Trimethylglycine is an

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

derivative with the formula . A colorless, water-soluble solid, it occurs in plants. Trimethylglycine is a

zwitterion In chemistry, a zwitterion ( ; ), also called an inner salt or dipolar ion, is a molecule that contains an equal number of positively and negatively charged functional groups. : (1,2- dipolar compounds, such as ylides, are sometimes excluded from ...

: the molecule contains both a

quaternary ammonium In organic chemistry, quaternary ammonium cations, also known as quats, are positively-charged polyatomic ions of the structure , where R is an alkyl group, an aryl group or organyl group. Unlike the ammonium ion () and the primary, secondary, o ...

group and a carboxylate group. Trimethylglycine was the first

betaine 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 cation, quaternary ammonium or phosphonium cation (generally: Onium compou ...

discovered; originally it was simply called betaine because it was discovered in

sugar beet A sugar beet is a plant whose root contains a high concentration of sucrose and that is grown commercially for sugar production. In plant breeding, it is known as the Altissima cultivar group of the common beet (''Beta vulgaris''). Together with ...

s (''Beta vulgaris'' subsp. ''vulgaris''). Several other betaines are now known.

Medical uses

Betaine, sold under the brand name Cystadane, is

indicated In medicine, an indication is a valid reason to use a certain test, medication, procedure, or surgery. There can be multiple indications to use a procedure or medication. An indication can commonly be confused with the term diagnosis. A diagnosis ...

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 Methionine (symbol Met or M) () is an essential amino acid in humans. As the precursor of other non-essential amino acids such as cysteine and taurine, versatile compounds such as SAM-e, and the important antioxidant glutathione, methionine play ...

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 Choline is a cation with the chemical formula . Choline forms various Salt (chemistry), salts, such as choline chloride and choline bitartrate. An essential nutrient for animals, it is a structural component of phospholipids and cell membrane ...

. The intermediate,

betaine aldehyde 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. Betain ...

, 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 A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is us ...

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 Cyanobacteria ( ) are a group of autotrophic gram-negative bacteria that can obtain biological energy via oxygenic photosynthesis. The name "cyanobacteria" () refers to their bluish green (cyan) color, which forms the basis of cyanobacteri ...

, as established by C nuclear magnetic resonance. It is proposed to protect for some enzymes, against inhibition by

NaCl Sodium chloride , commonly known as edible salt, is an ionic compound with the chemical formula NaCl, representing a 1:1 ratio of sodium and chloride ions. It is transparent or translucent, brittle, hygroscopic, and occurs as the mineral hali ...

and KCl.

Osmolyte

Trimethylglycine is an

osmolyte Osmolytes are low-molecular-weight organic compounds that influence the properties of biological fluids. Osmolytes are a class of organic molecules that play a significant role in regulating osmotic pressure and maintaining cellular homeostasis in ...

, a water-soluble salt-like substance. Sugar beet was cultivated from

sea beet The sea beet, ''Beta vulgaris'' subsp. ''maritima'' (L.) Arcangeli., is an Old World perennial plant with edible leaves, leading to the common name wild spinach. Description Sea beet is an erect and sprawling perennial plant up to high with da ...

, 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 Crustaceans (from Latin meaning: "those with shells" or "crusted ones") are invertebrate animals that constitute one group of arthropods that are traditionally a part of the subphylum Crustacea (), a large, diverse group of mainly aquatic arthrop ...

s and

mollusc Mollusca is a phylum of protostome, protostomic invertebrate animals, whose members are known as molluscs or mollusks (). Around 76,000 extant taxon, extant species of molluscs are recognized, making it the second-largest animal phylum ...

s. It serves as a appetitive attractant to generalist carnivores such as the predatory

sea slug Sea slug is a common name for some Marine biology, marine invertebrates with varying levels of resemblance to terrestrial Slug, slugs. Most creatures known as sea slugs are gastropods, i.e. they are Sea snail, sea snails (marine gastropod moll ...

'' Pleurobranchaea californica''.

Methyl donor

Trimethylglycine is a cofactor in

methylation Methylation, in the chemistry, chemical sciences, is the addition of a methyl group on a substrate (chemistry), substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replac ...

, a process that occurs in all mammals. These processes include the synthesis of

neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotra ...

s such as

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

and

serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

. Methylation is also required for the biosynthesis of

melatonin Melatonin, an indoleamine, is a natural compound produced by various organisms, including bacteria and eukaryotes. Its discovery in 1958 by Aaron B. Lerner and colleagues stemmed from the isolation of a substance from the pineal gland of cow ...

and the

electron transport chain An electron transport chain (ETC) is a series of protein complexes and other molecules which transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples th ...

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

. 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 Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing and ...

and other

B vitamins B vitamins are a class of water-soluble vitamins that play important roles in Cell (biology), cell metabolism and synthesis of red blood cells. They are a chemically diverse class of compounds. Dietary supplements containing all eight are referr ...

. 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 Sucrose, a disaccharide, is a sugar composed of glucose and fructose subunits. It is produced naturally in plants and is the main constituent of white sugar. It has the molecular formula . For human consumption, sucrose is extracted and refined ...

from sugar beets yields glycine betaine as a

byproduct A by-product or byproduct is a secondary product derived from a production process, manufacturing process or chemical reaction; it is not the primary product or service being produced. A by-product can be useful and marketable or it can be cons ...

. 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 Adipose tissue (also known as body fat or simply fat) is a loose connective tissue composed mostly of adipocytes. It also contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, Blood vessel, vascular endothel ...

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.

Dietary supplement

Trimethylglycine supplementation decreases the amount of

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 The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(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 In common usage, salt is a mineral composed primarily of sodium chloride (NaCl). When used in food, especially in granulated form, it is more formally called table salt. In the form of a natural crystalline mineral, salt is also known as r ...

(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 Diarrhea (American English), also spelled diarrhoea or diarrhœa (British English), is the condition of having at least three loose, liquid, or watery bowel movements in a day. It often lasts for a few days and can result in dehydration d ...

, bloating, cramps,

dyspepsia Indigestion, also known as dyspepsia or upset stomach, is a condition of impaired digestion. Symptoms may include upper abdominal fullness, heartburn, nausea, belching, or upper abdominal pain. People may also experience feeling full earlier ...

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...

or vomiting. Although rare, it can also causes excessive increases in serum methionine concentrations in the brain, which may lead to

cerebral edema Cerebral edema is excess accumulation of fluid ( edema) in the intracellular or extracellular spaces of the brain. This typically causes impaired nerve function, increased pressure within the skull, and can eventually lead to direct compres ...

, 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.

References

External links

USDA Database for the Choline Content of Common Foods
– including the data on choline metabolites, such as betaine, in 434 food items. {{Portal bar , Medicine Amino acid derivatives Alpha-Amino acids Food additives Orphan drugs Quaternary ammonium compounds Zwitterions