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Trimethylglycine is an
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
derivative that occurs in plants. Trimethylglycine was the first
betaine A betaine () in chemistry is any neutral chemical compound with a positively charged cationic functional group, such as a quaternary ammonium or phosphonium cation (generally: onium ions) that bears no hydrogen atom and with a negatively charged ...
discovered; originally it was simply called betaine because, in the 19th century, it was discovered in
sugar beet A sugar beet is a plant whose root contains a high concentration of sucrose and which is grown commercially for sugar production. In plant breeding, it is known as the Altissima cultivar group of the common beet (''Beta vulgaris''). Together wi ...
s. It has a sweet and umami taste. Since then, many other
betaine A betaine () in chemistry is any neutral chemical compound with a positively charged cationic functional group, such as a quaternary ammonium or phosphonium cation (generally: onium ions) that bears no hydrogen atom and with a negatively charged ...
s have been discovered, and the more specific name ''glycine betaine'' distinguishes this one.


Medical uses

Betaine 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).


Structure and reactions

Trimethylglycine is an ''N''-methylated amino acid. It 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. : With amino acids, for example, in solution a chemical equilibrium wil ...
as the molecule contains both a
quaternary ammonium In chemistry, quaternary ammonium cations, also known as quats, are positively charged polyatomic ions of the structure , R being an alkyl group or an aryl group. Unlike the ammonium ion () and the primary, secondary, or tertiary ammonium cations ...
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 (p''K''a + 2). : (aq) + (aq)
Demethylation Demethylation is the chemical process resulting in the removal of a methyl group (CH3) from a molecule. A common way of demethylation is the replacement of a methyl group by a hydrogen atom, resulting in a net loss of one carbon and two hydrogen ato ...
of trimethylglycine gives
dimethylglycine Dimethylglycine (DMG) is a derivative of the amino acid glycine with the structural formula (CH3)2NCH2COOH. It can be found in beans and liver, and has a sweet taste. It can be formed from trimethylglycine upon the loss of one of its methyl groups ...
.


Production and biochemical processes

Processing Processing is a free graphical library and integrated development environment (IDE) built for the electronic arts, new media art, and visual design communities with the purpose of teaching non-programmers the fundamentals of computer programming ...
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 consid ...
. The economic value of the trimethylglycine rivals that of the sugar content in sugar beets.


Biosynthesis

In most organisms, glycine betaine is biosynthesized by oxidation of
choline Choline is an essential nutrient for humans and many other animals. Choline occurs as a cation that forms various salts (X− in the depicted formula is an undefined counteranion). Humans are capable of some ''de novo synthesis'' of choline but re ...
in two steps. 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. Betai ...
, is generated by the action of the enzyme mitochondrial choline oxidase (
choline dehydrogenase In enzymology, a choline dehydrogenase () is an enzyme that catalyzes the chemical reaction :choline + acceptor \rightleftharpoons betaine aldehyde + reduced acceptor Thus, the two substrates of this enzyme are choline and acceptor, whereas i ...
, EC 1.1.99.1). Betaine aldehyde is further oxidised in the
mitochondria A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...
in mice to betaine by the enzyme
betaine-aldehyde dehydrogenase In enzymology, a betaine-aldehyde dehydrogenase () is an enzyme that catalyzes the chemical reaction :betaine aldehyde + NAD+ + H2O \rightleftharpoons betaine + NADH + 2 H+ The 3 substrates of this enzyme are betaine aldehyde, NAD+, and H2O, ...
(EC 1.2.1.8). In humans betaine aldehyde activity is performed by a nonspecific cystosolic aldehyde dehydrogenase enzyme (EC 1.2.1.3)


Biological function

Trimethylglycine is an organic
osmolyte Osmolytes are low-molecular weight organic compounds that influence the properties of biological fluids. Their primary role is to maintain the integrity of cells by affecting the viscosity, melting point, and ionic strength of the aqueous solution. ...
. Sugar beet was cultivated from
sea beet The sea beet, ''Beta vulgaris'' subsp. ''maritima'' ((L.) Arcangeli.), is a member of the family Amaranthaceae, previously of the Chenopodiaceae. Carl Linnaeus first described ''Beta vulgaris'' in 1753; in the second edition of '' Species Plantaru ...
, 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
crustacean Crustaceans (Crustacea, ) form a large, diverse arthropod taxon which includes such animals as decapods, seed shrimp, branchiopods, fish lice, krill, remipedes, isopods, barnacles, copepods, amphipods and mantis shrimp. The crustacean group ...
s and
mollusc Mollusca is the second-largest phylum of invertebrate animals after the Arthropoda, the members of which are known as molluscs or mollusks (). Around 85,000  extant species of molluscs are recognized. The number of fossil species is esti ...
s. It serves as a potent appetitive attractant to generalist carnivores such as the predatory
sea slug Sea slug is a common name for some marine invertebrates with varying levels of resemblance to terrestrial slugs. Most creatures known as sea slugs are gastropods, i.e. they are sea snails (marine gastropod mollusks) that over evolutionary t ...
''
Pleurobranchaea californica ''Pleurobranchaea californica'' is a species of gastropods The gastropods (), commonly known as snails and slugs, belong to a large taxonomic class of invertebrates within the phylum Mollusca called Gastropoda (). This class comprises snails ...
''. Trimethylglycine is an important cofactor in
methylation In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These t ...
, a process that occurs in every mammalian cell donating
methyl group In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula . In formulas, the group is often abbreviated as Me. This hydrocarbon group occurs in many ...
s (–CH3) for other processes in the body. These processes include the synthesis of
neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell. Neuro ...
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 compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...
and
serotonin Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and vas ...
. Methylation is also required for the biosynthesis of
melatonin Melatonin is a natural product found in plants and animals. It is primarily known in animals as a hormone released by the pineal gland in the brain at night, and has long been associated with control of the sleep–wake cycle. In vertebrates ...
and the
electron transport chain An electron transport chain (ETC) is a series of protein complexes and other molecules that 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. The major step in the methylation cycle is the remethylation of
homocysteine Homocysteine is a non-proteinogenic α-amino acid. It is a homologue of the amino acid cysteine, differing by an additional methylene bridge (-CH2-). It is biosynthesized from methionine by the removal of its terminal Cε methyl group. In the b ...
, a compound which is naturally generated during demethylation of the essential amino acid
methionine Methionine (symbol Met or M) () is an essential amino acid in humans. As the precursor of other amino acids such as cysteine and taurine, versatile compounds such as SAM-e, and the important antioxidant glutathione, methionine plays a critical ro ...
. 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 Methionine synthase also known as MS, MeSe, MTR is responsible for the regeneration of methionine from homocysteine. In humans it is encoded by the ''MTR'' gene (5-methyltetrahydrofolate-homocysteine methyltransferase). Methionine synthase forms ...
(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 metabolism and synthesis of red blood cells. Though these vitamins share similar names (B1, B2, B3, etc.), they are chemically distinct compounds that often coexist ...
. 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. Trimethylglycine is produced by some
cyanobacteria Cyanobacteria (), also known as Cyanophyta, are a phylum of gram-negative bacteria that obtain energy via photosynthesis. The name ''cyanobacteria'' refers to their color (), which similarly forms the basis of cyanobacteria's common name, blu ...
. Gabbay-Azaria et al 1988 uses C nuclear magnetic resonance to detect trimethylglycines produced by
halophilic The halophiles, named after the Greek word for "salt-loving", are extremophiles that thrive in high salt concentrations. While most halophiles are classified into the domain Archaea, there are also bacterial halophiles and some eukaryotic species, ...
cyanobacteria. They find it is providing partial protection for their enzymes, against inhibition by
NaCl Sodium chloride , commonly known as salt (although sea salt also contains other chemical salts), is an ionic compound with the chemical formula NaCl, representing a 1:1 ratio of sodium and chloride ions. With molar masses of 22.99 and 35.45 g ...
and
KCl Potassium chloride (KCl, or potassium salt) is a metal halide Salt (chemistry), salt composed of potassium and chlorine. It is odorless and has a white or colorless vitreous lustre, vitreous crystal appearance. The solid dissolves readily in wa ...
.


Agriculture and aquaculture

Factory farms Intensive animal farming or industrial livestock production, also known by its opponents as factory farming and macro-farms, is a type of intensive agriculture, specifically an approach to animal husbandry designed to maximize production, while ...
supplement
fodder Fodder (), also called provender (), is any agriculture, agricultural foodstuff used specifically to feed domesticated livestock, such as cattle, domestic rabbit, rabbits, sheep, horses, chickens and pigs. "Fodder" refers particularly to food g ...
with trimethylglycine and
lysine Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. It contains an α-amino group (which is in the protonated form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −C ...
to increase livestock's
muscle mass Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscle ...
(and, therefore, "carcass yield", the amount of usable meat).
Salmon farm The aquaculture of salmonids is the farming and harvesting of salmonids under controlled conditions for both commercial and recreational purposes. Salmonids (particularly salmon and rainbow trout), along with carp, and tilapia are the three most ...
s 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, body fat, or simply fat is a loose connective tissue composed mostly of adipocytes. In addition to adipocytes, adipose tissue contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular e ...
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. Dietary betaine can partially, but not fully, substitute for choline. 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

Although trimethylglycine supplementation decreases the amount of
adipose tissue Adipose tissue, body fat, or simply fat is a loose connective tissue composed mostly of adipocytes. In addition to adipocytes, adipose tissue contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular e ...
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. 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 respon ...
(FDA) approved betaine trimethylglycine (also known by the brand name Cystadane) for the treatment of
homocystinuria Homocystinuria or 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 inh ...
, a disease caused by abnormally high
homocysteine Homocysteine is a non-proteinogenic α-amino acid. It is a homologue of the amino acid cysteine, differing by an additional methylene bridge (-CH2-). It is biosynthesized from methionine by the removal of its terminal Cε methyl group. In the b ...
levels at birth. Trimethylglycine is also used as the
hydrochloride In chemistry, a hydrochloride is an acid salt resulting, or regarded as resulting, from the reaction of hydrochloric acid with an organic base (e.g. an amine). An alternative name is chlorhydrate, which comes from French. An archaic alternative na ...
salt Salt is a mineral composed primarily of sodium chloride (NaCl), a chemical compound belonging to the larger class of salts; salt in the form of a natural crystalline mineral is known as rock salt or halite. Salt is present in vast quantitie ...
(marketed as betaine hydrochloride or betaine HCl). Betaine hydrochloride was once permitted in over-the-counter (OTC) drugs as a gastric aid in the United States. US Code of Federal Regulations, Title 21, Section 310.540, which became effective on November 10, 1993, banned betaine hydrochloride from being used in OTC products due to insufficient evidence to classify it as "generally recognized as safe and effective". Trimethylglycine supplementation may cause
diarrhea Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin wi ...
, stomach upset, or
nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...
. Trimethylglycine supplementation lowers homocysteine but also raises LDL-cholesterol in obese individuals and renal patients.


Other uses


Polymerase chain reaction

Trimethylglycine can act as an
adjuvant In pharmacology, an adjuvant is a drug or other substance, or a combination of substances, that is used to increase the efficacy or potency of certain drugs. Specifically, the term can refer to: * Adjuvant therapy in cancer management * Analgesic ...
of the
polymerase chain reaction The polymerase chain reaction (PCR) is a method widely used to rapidly make millions to billions of copies (complete or partial) of a specific DNA sample, allowing scientists to take a very small sample of DNA and amplify it (or a part of it) t ...
(PCR) process, and other
DNA polymerase A DNA polymerase is a member of a family of enzymes that catalyze the synthesis of DNA molecules from nucleoside triphosphates, the molecular precursors of DNA. These enzymes are essential for DNA replication and usually work in groups to create ...
-based assays such as
DNA sequencing DNA sequencing is the process of determining the nucleic acid sequence – the order of nucleotides in DNA. It includes any method or technology that is used to determine the order of the four bases: adenine, guanine, cytosine, and thymine. Th ...
. 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 Guanosine (symbol G or Guo) is a purine nucleoside comprising guanine attached to a ribose (ribofuranose) ring via a β-N9-glycosidic bond. Guanosine can be phosphorylated to become guanosine monophosphate (GMP), cyclic guanosine monophosphate (c ...
and
cytidine Cytidine (symbol C or Cyd) is a nucleoside molecule that is formed when cytosine is attached to a ribose ring (also known as a ribofuranose) via a β-N1- glycosidic bond. Cytidine is a component of RNA. It is a white water-soluble solid. which ...
(strong binders) behave with thermodynamics similar to those of
thymidine Thymidine (symbol dT or dThd), also known as deoxythymidine, deoxyribosylthymine, or thymine deoxyriboside, is a pyrimidine deoxynucleoside. Deoxythymidine is the DNA nucleoside T, which pairs with deoxyadenosine (A) in double-stranded DNA. I ...
and
adenosine Adenosine ( symbol A) is an organic compound that occurs widely in nature in the form of diverse derivatives. The molecule consists of an adenine attached to a ribose via a β-N9-glycosidic bond. Adenosine is one of the four nucleoside building ...
(weak binders). It has been determined under experiment that it is best used at a final concentration of 1 M.


Medical research

Laboratory studies and two clinical trials have indicated that trimethylglycine is a potential treatment of non-alcoholic
steatohepatitis Steatohepatitis is a type of fatty liver disease, characterized by inflammation of the liver with concurrent fat accumulation in liver. Mere deposition of fat in the liver is termed steatosis, and together these constitute fatty liver changes. T ...
. Trimethylglycine has been proposed as a treatment for depression. In theory, it would increase ''S''-adenosylmethionine (SAMe) by remethylating homocysteine. The same homocysteine-to-methionine result could be achieved by supplementing with folic acid and vitamin B12, methionine then serving as a precursor to synthesis of SAMe. SAMe as a dietary supplement has been shown to work as a nonspecific antidepressant.


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 Amino acids Food additives Orphan drugs Quaternary ammonium compounds Zwitterions