Methylglyoxal (MGO) is the

organic compound Some chemical authorities define an organic compound as a chemical compound that contains a carbon–hydrogen or carbon–carbon bond; others consider an organic compound to be any chemical compound that contains carbon. For example, carbon-co ...

with the formula CH₃C(O)CHO. It is a reduced derivative of

pyruvic acid Pyruvic acid (CH3COCOOH) is the simplest of the keto acids, alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate acid, conjugate base, CH3COCOO−, is an metabolic intermediate, intermediate in several m ...

. It is a reactive compound that is implicated in the biology of

diabetes Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or the cells of th ...

. Methylglyoxal is produced industrially by degradation of carbohydrates using overexpressed

methylglyoxal synthase The enzyme methylglyoxal synthase () catalysis, catalyzes the chemical reaction :glycerone phosphate \rightleftharpoons 2-oxopropanalCommonly known as methylglyoxal + phosphate Attempts to observe Reversible reaction, reversibility of this react ...

Chemical structure

Gaseous methylglyoxal has two

carbonyl In organic chemistry, a carbonyl group is a functional group with the formula , composed of a carbon atom double bond, double-bonded to an oxygen atom, and it is divalent at the C atom. It is common to several classes of organic compounds (such a ...

groups: an

aldehyde In organic chemistry, an aldehyde () (lat. ''al''cohol ''dehyd''rogenatum, dehydrogenated alcohol) is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred ...

and a

ketone In organic chemistry, a ketone is an organic compound with the structure , where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group (a carbon-oxygen double bond C=O). The simplest ketone is acetone ( ...

. In the presence of water, it exists as hydrates and

oligomer In chemistry and biochemistry, an oligomer () is a molecule that consists of a few repeating units which could be derived, actually or conceptually, from smaller molecules, monomers.Quote: ''Oligomer molecule: A molecule of intermediate relativ ...

s. The formation of these hydrates is indicative of the high reactivity of MGO, which is relevant to its biological behavior.

Biochemistry

Biosynthesis and biodegradation

In organisms, methylglyoxal is formed as a side-product of several

metabolic pathway In biochemistry, a metabolic pathway is a linked series of chemical reactions occurring within a cell (biology), cell. The reactants, products, and Metabolic intermediate, intermediates of an enzymatic reaction are known as metabolites, which are ...

s. Methylglyoxal mainly arises as side products of

glycolysis Glycolysis is the metabolic pathway that converts glucose () into pyruvic acid, pyruvate and, in most organisms, occurs in the liquid part of cells (the cytosol). The Thermodynamic free energy, free energy released in this process is used to form ...

involving

glyceraldehyde-3-phosphate Glyceraldehyde 3-phosphate, also known as triose phosphate or 3-phosphoglyceraldehyde and abbreviated as G3P, GA3P, GADP, GAP, TP, GALP or PGAL, is a metabolite that occurs as an intermediate in several central pathways of all organisms.Nelson, D ...

and

dihydroxyacetone phosphate Dihydroxyacetone phosphate (DHAP, also glycerone phosphate in older texts) is the anion with the formula HOCH2C(O)CH2OPO32-. This anion is involved in many metabolic pathways, including the Calvin cycle in plants and glycolysis.Nelson, D. L.; Co ...

. It is also thought to arise via the degradation of

acetone Acetone (2-propanone or dimethyl ketone) is an organic compound with the chemical formula, formula . It is the simplest and smallest ketone (). It is a colorless, highly Volatile organic compound, volatile, and flammable liquid with a charact ...

and

threonine Threonine (symbol Thr or T) is an amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form when dissolved in water), a carboxyl group (which is in the deprotonated −COO− ...

. Illustrative of the myriad pathways to MGO,

aristolochic acid Aristolochic acids () are a family of carcinogenic, mutagenic, and nephrotoxic phytochemicals commonly found in the flowering plant family Aristolochiaceae (birthworts). Aristolochic acid (AA) I is the most abundant one. The family Aristolochiace ...

caused 12-fold increase of methylglyoxal from 18 to 231 μg/mg of kidney protein in poisoned mice. It may form from

3-aminoacetone Aminoacetone is the organic compound with the formula CH3C(O)CH2NH2. Although stable in the gaseous form, once condensed it reacts with itself. The protonated derivative forms isolable salts, e.g. aminoacetone hydrochloride ( H3C(O)CH2NH3l)). The ...

, which is an intermediate of threonine

catabolism Catabolism () is the set of metabolic pathways that breaks down molecules into smaller units that are either oxidized to release energy or used in other anabolic reactions. Catabolism breaks down large molecules (such as polysaccharides, lipid ...

, as well as through

lipid peroxidation Lipid peroxidation, or lipid oxidation, is a complex chemical process that leads to oxidative degradation of lipids, resulting in the formation of peroxide and hydroperoxide derivatives.{{Cite journal , last1=Ayala , first1=Antonio , last2=Muñoz ...

. However, the most important source is

. Here, methylglyoxal arises from nonenzymatic phosphate elimination from glyceraldehyde phosphate and

(DHAP), two intermediates of glycolysis. This conversion is the basis of a potential biotechnological route to the commodity chemical

1,2-propanediol Propylene glycol (IUPAC name: propane-1,2-diol) is a viscous, colorless liquid. It is almost odorless and has a faintly sweet taste. Its chemical formula is CH3CH(OH)CH2OH. As it contains two alcohol groups, it is classified as a diol. An aliph ...

. Since methylglyoxal is highly

cytotoxic Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are toxic metals, toxic chemicals, microbe neurotoxins, radiation particles and even specific neurotransmitters when the system is out of balance. Also some types of dr ...

, several detoxification mechanisms have evolved. One of these is the

glyoxalase system The glyoxalase system is a set of enzymes that carry out the detoxification of methylglyoxal and the other reactive aldehydes that are produced as a normal part of metabolism. This system has been studied in both bacteria and eukaryotes. This detox ...

. Methylglyoxal is detoxified by

glutathione Glutathione (GSH, ) is an organic compound with the chemical formula . It is an antioxidant in plants, animals, fungi, and some bacteria and archaea. Glutathione is capable of preventing damage to important cellular components caused by sources ...

. Glutathione reacts with methylglyoxal to give a

hemithioacetal In organic chemistry, hemithioacetals (or thiohemiacetals) are organosulfur compounds with the general Chemical formula, formula . They are the sulfur Structural analog, analogues of the acetals, , with an oxygen atom replaced by sulfur (as impli ...

, which converted into ''S''--lactoyl-glutathione by glyoxalase I. This

thioester In organic chemistry, thioesters are organosulfur compounds with the molecular structure . They are analogous to carboxylate esters () with the sulfur in the thioester replacing oxygen in the carboxylate ester, as implied by the thio- prefix ...

is hydrolyzed to -lactate by glyoxalase II.

Biochemical function

Methylglyoxal is involved in the formation of

advanced glycation end product Advanced glycation end-products (AGEs) are proteins or lipids that become glycated as a result of exposure to sugars. They are a bio-marker implicated in aging and the development, or worsening, of many degenerative diseases, such as diabetes, at ...

s (AGEs). In this process, methylglyoxal reacts with free amino groups of

lysine Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. Lysine contains an α-amino group (which is in the protonated form when the lysine is dissolved in water at physiological pH), an α-carboxylic acid group ( ...

and

arginine Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidinium, guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) a ...

and with thiol groups of

cysteine Cysteine (; symbol Cys or C) is a semiessential proteinogenic amino acid with the chemical formula, formula . The thiol side chain in cysteine enables the formation of Disulfide, disulfide bonds, and often participates in enzymatic reactions as ...

forming AGEs.

Histone In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei and in most Archaeal phyla. They act as spools around which DNA winds to create structural units called nucleosomes ...

s are also heavily susceptible to modification by methylglyoxal and these modifications are elevated in breast cancer. Argpyrimidine Hydroimidazolone

DNA damages are induced by reactive

carbonyls In organic chemistry, a carbonyl group is a functional group with the formula , composed of a carbon atom double-bonded to an oxygen atom, and it is divalent at the C atom. It is common to several classes of organic compounds (such as aldehydes, ...

, principally methylglyoxal and

glyoxal Glyoxal is an organic compound with the chemical formula OCHCHO. It is the smallest dialdehyde (a compound with two aldehyde groups). It is a crystalline solid, white at low temperatures and yellow near the melting point (15 °C). The liquid ...

, at a frequency similar to that of oxidative DNA damages.Richarme G, Liu C, Mihoub M, Abdallah J, Leger T, Joly N, Liebart JC, Jurkunas UV, Nadal M, Bouloc P, Dairou J, Lamouri A. Guanine glycation repair by DJ-1/Park7 and its bacterial homologs. Science. 2017 Jul 14;357(6347):208-211. doi: 10.1126/science.aag1095. Epub 2017 Jun 8. PMID 28596309 Such damage, referred to as DNA

glycation Glycation (non-enzymatic glycosylation) is the covalent bond, covalent attachment of a sugar to a protein, lipid or nucleic acid molecule. Typical sugars that participate in glycation are glucose, fructose, and their derivatives. Glycation is th ...

, can cause

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...

, breaks in DNA and

cytotoxicity Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are toxic metals, toxic chemicals, microbe neurotoxins, radiation particles and even specific neurotransmitters when the system is out of balance. Also some types of d ...

. In humans, a protein DJ-1 (also named

PARK7 DJ1, also known as Parkinson disease protein 7, is a protein which in humans is encoded by the ''PARK7'' gene. Its weak glyoxalase activity has been verified by many labs, however the reported protein deglycase activity is likely to be an artifact ...

), has a key role in the repair of glycated DNA bases.

Biomedical aspects

Due to increased blood glucose levels, methylglyoxal has higher concentrations in diabetics and has been linked to

arterial An artery () is a blood vessel in humans and most other animals that takes oxygenated blood away from the heart in the systemic circulation to one or more parts of the body. Exceptions that carry deoxygenated blood are the pulmonary arteries in ...

atherogenesis Atherosclerosis is a pattern of the disease arteriosclerosis, characterized by development of abnormalities called lesions in walls of arteries. This is a chronic inflammatory disease involving many different cell types and is driven by eleva ...

. Damage by methylglyoxal to

low-density lipoprotein Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons (aka ULDL by the overall density ...

through glycation causes a fourfold increase of atherogenesis in diabetics. Methylglyoxal binds directly to the nerve endings and by that increases the chronic extremity soreness in

diabetic neuropathy Diabetic neuropathy includes various types of nerve damage associated with diabetes mellitus. The most common form, diabetic peripheral neuropathy, affects 30% of all diabetic patients. Studies suggests that cutaneous nerve branches, such as the s ...

Occurrence, other

Methylglyoxal is a component of some kinds of honey, including

manuka honey Mānuka (''Leptospermum scoparium'') is a plant. Manuka or mānuka may also refer to: *Manuka, Australian Capital Territory **Manuka Oval, a stadium in the above territory ***Manuka Football Club, a defunct Australian Rules Football club that play ...

; it appears to have activity against ''

E. coli ''Escherichia coli'' ( )Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. is a gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus ''Escherichia'' that is commonly foun ...

'' and '' S. aureus'' and may help prevent formation of

biofilm A biofilm is a Syntrophy, syntrophic Microbial consortium, community of microorganisms in which cell (biology), cells cell adhesion, stick to each other and often also to a surface. These adherent cells become embedded within a slimy ext ...

s formed by '' P. aeruginosa''. Research suggests that methylglyoxal contained in honey does not cause an increased formation of advanced glycation end products (AGEs) in healthy persons.

References

{{Authority control Aldehydes Endogenous aldehydes GABAA receptor agonists Metabolism Conjugated ketones Advanced glycation end-products