Pyroglutamic acid (also known as PCA, 5-oxoproline, pidolic acid) is a ubiquitous but little studied natural

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 ...

derivative in which the free amino group of

glutamic acid Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can syn ...

glutamine Glutamine (symbol Gln or Q) is an α-amino acid that is used in the biosynthesis of proteins. Its side chain is similar to that of glutamic acid, except the carboxylic acid group is replaced by an amide. It is classified as a charge-neutral ...

cyclizes to form a

lactam A lactam is a cyclic amide, formally derived from an amino alkanoic acid. The term is a portmanteau of the words ''lactone'' + ''amide''. Nomenclature Greek prefixes in alphabetical order indicate ring size: * α-Lactam (3-atom rings) * β-Lact ...

. The names of pyroglutamic acid

conjugate base A conjugate acid, within the Brønsted–Lowry acid–base theory, is a chemical compound formed when an acid donates a proton () to a base—in other words, it is a base with a hydrogen ion added to it, as in the reverse reaction it loses a ...

anion An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conve ...

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 quanti ...

s, and

ester In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides ...

s are pyroglutamate, 5-oxoprolinate, or pidolate. Formation_of_5-oxoproline_from_N-terminal_Gln

It is a metabolite in the glutathione cycle that is converted to glutamate by 5-oxoprolinase. Pyroglutamate is found in many proteins including

bacteriorhodopsin Bacteriorhodopsin is a protein used by Archaea, most notably by haloarchaea, a class of the Euryarchaeota. It acts as a proton pump; that is, it captures light energy and uses it to move protons across the membrane out of the cell. The resulting ...

. ''N''-terminal glutamic acid and glutamine residues can spontaneously cyclize to become pyroglutamate, or enzymatically converted by glutaminyl cyclases. This is one of several forms of blocked ''N''-termini which present a problem for ''N''-terminal sequencing using Edman chemistry, which requires a free primary amino group not present in pyroglutamic acid. The enzyme

pyroglutamate aminopeptidase Pyroglutamate aminopeptidase is a type of enzyme that cleaves the peptide bond linking the N-terminal end of a polypeptide forming a cyclical lactam to the next amino acid residue. This cyclic structure protects the polypeptide from degradation bu ...

can restore a free ''N''-terminus by cleaving off the pyroglutamate residue. Pyroglutamic acid exists as two distinct

enantiomers In chemistry, an enantiomer ( /ɪˈnænti.əmər, ɛ-, -oʊ-/ ''ih-NAN-tee-ə-mər''; from Ancient Greek ἐνάντιος ''(enántios)'' 'opposite', and μέρος ''(méros)'' 'part') – also called optical isomer, antipode, or optical ant ...

: *(2''R'') or D which happens to be (+) or ''d'' *(2''S'') or L which happens to be (–) or ''l''

Metabolism

As first discovered in 1882, pyroglutamic acid can be formed by heating glutamic acid at 180 °C, which results in the loss of a molecule of water. In living cells, it is derived from

glutathione Glutathione (GSH, ) 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 such as reactive oxygen species, free radicals, pe ...

through the action of an enzyme,

γ-glutamyl cyclotransferase In enzymology, a gamma-glutamylcyclotransferase () is an enzyme that catalysis, catalyzes the chemical reaction :(5-L-glutamyl)-L-amino acid \rightleftharpoons 5-oxoproline + L-amino acid Hence, this enzyme has one substrate (biochemistry), subst ...

. Pyroglutamic acid may function in glutamate storage, and acts to oppose the action of glutamate, including in the brain. It also acts on the brain's

cholinergic system Cholinergic agents are compounds which mimic the action of acetylcholine and/or butyrylcholine. In general, the word "choline" describes the various quaternary ammonium salts containing the ''N'',''N'',''N''-trimethylethanolammonium cation. F ...

;

Amyloid β Amyloid beta (Aβ or Abeta) denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid precursor protein (APP), which i ...

containing pyroglutamic acid is increased in Alzheimer's disease; this may be part of the disease process. Increased levels of pyroglutamic acid in the blood, or

5-oxoprolinuria Glutathione synthetase deficiency (GSD) is a rare autosomal recessive metabolic disorder that prevents the production of glutathione. Glutathione helps prevent damage to cells by neutralizing harmful molecules generated during energy production. G ...

, can occur following

paracetamol overdose Paracetamol poisoning, also known as acetaminophen poisoning, is caused by excessive use of the medication paracetamol (acetaminophen). Most people have few or non-specific symptoms in the first 24 hours following overdose. These include ...

, as well as in certain

inborn errors of metabolism Inborn errors of metabolism form a large class of genetic diseases involving congenital disorders of enzyme activities. The majority are due to defects of single genes that code for enzymes that facilitate conversion of various substances (substra ...

, causing an

acidosis Acidosis is a process causing increased acidity in the blood and other body tissues (i.e., an increase in hydrogen ion concentration). If not further qualified, it usually refers to acidity of the blood plasma. The term ''acidemia'' describes ...

known as

high anion gap metabolic acidosis High anion gap metabolic acidosis is a form of metabolic acidosis characterized by a high anion gap (a medical value based on the concentrations of ions in a patient's serum). Metabolic acidosis occurs when the body produces too much acid, or when ...

Uses

The

sodium Sodium is a chemical element with the symbol Na (from Latin ''natrium'') and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 of the periodic table. Its only stable ...

of pyroglutamic acid—known either as sodium pyroglutamate, sodium PCA, or sodium pidolate—is used for

dry skin Xeroderma, xerosis or xerosis cutis, or simply dry skin, is a skin condition characterized by excessively dry skin. The medical term ''xeroderma'', meaning "dry skin", derives from modern Latin, ''xero-'' 'dry' + Greek ''derma'' 'skin'. In most ...

and hair products, as it is a

humectant A humectant is a hygroscopic (water-absorbing) substance used to keep things moist. They are used in many products, including food, cosmetics, medicines and pesticides. When used as a food additive, a humectant has the effect of keeping moisture ...

. It has low toxicity and is not a skin irritant, but its use in products is limited by a high price. L-pyroglutamic acid is sold online as a

nootropic Nootropics ( , or ) ( colloquial: smart drugs and cognitive enhancers, similar to adaptogens) are a wide range of natural or synthetic supplements or drugs and other substances that are claimed to improve cognitive function or to promote re ...

dietary supplement A dietary supplement is a manufactured product intended to supplement one's diet by taking a pill, capsule, tablet, powder, or liquid. A supplement can provide nutrients either extracted from food sources or that are synthetic in orde ...

Magnesium pidolate Magnesium pidolate, the magnesium salt of pidolic acid (also known as pyroglutamic acid), is a mineral supplement In the context of nutrition, a mineral is a chemical element required as an essential nutrient by organisms to perform functions n ...

, the magnesium salt of pyroglutamic acid, is found in some

mineral supplement In the context of nutrition, a mineral is a chemical element required as an essential nutrient by organisms to perform functions necessary for life. However, the four major structural elements in the human body by weight (oxygen, hydrogen, carbon, ...

s. In a preclinical study, additional pharmacological properties of pyroglutamic acid were revealed such as anti-

phosphodiesterase type 5 Cyclic guanosine monophosphate-specific phosphodiesterase type 5 is an enzyme () from the phosphodiesterase class. It is found in various tissues, most prominently the corpus cavernosum and the retina. It has also been recently discovered to p ...

, anti-

angiotensin-converting enzyme Angiotensin-converting enzyme (), or ACE, is a central component of the renin–angiotensin system (RAS), which controls blood pressure by regulating the volume of fluids in the body. It converts the hormone angiotensin I to the active vasoconstr ...

, and anti-

urease Ureases (), functionally, belong to the superfamily of amidohydrolases and phosphotriesterases. Ureases are found in numerous bacteria, fungi, algae, plants, and some invertebrates, as well as in soils, as a soil enzyme. They are nickel-containi ...

activities.

References

{{Protein primary structure Pyrrolidones Amino acids Glutamates Non-proteinogenic amino acids Cyclic amino acids Secondary amino acids