Trimethylglycine 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 (Beta vulgaris subsp. vulgaris).[6]
Medical uses
Betaine, sold under the brand name Cystadane among others, 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).[3][4][5]
The most common side effect is elevated levels of methionine in the blood.[4]
Trimethylglycine is an N-methylated amino acid. It is a zwitterion as the molecule contains both a 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 (pKa + 2).
Processingsucrose from sugar beets yields glycine betaine as a byproduct. The economic value of the trimethylglycine rivals that of the sugar content in sugar beets.[7]
Trimethylglycine is an organic osmolyte. Sugar beet was cultivated from sea beet, which requires osmolytes in order to survive in 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 potent appetitive attractant to generalist carnivores such as the predatory sea slugPleurobranchaea californica.[11]
The major 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.[12] 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.
Factory farms supplement fodder with trimethylglycine and lysine to increase livestock's muscle mass (and, therefore, "carcass yield", the amount of usable meat).
Salmon farms apply trimethylglycine to relieve the osmotic pressure on the fishes' cells when workers transfer the fish from freshwater to saltwater.[7][14]
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.[15]
Nutrition
Nutritionally, betaine is not needed when sufficient dietary choline is present for synthesis.[16] 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.[17]
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.[15] 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.[19] Trimethylglycine is also used as the hydrochloridesalt (marketed as betaine hydrochloride or betaine HCl). Betaine hydrochloride was sold over-the-counter (OTC) as a 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.[20]
Side effects
Trimethylglycine supplementation may cause diarrhea, bloating, cramps, dyspepsia, nausea or vomiting.[21] 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.[21]
Trimethylglycine supplementation lowers homocysteine but also raises LDL-cholesterol in obese individuals and renal patients.[22]
Other uses
Polymerase chain reaction
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.[23]
References
^Acheson, R. M.; Bond, G. J. F. (1956). "52. Addition reactions of heterocyclic compounds. Part II. Phenanthridine and methyl acetylenedicarboxylate in methanol". J. Chem. Soc. 1956: 246. doi:10.1039/JR9560000246.
^ abc"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.
^ ab"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.
^Chern, M. K.; 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. PMID10505788.
^ ab"Betaine", LiverTox: Clinical and Research Information on Drug-Induced Liver Injury, Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases, 2012, PMID31644082, retrieved 14 July 2023
