Pyroglutamát - Pyroglutamová kyselina

Synonyma

• Pyroglutamic acid
• 5-oxoproline
• pidolic acid
• pyroglutamate
• (S)-(-)-2-Pyrrolidone-5-carboxylic acid
• (S)-5-Oxo-2-pyrrolidinecarboxylic acid
• 5-Oxo-2-pyrrolidinecarboxylate
• 2-oxo-pyrrolidone carboxylic acid
• PCA
• C5H7NO3
• 5-oxo-L-proline
• Glutiminate
• Pidolidone
• Glutimate
• H-Pyr-OH

Význam

• Cyclic lactam of glutamic acid [17]
• Intermediate of the gamma-glutamyl cycle of glutathione synthesis and degradation [4]
• Role as an analogue or reservoir of glutamate [16]
• Possible role in osmoprotection [16]
• As an N-terminal modification in many neuronal peptides and hormones [16]
• Include the accumulating peptides in Alzheimer’s disease and familial dementia [16]
• Amyloid beta (Aß) peptide containing N-terminal pGlu is the major peptide in amyloid plaques [16]
• Glutaminyl cyclase enzyme largely responsible for the pGlu generation upregulated in cortices of individuals with Alzheimer’s disease [16]
• Inhibition of glutaminyl cyclase by inhibitors in a mouse model led to decreased level of pGlu-modified Aß peptides and also attenuated Alzheimer’s disease [16]
• Modification is also observed in proteins that include many antibodies, some enzymes and structural proteins [16]
• Post-translational event resulting from conversion of N-terminal glutamate and glutamine into pyroglutamic acid by the action of glutaminyl cyclase [16]
• The pGlu moiety provides
• proteins resistance from degradation by amino peptidases [16]
• Structural proteins
• Fibrin
• Fibrinogen
• Collagen-like proteins [16]
• Important determinant of the functionality of many neuropeptides [16]
• Thyrotropin releasing hormone (TRH)
• Gastrin
• Neuropeptide neurotensin
• Human chemokines MCP1–MCP4 [16]
• Formation of pGlu in antibodies and therapeutic proteins is a major irritant in the biotech industry [16]
• Inhibition of 5-oxoprolinase and ?-glutamyl transpeptidase, enzymes that liberate glutamate from glutathione, leads to decrease in glutamate in neuronal cells [16]
• Osmoprotectant in some microbial cells [16]

Reakce

Vznik

• By gamma-glutamyl cyclotransferase from glutathione in living tissues [16]
• At 180°C glutamate is converted into pyroglutamate by losing a molecule of water [16]
• Spontaneous formation from glutamine and glutamate [16]
• Phosphorylated activated glutamate is highly unstable and is transferred to an acceptor molecule
• Cysteine, ammonia and NADPH [16]
• Spontaneous cyclization into pyroglutamic acid if the acceptor molecule is not present or unavailable [16]
• N-terminal glutamic acid and glutamine residues can spontaneously cyclize to become pyroglutamate. [1]
• 
• 
• The cleavage of N-terminal pyroglutamic acid generates 5-oxoproline [16]

Využití a degradace

• 5-oxoproline + ATP + 2 H2O = L-glutamate + phosphate + ADP [13]

• 5-oxoprolinase = pyroglutamic acid-cleaving enzyme na glutamát
• ATP-dependent enzyme [16]

Stanovení

Moč

• OK
• pyroglutamic acid levels vary from 0.5 to 5 mg/day in excretion
• In diseased conditions
• Increases up to 50 g/day

Nadbytek

Pyroglutamic acidemia

• Causing clinically significant acidosis [2]
• Cause of high anion gap metabolic acidosis [2]
• Abolition of feedback inhibition of gamma glutamylcysteine synthetase
• Increased production of gamma glutamylcysteine [3]
• Converted to pyroglutamic acid
• Associated with glutathione depletion [3]
• Abnormalities of alpha-hydroxybutyrate, pyroglutamate, and sulfate can indicate
• Up-regulated glutathione biosynthesis
• Impaired reformation of glutathione in the gamma-glutamyl cycle
• Depleted total body glutathione status [11]
• Need additional information about the methionine status of the system to relate them uniquely to intracellular glutathione concentration [12]

Sepsis

Hepatic, and/or renal dysfunction

Paracetamol (acetaminophen) [3]

• Glutathione depletion by its metabolite NAPQI [5]
• N-acetylbenzoquinonimine reacts irreversibly with glutathione synthetase
• Precursors accumulate [8]
• N-acetylbenzoquinonimine forms hepatotoxic compounds [8]

Flucloxacillin

• Inhibits 5-oxoprolinase [5]
• May also precipitate acidosis [3]

Vigabatrin [2]

• Inhibition of 5 oxoprolinase [3]

Netilmicin [6]

Congenital pyroglutamic acidosis

• 5-oxoprolinemia
• Pyroglutamic acidemia
• Pyroglutamic aciduria [6]
• Specific enzyme defects
• Glutathione synthetase defic.
• Autossomic recessive inherited disorder
• Hemolytic anemia
• Metabolic acidosis
• Severe neurological symptoms whose mechanisms are poorly known
• Acute administration of 5-oxoproline
• Able to promote both lipid and protein oxidation
• Impair brain antioxidant defenses
• Alter SH/SS ratio
• Enhance hydrogen peroxide content
• Mechanism that may be involved in the neuropathology of gluthatione synthetase deficiency [10]
• 5-oxoprolinase deficiency [8]
• 5-Oxoprolinuria has also been observed in patients of cystinosis. [16]
• Defect in the lysosomal cystine transporter (CTNS) [16]
• Cystine in the lysosome, and leads to renal proximal tubular dysfunction [16]
• Contain almost 60-fold higher levels of pyroglutamic acid in their urine [16]

Malnutrition [5]

Pregnancy [5]

Irritable bowel syndrome

• Gut microflora in patients produces high levels of pyroglutamic acid in addition to a few other metabolites [16]
• Correlated with increased presence of lactobacilli and clostridium [16]

Symptomy

Akutní

• Tachycardia, tachypnoea, altered LOC [5]
• Central nervous system dysfunction [16]
• Hemolytic anaemia [16]
• High anion gap metabolic acidosis (HAGMA)
• Normal osmolar gap
• Normal lactate
• Normal beta-hydroxybutyrate
• High pyroglutamic acid (urine or blood) [5]

Chronické

• Delayed growth
• Developmental delays
• Intellectual Delays
• Pale Skin Color
• Yellow Skin Color (Jaundice)
• Irritability
• Poor appetite
• Sleeping longer or more often
• Breathing trouble
• Trouble regulating body temperature (your baby might get cold easily) [7]

Diagnoza

• Vyloučení jiných častějších příčin metabolické acidózy:“MUDPILES:”
• Methanol
• Uremia
• Diabetic ketoacidosis
• Paraldehyde
• Isoniazid, iron, inborn errors of metabolism
• Lactic acid, Dlactate, which results from short bowel syndrome [5]
• Ethylene glycol
• Salicylates [5] [16]
• Pyruvate, betahydroxybutyrate, acetoacetate, citrate, creatinine, albumin, or amino acids [16]
• Urinary estimation of organic acids will identify pyroglutamic aciduria [16]

Terapie

• N-acetylcysteine to replete glutathione [3] [16]
• Salts of L-2-oxothiazolidine-4-carboxylic acid (OTC) [14]
• Production of L-cysteine in an in vivo system by the action of 5-oxo-L-prolinase in the presence of adenosine triphosphate, for use in increasing the glutathione level [14]
• Studie s terapií catarakty [15]
• Depigmenting or bleaching mammalian skin using L-2-oxothiazolidine-4-carboxylic acid [15]
• 2-methylthiazolidine-2,4-dicarboxylic acid and paracetamol v jednom [15]
• Cessation of known precipitants [16]
• Aggressive management of infection [16]

Degradace

• 5-oxoprolinase
• pyroglutamate aminopeptidase
• Can restore a free N-terminus by cleaving off the pyroglutamate residue [1]

Využití pryglutamátu

Po požití a vliv na CNS

• Pyroglutamic acid is orally active [16]
• Cross the blood–brain barrier [16]
• Accumulates in high concentration in the brain after oral administration [16]
• Prevent scopolamine-induced amnesia in rats [16]
• Improved learning in age-associated and alcohol-induced memory loss [16]
• Can bind glutamate receptors [16]
• Inhibit glutamate uptake by synaptosome and chronic intrastriatal infusion [16]
• Cause severe brain cell loss in adult rat [16]
• Secondary messenger for the regulation of amino acid availability in brain [16]
• By binding to the amino acid efflux pumps of the blood–brain barrier it stimulates them leading to the efflux of amino acids from the brain [16]
• Similar function of pyroglutamic acid has also been found in the placenta and mammary glands [16]

Sodium pidolate

• Used on the skin to retain moisture [1]
• Gamma-GCT, is comparatively high in skin, and it appears that it might function as a natural moisturizer [16]

Pyroglutamic acid

• dietary supplement in the United States [1]
• Bez schálení FDA

Magnesium pidolate

• Prevention of erythrocyte dehydration by specific blockade of the transport pathways promoting loss of potassium (K) by Mg salts [9]
• Potential therapeutic strategy for sickle cell (SS) disease [9]
• Dietary magnesium (Mg) pidolate supplementation over a 4-week period has been shown to:
• Inhibit K-Cl co-transport and reduce dehydration. [9]
• Decrease in the distribution widths for red cell mean cell haemoglobin concentration (MCHC) (haemoglobin distribution width; HDW)
• Decrease in reticulocyte mean cell volume (red cell distribution width of reticulocytes; RDWr)
• Inh. Na/Mg exchanger
• Inh. Ca2+-activated (Gardos) K+ channel
• Incr. red cell K and Mg contents [9]
• Hb levels and absolute reticulocyte counts did not change with Mg therapy [9]
• Median number of painful days in a 6-month period decreased from 15 (range 0-60) to 1 (range 0-18; P < 0.0005) during the period of Mg therapy [9]
• Dietary Mg supplementation improves some of the characteristic cellular function abnormalities of b thalassemia intermedia [10]

Obsah v potravinách

• Thermophilic lactobacilli used as starters in the ripening of Italian cheeses (Grana Padano and Parmigiano Reggiano), cause the accumulation of significant levels of pyroglutamic acid in the cheese (up to 0.5 g/100 g). [16]

Literatura: