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Trimethylglycine

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Trimethylglycine
Names
IUPAC name
2-trimethylammonioacetate
Other names
  • Betaine
  • TMG
  • glycine betaine
  • N,N,N-trimethylglycine
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.003.174 Edit this at Wikidata
MeSH Betaine
UNII
  • InChI=1S/C5H11NO2/c1-6(2,3)4-5(7)8/h4H2,1-3H3 checkY
    Key: KWIUHFFTVRNATP-UHFFFAOYSA-N checkY
  • 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
Appearance White solid
Melting point 180 °C (356 °F; 453 K)[1] (decomposes)
Soluble
Solubility Methanol
Acidity (pKa) 1.84
Pharmacology
A16AA06 (WHO)
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).
☒N verify (what is checkY☒N ?)

Trimethylglycine (TMG) is an amino acid derivative that occurs in plants. Trimethylglycine was the first betaine discovered; originally it was simply called betaine because, in the 19th century, it was discovered in sugar beets.[2] Since then, many other betaines have been discovered, and the more specific name glycine betaine distinguishes this one.

Structure and reactions

Trimethylglycine is an N-trimethylated amino acid. This quaternary ammonium exists as the zwitterion at neutral pH. Strong acids such as hydrochloric acid convert TMG to various salts, with HCl yielding betaine hydrochloride:

(CH3)3N+CH2CO2− + HCl → [(CH3)3N+CH2CO2H]Cl−

Demethylation of TMG gives dimethylglycine. Degradation of TMG yields trimethylamine, the scent of putrifying fish.

Production and biochemical processes

Processing sucrose from sugar beets yields glycine betaine as a byproduct. The value of the TMG rivals that of the sugar content in sugar beets.[3] Glycine betaine production involves chromatographic separation.

Biosynthesis

In most organisms, glycine betaine is biosynthesized by oxidation of choline in two steps. The intermediate, betaine aldehyde, is generated by the action of the enzyme mitochondrial choline oxidase (choline dehydrogenase, EC 1.1.99.1). Betaine aldehyde is further oxidised in the mitochondria in mice to betaine by the enzyme betaine aldehyde dehydrogenase (EC 1.2.1.8).[4] [5] In humans betaine aldehyde activity is performed by a nonspecific cystosolic aldehyde dehydrogenase enzyme (EC 1.2.1.3) [6]

Biological function

TMG is an organic osmolyte that occurs in high concentrations (10s of millimolar) in many marine invertebrates, such as crustaceans and molluscs. It serves as a potent appetitive attractant to generalist carnivores such as the predatory sea-slug Pleurobranchaea californica.[7]

TMG is an important cofactor in methylation, a process that occurs in every cell of mammals to synthesize and donate methyl groups (CH3) for other processes in the body. 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.

The major step in the methylation cycle is the remethylation of homocysteine, a compound which is naturally generated during deamination of the essential amino acid methionine. Despite its natural formation, homocysteine has 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 major pathway involves the enzyme methionine synthase, which requires vitamin B12 as a cofactor, and also depends indirectly on folate and other B vitamins. The minor pathway involves betaine-homocysteine methyltransferase and requires TMG as a cofactor. 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 BHMT gene.

TMG in agriculture and aquaculture

Factory farms supplement fodder with TMG and lysine to increase livestocks' muscle mass (and, therefore, "carcass yield", the amount of usable meat).

Salmon farms apply TMG to relieve the osmotic pressure on salmons' cells when workers transfer the fish from freshwater to saltwater.[3][8]

TMG 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.[9]

TMG in the human diet

TMG in foods
Food TMG per 100g
Quinoa 630 mg
Spinach 577 mg
Wheat bran 360 mg
Lamb's quarters 332 mg
Beet 256 mg

Nutritional supplement

Although TMG 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 hypoenergetic diet.[9] The Food and Drug Administration of the United States approved anhydrous trimethylglycine (also known by the brand name Cystadane) for the treatment of homocystinuria, a disease caused by abnormally high homocysteine levels at birth.[10]

TMG supplementation may cause diarrhea, stomach upset, or nausea. Obese persons or those with kidney disease supplementing with TMG, folic acid, and vitamin B6 can experience an increase in total cholesterol levels.[11]

Other uses: PCR

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 1M.[12]

Speculative uses

Laboratory studies and two clinical trials have indicated that TMG is a potential treatment of non-alcoholic steatohepatitis.[13][14][15]

TMG is sometimes used as a treatment for depression, as it can increase S-adenosylmethionine (SAMe) by remethylating homocysteine. SAMe has been shown to work as a nonspecific antidepressant in several studies.[16][17][18]

IEX Ion Exchange Chromatography

In the book from Amersham Biosciences/GE Healthcare, Ion Exchange Chromatography & Chromatofocusing - Principles and Methods, page 48. "Zwitterionic additives such as betaine can prevent precipitation and can be used at high concentrations without interfering with the gradient elution"

References

  1. ^ Acheson, R. M.; Bond, G. J. F. "52. Addition reactions of heterocyclic compounds. Part II. Phenanthridine and methyl acetylenedicarboxylate in methanol". Journal of the Chemical Society (Resumed): 246. doi:10.1039/JR9560000246.
  2. ^ Hubert Schiweck, Margaret Clarke, Günter Pollach "Sugar" in Ullmann’s Encyclopedia of Industrial Chemistry 2007, Wiley-VCH, Weinheim.doi:10.1002/14356007.a25_345.pub2
  3. ^ a b P. Mäkelä "Agro-industrial uses of glycinebetaine" Sugar Tech 2004 Volume 6, 207-212. doi:10.1007/BF02942500
  4. ^ Kempf, B.; Bremer, E. (1998). "Uptake and synthesis of compatible solutes as microbial stress responses to high-osmolality environments". Arch Microbiol. 170: 319–30. doi:10.1007/s002030050649. PMID 9818351.
  5. ^ http://www.brenda-enzymes.org/enzyme.php?ecno=1.2.1.8
  6. ^ 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". Biochem Cell Biol. 77 (3): 179–87. doi:10.1139/o99-030. PMID 10505788.
  7. ^ 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. U.S.A. 97 (7): 3585–90. doi:10.1073/pnas.97.7.3585. PMC 16283. PMID 10737805.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  8. ^ 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: 473-482.
  9. ^ 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): 961–7. PMID 12399266.
  10. ^ 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): 379–85. doi:10.1161/01.ATV.0000151283.33976.e6. PMID 15550695.
  11. ^ http://www.umm.edu/altmed/articles/betaine-000287.htm
  12. ^ Henke W, Herdel K, Jung K, Schnorr D, Loening SA (October 1997). "Betaine improves the PCR amplification of GC-rich DNA sequences". Nucleic Acids Res. 25 (19): 3957–8. doi:10.1093/nar/25.19.3957. PMC 146979. PMID 9380524.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  13. ^ Angulo P, Lindor KD (2001). "Treatment of nonalcoholic fatty liver: present and emerging therapies". Semin Liver Dis. 21 (1): 81–88. doi:10.1055/s-2001-12931. PMID 11296699.
  14. ^ Abdelmalek MF, Sanderson SO, Angulo P, et al. (December 2009). "Betaine for nonalcoholic fatty liver disease: results of a randomized placebo-controlled trial". Hepatology. 50 (6): 1818–26. doi:10.1002/hep.23239. PMID 19824078.
  15. ^ Miglio F, Rovati LC, Santoro A, Setnikar I (August 2000). "Efficacy and safety of oral betaine glucuronate in non-alcoholic steatohepatitis. A double-blind, randomized, parallel-group, placebo-controlled prospective clinical study". Arzneimittelforschung. 50 (8): 722–7. doi:10.1055/s-0031-1300279. PMID 10994156.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  16. ^ "Investigating SAM-e". Geriatric Times. 2001. Retrieved 2006-12-08.
  17. ^ Kagan, BL; Sultzer, DL; Rosenlicht, N; Gerner, RH (May 1, 1990). "Oral S-adenosylmethionine in depression: a randomized, double-blind, placebo-controlled trial". Am J Psychiatry. 147 (5): 591–5. doi:10.1176/ajp.147.5.591. PMID 2183633. Retrieved 2007-02-16.
  18. ^ Rosenbaum, JF; Fava, M; Falk, WE; Pollack, MH; Cohen, LS; Cohen, BM; Zubenko, GS (May 1990). "The antidepressant potential of oral S-adenosyl-l-methionine". Acta Psychiatrica Scandinavica. 81 (5): 432–6. doi:10.1111/j.1600-0447.1990.tb05476.x. PMID 2113347.
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