"Heard melodies are sweet,
those unheard are sweeter"
- John Keats
- John Keats
Pyroglutamic acid (5-oxoproline) is an intermediate metabolite of gamma glutamyl cycle. Gamma glutamyl cycle is responsible for glutathione synthesis and degradation.
Glutathione (gamma glutamyl cysteinyl glycine-GSH) is an antioxidant
substance, involved in many biological function, including inactivation of free
radicals.
Glutathione is synthesized by glutamate, glycine and cysteine.
Glutamate and cysteine is converted to gamma glutamyl
cysteine, by gamma glutamyl cysteine synthetase (GCS), which then reacts with
glycine, in the presence of glutathione synthetase, to produce glutathione.
Glutathione is degraded by gamma glutamyl transpeptidase (GGT)
and gamma glutamyl cyclotransferase to pyroglutamic acid (5-oxoproline).
Pyroglutamic acid (5-oxoproline) is catalyzed by
5-oxoprolinase to glutamate, which enters into gamma glutamyl cycle.
Glutathione synthesis is kept under control by, negative
feedback of glutathione, over gamma glutamyl cysteine synthetase (GCS). In
other words glutathione inhibits gamma glutamyl cysteine synthetase.
Second mechanism of this control is, that excess gamma
glutamyl cysteine is converted into pyroglutamic acid (5-oxoproline), by gamma
glutamyl cyclotransferase.
PATHOPHYSIOLOGY: Glutathione deficiency, leads to
disinhibition of gamma glutamylcysteine synthase (GCS). This results in unchecked
production of gamma glutamyl cysteine, which is further converted into
pyroglutamic acid (5-oxoproline).
Some of the pyroglutamic acid is catalyzed into glutathione.
But persistently disinhibited gamma glutamyl cysteine synthetase, by deficient
glutathione, results in accumulation of pyroglutamic acid, producing high
anionic gap metabolic acidosis.
Glycine deficiency may also results in excess gamma glutamyl
cysteine, and excess production and accumulation of pyroglutamic acid.
Genetic enzyme deficiency or acquired enzymatic inhibition,
may also cause excess pyroglutamic acid production and accumulation.
Glutathione deficiency is seen in chronic paracetamol abuse,
chronic ethanol abuse, malnutrition, pregnancy, hepatic and renal impairment,
sepsis and vigabatrin toxicity.
Flucloxacillin and netilmycin inhibit enzyme 5-oxoprolinase.
DIAGNOSIS: Pyroglutamic acidosis should be suspected if
other causes of HAG metabolic acidosis is ruled out, and established by high serum
or urine 5-oxoproline level.
5-oxoproline level is not readily available, therefore PYROGLUTAMIC acidosis should be suspected in a patient with no explainable cause for HAG metabolic acidosis, and conditions predisposing to glutathione deficiency.
MANAGEMENT: 5-oxoproline is water soluble. IV fluid and diuresis leads
to rapid resolution in 24-48 hours.
Removal of causative agents like drugs, or correction of
causative factor like sepsis, malnutrition and glutathione repletion (N acetyl
cysteine), is the cornerstone of therapy.
Gamma Glutamyl Cycle |
Comments
Post a Comment