# Trimethylglycine

Trimethylglycine is an amino acid derivative with the formula (CH$_3$)$_3$N$^+$CH$_2$CO−2. A colorless, water-soluble solid, it occurs in plants. 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). 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).
The most common side effect is elevated levels of methionine in the blood.
The EU has authorized the health claim that betaine "contributes to normal homocysteine metabolism.".

## 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). In humans betaine aldehyde activity is performed by a nonspecific cystosolic aldehyde dehydrogenase enzyme (EC 1.2.1.3)
Trimethylglycine is produced by some cyanobacteria, as established by $^{13}$C nuclear magnetic resonance. It is proposed to protect for some enzymes, against inhibition by NaCl and KCl.

#### 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.

#### 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 Q$_{10}$, 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 B$_{12}$ 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. 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. 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.
Salmon farms apply trimethylglycine to relieve the osmotic pressure on the fishes' cells when workers transfer the fish from freshwater to saltwater.
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.

## Nutrition

Nutritionally, betaine is not needed when sufficient dietary choline is present for synthesis. 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.
Betaine in foods :
| Food | Betaine (mg/100 g) |
| Wheat germ, toasted | 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

Trimethylglycine supplementation decreases the amount of adipose tissue in pigs, and new research on human subjects has shown a statistically significant effect on body fat reduction when used in conjunction with a low calorie diet. 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. 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.

#### Side effects

Trimethylglycine supplementation may cause diarrhea, bloating, cramps, dyspepsia, nausea or vomiting. 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.
Trimethylglycine supplementation lowers homocysteine but also raises (given in high doses of 6g/day) LDL-cholesterol in obese individuals and renal patients.