plasma homocysteine concentrations but does not affect body weight, body composition, or resting energy expenditure in human subjects". Am. J. Clin. Nutr. 76 (5): 961–967. doi:10.1093/ajcn/76.5.961. PMID 12399266.
- ^ Rucker RB, Zempleni J, Suttie JW, McCormick DB (2007). Handbook of vitamins (4th ed.). Taylor & Francis. pp. 459–477. ISBN 978-0-8493-4022-2.
- ^ "Dietary reference values for choline". EFSA Journal. 14 (8). 2016. doi:10.2903/j.efsa.2016.4484.
- ^ Patterson KY, Bhagwat SA, Williams JR, Howe JC, Holden JM, Zeisel SH, Dacosta KA, Mar MH (1 November 2019). "USDA Database for the Choline Content of Common Foods, Release 2 (2008)". United States Department of Agriculture. doi:10.15482/USDA.ADC/1178141. Archived from the original on 30 July 2022. Retrieved 2 February 2021.
- ^ Steven H Zeisel, Mei-Heng Mar, Juliette C Howe, Joanne M Holden (May 2003). "Concentrations of choline-containing compounds and betaine in common foods". The Journal of Nutrition. 133 (5): 1302–7. doi:10.1093/jn/133.5.1302. PMID 12730414.
- ^ Holm PI, Ueland PM, Vollset SE, et al. (February 2005). "Betaine and folate status as cooperative determinants of plasma homocysteine in humans". Arterioscler. Thromb. Vasc. Biol. 25 (2): 379–385. doi:10.1161/01.ATV.0000151283.33976.e6. PMID 15550695.
- ^ "CFR - Code of Federal Regulations Title 21". U.S. Food & Drug Administration. Archived from the original on 27 July 2020. Retrieved 4 September 2018.
- ^ a b "Betaine", LiverTox: Clinical and Research Information on Drug-Induced Liver Injury, Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases, 2012, PMID 31644082, retrieved 14 July 2023
- ^ Olthof MR, van Vliet T, Verhoef P, Zock PL, Katan MB (2005). "Effect of homocysteine-lowering nutrients on blood lipids: results from four randomised, placebo-controlled studies in healthy humans". PLOS Med. 2 (5): e135. doi:10.1371/journal.pmed.0020135. PMC 1140947. PMID 15916468.
External links
[edit]- USDA Database for the Choline Content of Common Foods – including the data on choline metabolites, such as betaine, in 434 food items.