In the present study we investigated the effects of L-
pyroglutamic acid (
PGA), which predominantly accumulates in the inherited
metabolic diseases glutathione synthetase deficiency (GSD) and
gamma-glutamylcysteine synthetase deficiency (GCSD), on some in vitro parameters of energy metabolism and
lipid biosynthesis. We evaluated the rates of CO2 production and
lipid synthesis from [U-14C]
acetate, as well as
ATP levels and the activities of
creatine kinase and of the respiratory chain complexes I-IV in cerebral cortex of young rats in the presence of
PGA at final concentrations ranging from 0.5 to 3 mM.
PGA significantly reduced brain CO2 production by 50% at the concentrations of 0.5 to 3 mM,
lipid biosynthesis by 20% at concentrations of 0.5 to 3 mM and
ATP levels by 52% at the concentration of 3 mM. Regarding the
enzyme activities,
PGA significantly decreased
NADH:
cytochrome c oxireductase (complex I plus CoQ plus
complex III) by 40% at concentrations of 0.5-3.0 mM and
cytochrome c oxidase activity by 22-30% at the concentration of 3.0 mM, without affecting the activities of
succinate dehydrogenase,
succinate:DCPIP oxireductase (complex II),
succinate:
cytochrome c oxireductase (complex II plus CoQ plus
complex III) or
creatine kinase. The results strongly indicate that
PGA impairs brain energy production. If these effects also occur in humans, it is possible that they may contribute to the neuropathology of patients affected by these diseases.