Pyroglutamic acid

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Pyroglutamic acid
Pyroglutamic acid.svg
Names
Preferred IUPAC name
5-Oxoproline
Systematic IUPAC name
5-Oxopyrrolidine-2-carboxylic acid
Other names
  • 2-Pyrrolidone-5-carboxylic acid
  • Pidolic acid
  • 5-Oxo-proline
Identifiers
3D model (JSmol)
3DMet
AbbreviationsGlp
82134
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.005.227 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 205-748-3
1473408
KEGG
MeSH Pyrrolidonecarboxylic+acid
PubChem CID
RTECS number
  • TW3710000
UNII
  • InChI=1S/C5H7NO3/c7-4-2-1-3(6-4)5(8)9/h3H,1-2H2,(H,6,7)(H,8,9) X mark.svgN
    Key: ODHCTXKNWHHXJC-UHFFFAOYSA-N X mark.svgN
  • InChI=1S/C5H7NO3/c7-4-2-1-3(6-4)5(8)9/h3H,1-2H2,(H,6,7)(H,8,9)/t3-/m0/s1
  • InChI=1S/C5H7NO3/c7-4-2-1-3(6-4)5(8)9/h3H,1-2H2,(H,6,7)(H,8,9)/t3-/m0/s1
    Key: ODHCTXKNWHHXJC-VKHMYHEASA-N
  • O=C(O)[C@H]1NC(=O)CC1
Properties
C5H7NO3
Molar mass 129.115 g·mol−1
Melting point 184 °C (363 °F; 457 K)
log P -0.89
Acidity (pKa)-1.76, 3.48, 12.76
Basicity (pKb)15.76, 10.52, 1.24
Isoelectric point 0.94
Related compounds
Related compounds
proline
2-Pyrrolidone
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

Pyroglutamic acid (also known as PCA, 5-oxoproline, pidolic acid) is a ubiquitous but understudied natural amino acid derivative in which the free amino group of glutamic acid or glutamine cyclizes to form a lactam. [1] The names of pyroglutamic acid conjugate base, anion, salts, and esters are pyroglutamate, 5-oxoprolinate, or pidolate.

Contents

Formation of pyroglutamic acid from N-terminal glutamine. Formation of 5-oxoproline from N-terminal Gln.svg
Formation of pyroglutamic acid from N-terminal glutamine.

It is a metabolite in the glutathione cycle that is converted to glutamate by 5-oxoprolinase. Pyroglutamate is found in many proteins including bacteriorhodopsin. N-terminal glutamic acid and glutamine residues can spontaneously cyclize to become pyroglutamate, or enzymatically converted by glutaminyl cyclases. [2] 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 can restore a free N-terminus by cleaving off the pyroglutamate residue. [3]

Pyroglutamic acid exists as two distinct enantiomers:

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 through the action of an enzyme, γ-glutamyl cyclotransferase. [1] Pyroglutamic acid may function in glutamate storage, and acts to oppose the action of glutamate, including in the brain. [1] It also acts on the brain's cholinergic system; [4] Amyloid β containing pyroglutamic acid is increased in Alzheimer's disease; this may be part of the disease process. [5] Increased levels of pyroglutamic acid in the blood, leading to excess in the urine (5-oxoprolinuria), can occur following paracetamol overdose, as well as in certain inborn errors of metabolism, causing high anion gap metabolic acidosis. [1] [6]

Uses

The sodium salt of pyroglutamic acid—known either as sodium pyroglutamate, sodium PCA, or sodium pidolate—is used for dry skin and hair products, as it is a humectant. It has low toxicity and is not a skin irritant, but its use in products is limited by a high price. [7] [8]

L-pyroglutamic acid is sold online as a nootropic dietary supplement. [9] [10]

Magnesium pidolate, the magnesium salt of pyroglutamic acid, is found in some mineral supplements. In a preclinical study, additional pharmacological properties of pyroglutamic acid were revealed such as anti-phosphodiesterase type 5, anti-angiotensin-converting enzyme, and anti-urease activities. [11]

Related Research Articles

<span class="mw-page-title-main">Aspartic acid</span> Amino acid

Aspartic acid, is an α-amino acid that is used in the biosynthesis of proteins. The L-isomer of aspartic acid is one of the 22 proteinogenic amino acids, i.e., the building blocks of proteins. D-aspartic acid is one of two D-amino acids commonly found in mammals. Apart from a few rare exceptions, D-aspartic acid is not used for protein synthesis but is incorporated into some peptides and plays a role as a neurotransmitter/neuromodulator.

<span class="mw-page-title-main">Glutamic acid</span> Amino acid and neurotransmitter

Glutamic acid 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 synthesize enough for its use. It is also the most abundant excitatory neurotransmitter in the vertebrate nervous system. It serves as the precursor for the synthesis of the inhibitory gamma-aminobutyric acid (GABA) in GABAergic neurons.

<span class="mw-page-title-main">Glutamine</span> Chemical compound

Glutamine 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, polar amino acid. It is non-essential and conditionally essential in humans, meaning the body can usually synthesize sufficient amounts of it, but in some instances of stress, the body's demand for glutamine increases, and glutamine must be obtained from the diet. It is encoded by the codons CAA and CAG. It is named after glutamic acid, which in turn is named after its discovery in cereal proteins, gluten.

<span class="mw-page-title-main">Transferase</span> Class of enzymes which transfer functional groups between molecules

In biochemistry, a transferase is any one of a class of enzymes that catalyse the transfer of specific functional groups from one molecule to another. They are involved in hundreds of different biochemical pathways throughout biology, and are integral to some of life's most important processes.

<span class="mw-page-title-main">Guanosine monophosphate</span> Chemical compound

Guanosine monophosphate (GMP), also known as 5′-guanidylic acid or guanylic acid, is a nucleotide that is used as a monomer in RNA. It is an ester of phosphoric acid with the nucleoside guanosine. GMP consists of the phosphate group, the pentose sugar ribose, and the nucleobase guanine; hence it is a ribonucleoside monophosphate. Guanosine monophosphate is commercially produced by microbial fermentation.

<span class="mw-page-title-main">Glutamine synthetase</span> Class of enzymes

Glutamine synthetase (GS) is an enzyme that plays an essential role in the metabolism of nitrogen by catalyzing the condensation of glutamate and ammonia to form glutamine:

<span class="mw-page-title-main">Deamidation</span>

Deamidation is a chemical reaction in which an amide functional group in the side chain of the amino acids asparagine or glutamine is removed or converted to another functional group. Typically, asparagine is converted to aspartic acid or isoaspartic acid. Glutamine is converted to glutamic acid or pyroglutamic acid (5-oxoproline). In a protein or peptide, these reactions are important because they may alter its structure, stability or function and may lead to protein degradation. The net chemical change is the addition of a water group and removal of an ammonia group, which corresponds to a +1 (0.98402) Da mass increase. Although deamidation occurs on glutamine, glycosylated asparagine and other amides, these are negligible under typical proteolysis conditions.

<span class="mw-page-title-main">Isopeptide bond</span> Type of chemical bond between 2 amino acids

An isopeptide bond is a type of amide bond formed between a carboxyl group of one amino acid and an amino group of another. An isopeptide bond is the linkage between the side chain amino or carboxyl group of one amino acid to the α-carboxyl, α-amino group, or the side chain of another amino acid. In a typical peptide bond, also known as eupeptide bond, the amide bond always forms between the α-carboxyl group of one amino acid and the α-amino group of the second amino acid. Isopeptide bonds are rarer than regular peptide bonds. Isopeptide bonds lead to branching in the primary sequence of a protein. Proteins formed from normal peptide bonds typically have a linear primary sequence.

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. Glutathione also plays a role in processing medications and cancer-causing compounds (carcinogens), and building DNA, proteins, and other important cellular components.

<span class="mw-page-title-main">Glutaminase</span>

Glutaminase is an amidohydrolase enzyme that generates glutamate from glutamine. Glutaminase has tissue-specific isoenzymes. Glutaminase has an important role in glial cells.

In enzymology, a 5-oxoprolinase (ATP-hydrolysing) (EC 3.5.2.9) is an enzyme that catalyzes the chemical reaction

In enzymology, a gamma-glutamylcyclotransferase is an enzyme that catalyzes the chemical reaction

In enzymology, a glutaminyl-peptide cyclotransferase (EC 2.3.2.5) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">QARS</span> Protein-coding gene in the species Homo sapiens

Glutaminyl-tRNA synthetase is an enzyme that in humans is encoded by the QARS gene.

Glutaminolysis (glutamine + -lysis) is a series of biochemical reactions by which the amino acid glutamine is lysed to glutamate, aspartate, CO2, pyruvate, lactate, alanine and citrate.

<span class="mw-page-title-main">QPCT</span> Protein-coding gene in the species Homo sapiens

Glutaminyl-peptide cyclotransferase is an enzyme that in humans is encoded by the QPCT gene.

γ-<small>L</small>-Glutamyl-<small>L</small>-cysteine Chemical compound

γ-L-Glutamyl-L-cysteine, also known as γ-glutamylcysteine (GGC), is a dipeptide found in animals, plants, fungi, some bacteria, and archaea. It has a relatively unusual γ-bond between the constituent amino acids, L-glutamic acid and L-cysteine and is a key intermediate in the γ-glutamyl cycle first described by Meister in the 1970s. It is the most immediate precursor to the antioxidant glutathione.

<span class="mw-page-title-main">Purine nucleotide cycle</span>

The Purine Nucleotide Cycle is a metabolic pathway in protein metabolism requiring the amino acids aspartate and glutamate. The cycle is used to regulate the levels of adenine nucleotides, in which ammonia and fumarate are generated. AMP converts into IMP and the byproduct ammonia. IMP converts to S-AMP (adenylosuccinate), which then converts to AMP and the byproduct fumarate. The fumarate goes on to produce ATP (energy) via oxidative phosphorylation as it enters the Krebs cycle and then the electron transport chain. Lowenstein first described this pathway and outlined its importance in processes including amino acid catabolism and regulation of flux through glycolysis and the Krebs cycle.

<span class="mw-page-title-main">Glutamate (neurotransmitter)</span> Anion of glutamic acid in its role as a neurotransmitter

In neuroscience, glutamate is the anion of glutamic acid in its role as a neurotransmitter. It is by a wide margin the most abundant excitatory neurotransmitter in the vertebrate nervous system. It is used by every major excitatory function in the vertebrate brain, accounting in total for well over 90% of the synaptic connections in the human brain. It also serves as the primary neurotransmitter for some localized brain regions, such as cerebellum granule cells.

References

  1. 1 2 3 4 Kumar, Akhilesh; Bachhawat, Anand K. (2012). "Pyroglutamic acid: throwing light on a lightly studied metabolite" (PDF). Current Science. 102 (2): 288–297. JSTOR   24083854.
  2. Schilling, Stephan; Wasternack, Claus; Demuth, Hans-Ulrich (1 August 2008). "Glutaminyl cyclases from animals and plants: a case of functionally convergent protein evolution". Biological Chemistry. 389 (8): 983–91. doi:10.1515/BC.2008.111. PMID   18979624. S2CID   24074284.
  3. Podell, David N.; Abraham, George N. (March 1978). "A technique for the removal of pyroglutamic acid from the amino terminus of proteins using calf liver pyroglutamate amino peptidase". Biochemical and Biophysical Research Communications. 81 (1): 176–185. doi:10.1016/0006-291X(78)91646-7. PMID   26343.
  4. Pepeu, Giancarlo; Spignoli, Giacomo (January 1989). "Nootropic drugs and brain cholinergic mechanisms". Progress in Neuro-Psychopharmacology and Biological Psychiatry. 13: S77–S88. doi:10.1016/0278-5846(89)90112-7. PMID   2694231. S2CID   11309268.
  5. Jawhar, Sadim; Wirths, Oliver; Bayer, Thomas A. (11 November 2011). "Pyroglutamate Amyloid-β (Aβ): A Hatchet Man in Alzheimer Disease". Journal of Biological Chemistry. 286 (45): 38825–38832. doi: 10.1074/jbc.R111.288308 . PMC   3234707 . PMID   21965666.
  6. Liss, D. B.; Paden, M. S.; Schwarz, E. S.; Mullins, M. E. (11 October 2013). "What is the clinical significance of 5-oxoproline (pyroglutamic acid) in high anion gap metabolic acidosis following paracetamol (acetaminophen) exposure?". Clinical Toxicology. 51 (9): 817–827. doi:10.3109/15563650.2013.844822. PMID   24111553. S2CID   43541851.
  7. "Hydromol® (Alliance)". British National Formulary. Retrieved December 5, 2015.
  8. Jungermann, Eric; Sonntag, Norman O.V (1991-07-19). "Alternatives to Glycerine". In Eric Jungermann; Norman O.V. Sonnta (eds.). Glycerine: A Key Cosmetic Ingredient. CRC Press. p. 424. ISBN   978-0-8247-8465-2.
  9. DellaVecchia, Matthew J. (December 2013). "Inaccurate Serelaxin Chemical Structure". Pharmacy and Therapeutics. 38 (12): 763. PMC   3875272 . PMID   24391398.
  10. McDougall, Graham J.; Austin-Wells, Vonnette; Zimmerman, Teena (24 June 2016). "Utility of Nutraceutical Products Marketed for Cognitive and Memory Enhancement". Journal of Holistic Nursing. 23 (4): 415–433. doi:10.1177/0898010105280097. PMC   2398696 . PMID   16251490.
  11. Šudomová, Miroslava; Hassan, Sherif T. S.; Khan, Haroon; Rasekhian, Mahsa; Nabavi, Seyed Mohammad (21 August 2019). "A Multi-Biochemical and In Silico Study on Anti-Enzymatic Actions of Pyroglutamic Acid against PDE-5, ACE, and Urease Using Various Analytical Techniques: Unexplored Pharmacological Properties and Cytotoxicity Evaluation". Biomolecules. 9 (9): 392. doi: 10.3390/biom9090392 . PMC   6770154 . PMID   31438631.