Trimethylglycine

Last updated

Contents

Trimethylglycine
Betain2.svg
Betaine-from-xtal-1999-3D-balls.png
Names
IUPAC name
(Trimethylammonio)acetate
Other names
  • Betaine
  • TMG
  • glycine betaine
  • N,N,N-trimethylglycine
  • Cystadane
  • Amversio
Identifiers
3D model (JSmol)
3537113
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.003.174 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 203-490-6
26434
KEGG
MeSH Betaine
PubChem CID
UNII
  • InChI=1S/C5H11NO2/c1-6(2,3)4-5(7)8/h4H2,1-3H3 Yes check.svgY
    Key: KWIUHFFTVRNATP-UHFFFAOYSA-N Yes check.svgY
  • InChI=1/C5H11NO2/c1-6(2,3)4-5(7)8/h4H2,1-3H3
    Key: KWIUHFFTVRNATP-UHFFFAOYAI
  • C[N+](C)(C)CC(=O)[O-]
Properties
C5H11NO2
Molar mass 117.146
AppearanceWhite 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:
GHS-pictogram-exclam.svg
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).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

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

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

Biosynthesis

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

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

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

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

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]

Betaine in foods [20]
FoodBetaine (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

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

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]

Related Research Articles

Vitamin B<sub>6</sub> Class of chemically related vitamins

Vitamin B6 is one of the B vitamins, and is an essential nutrient for humans. The term essential nutrient refers to a group of six chemically similar compounds, i.e., "vitamers", which can be interconverted in biological systems. Its active form, pyridoxal 5′-phosphate, serves as a coenzyme in more than 140 enzyme reactions in amino acid, glucose, and lipid metabolism.

<span class="mw-page-title-main">Methionine</span> Sulfur-containing amino acid

Methionine is an essential amino acid in humans.

<span class="mw-page-title-main">Choline</span> Chemical compound and essential nutrient

Choline is a cation with the chemical formula [(CH3)3NCH2CH2OH]+. Choline forms various salts, such as choline chloride and choline bitartrate. An essential nutrient for animals, it is a structural component of phospholipids and cell membranes.

<span class="mw-page-title-main">Sarcosine</span> Chemical compound

Sarcosine, also known as N-methylglycine, or monomethylglycine, is a amino acid with the formula CH3N(H)CH2CO2H. It exists at neutral pH as the zwitterion CH3N+(H)2CH2CO2−, which can be obtained as a white, water-soluble powder. Like some amino acids, sarcosine converts to a cation at low pH and an anion at high pH, with the respective formulas CH3N+(H)2CH2CO2H and CH3N(H)CH2CO2−. Sarcosine is a close relative of glycine, with a secondary amine in place of the primary amine.

Lipotropic compounds are those that help catalyse the breakdown of fat during metabolism in the body. A lipotropic nutrient promotes or encourages the export of fat from the liver. Lipotropics are necessary for maintenance of a healthy liver, and for burning the exported fat for additional energy. Without lipotropics, such as choline and inositol, fats and bile can become trapped in the liver, causing severe problems such as cirrhosis and blocking fat metabolism.

<span class="mw-page-title-main">Homocystinuria</span> Disorder of amino acid metabolism

Homocystinuria (HCU) is an inherited disorder of the metabolism of the amino acid methionine due to a deficiency of cystathionine beta synthase or methionine synthase. It is an inherited autosomal recessive trait, which means a child needs to inherit a copy of the defective gene from both parents to be affected. Symptoms of homocystinuria can also be caused by a deficiency of vitamins B6, B12, or folate.

A betaine in chemistry is any neutral chemical compound with a positively charged cationic functional group that bears no hydrogen atom, such as a quaternary ammonium or phosphonium cation, and with a negatively charged functional group, such as a carboxylate group that may not be adjacent to the cationic site. Historically, the term was reserved for trimethylglycine (TMG), which is involved in methylation reactions and detoxification of homocysteine. This is a modified amino acid consisting of glycine with three methyl groups serving as methyl donor for various metabolic pathways.

<span class="mw-page-title-main">Methionine synthase</span> Mammalian protein found in Homo sapiens

Methionine synthase (MS, MeSe, MTR) is primarily responsible for the regeneration of methionine from homocysteine in most individuals. In humans it is encoded by the MTR gene (5-methyltetrahydrofolate-homocysteine methyltransferase). Methionine synthase forms part of the S-adenosylmethionine (SAMe) biosynthesis and regeneration cycle, and is the enzyme responsible for linking the cycle to one-carbon metabolism via the folate cycle. There are two primary forms of this enzyme, the Vitamin B12 (cobalamin)-dependent (MetH) and independent (MetE) forms, although minimal core methionine synthases that do not fit cleanly into either category have also been described in some anaerobic bacteria. The two dominant forms of the enzymes appear to be evolutionary independent and rely on considerably different chemical mechanisms. Mammals and other higher eukaryotes express only the cobalamin-dependent form. In contrast, the distribution of the two forms in Archaeplastida (plants and algae) is more complex. Plants exclusively possess the cobalamin-independent form, while algae have either one of the two, depending on species. Many different microorganisms express both the cobalamin-dependent and cobalamin-independent forms.

<span class="mw-page-title-main">Hyperhomocysteinemia</span> Medical condition

Hyperhomocysteinemia is a medical condition characterized by an abnormally high level of total homocysteine in the blood, conventionally described as above 15 μmol/L.

<span class="mw-page-title-main">Betaine—homocysteine S-methyltransferase</span> Class of enzymes

In the field of enzymology, a betaine-homocysteine S-methyltransferase also known as betaine-homocysteine methyltransferase (BHMT) is a zinc metallo-enzyme that catalyzes the transfer of a methyl group from trimethylglycine and a hydrogen ion from homocysteine to produce dimethylglycine and methionine respectively:

<span class="mw-page-title-main">Phosphatidylethanolamine N-methyltransferase</span> Class of enzymes

Phosphatidylethanolamine N-methyltransferase is a transferase enzyme which converts phosphatidylethanolamine (PE) to phosphatidylcholine (PC) in the liver. In humans it is encoded by the PEMT gene within the Smith–Magenis syndrome region on chromosome 17.

In enzymology, a choline monooxygenase (EC 1.14.15.7) is an enzyme that catalyzes the chemical reaction

In enzymology, a choline dehydrogenase is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Choline oxidase</span>

In enzymology, a choline oxidase (EC 1.1.3.17) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">MTRR (gene)</span> Protein-coding gene in the species Homo sapiens

Methionine synthase reductase, also known as MSR, is an enzyme that in humans is encoded by the MTRR gene.

<span class="mw-page-title-main">Glycocyamine</span> Chemical compound

Glycocyamine is a metabolite of glycine in which the amino group has been converted into a guanidine by guanylation. In vertebrate organism it is then transformed into creatine by methylation.

<span class="mw-page-title-main">Glycine betaine aldehyde</span> Chemical compound

Glycine betaine aldehyde, often simply called betaine aldehyde, is an intermediate in the metabolism of glycine, serine and threonine. The human aldehyde dehydrogenase stimulates the transformation of betaine aldehyde to glycine betaine. Betaine aldehyde is a substrate for choline dehydrogenase (mitochondrial).

Sarcosine/dimethylglycine N-methyltransferase is an enzyme with systematic name S-adenosyl-L-methionine:sarcosine(or N,N-dimethylglycine) N-methyltransferase . This enzyme catalyses the following chemical reaction

Glycine/sarcosine/dimethylglycine N-methyltransferase is an enzyme with systematic name S-adenosyl-L-methionine:glycine(or sarcosine or N,N-dimethylglycine) N-methyltransferase . This enzyme catalyses the following chemical reaction

Remethylation involves methylation that occurs in some biochemical cycles. Often methyl groups are not mobile when attached to nitrogen and sulfur, but the removal and reinstallation of methyl groups does occur with the assistance of certain enzymes.

References

  1. ↑ "Notice of Amendment: Betaine removed from the Prescription Drug List (PDL)". Health Canada . 6 January 2023. Retrieved 3 January 2024.
  2. 1 2 "Cystadane- betaine powder, for solution". DailyMed. 3 October 2019. Archived from the original on 4 August 2021. Retrieved 29 July 2022.
  3. 1 2 3 "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.
  4. 1 2 "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.
  5. 1 2 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.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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).
  9. ↑ 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.
  10. ↑ "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.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  15. 1 2 Mäkelä P (2004). "Agro-industrial uses of glycinebetaine". Sugar Tech. 6 (4): 207–212. doi:10.1007/BF02942500. hdl: 10138/312331 . S2CID   25219649.
  16. ↑ 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.
  17. 1 2 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.
  18. ↑ 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.
  19. ↑ "Dietary reference values for choline". EFSA Journal. 14 (8). 2016. doi: 10.2903/j.efsa.2016.4484 .
  20. ↑ 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.
  21. ↑ 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.
  22. ↑ 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.
  23. ↑ "CFR - Code of Federal Regulations Title 21". U.S. Food & Drug Administration. Archived from the original on 27 July 2020. Retrieved 4 September 2018.
  24. 1 2 "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
  25. ↑ 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.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.