Cystinosis is a metabolic disturb associated with excessive lysosomal
cystine accumulation secondary to defective
cystine efflux. Patients affected by this disease develop a variable degree of symptoms depending of the involved tissues. Accumulation of
cystine in the brain may lead to severe neurological symptoms. However, the mechanisms by which
cystine is neurotoxic are not fully understood. Considering that
pyruvate kinase (PK) is a thiolic
enzyme crucial for the glycolytic pathway, and
disulfides like
cystine may alter thiolic
enzymes by
thiol/
disulfide exchange, the main objective of the present study was to investigate the effect of
cystine on PK activity in the brain cortex of developing Wistar rats. We also performed kinetic studies and investigated the effects of GSH, a biologically occurring
thiol groups protector, and
cysteamine (CysN), the drug used for
cystinosis treatment, on the
enzyme activity. We observed that
cystine inhibited the
enzyme activity by two different mechanisms, one through the competition with
ADP and
phosphoenolpyruvate (PEP), and the other non-competitively, probably through oxidation of the
thiol groups of PK. We also observed that GSH and
cysteamine fully prevented and reversed the inhibition caused by
cystine. Considering that
cysteamine is used in patients with
cystinosis because it causes parenkimal organ
cystine depletion, the present data provides a possible new beneficial effect for the use of this drug.