Inhibition of creatine kinase activity by lysine in rat cerebral cortex

Accumulation of lysine (Lys) in tissues and biochemical fluids is the biochemical hallmark of patients affected by familial hyperlysinemia (FH) and also by other inherited neurometabolic disorders. In the present study, we investigated the in vitro effect of Lys on various parameters of energy metabolism in cerebral cortex of 30-day-old Wistar rats. We verified that total (tCK) and cytosolic creatine kinase activities were significantly inhibited by Lys, in contrast to the mitochondrial isoform which was not affected by this amino acid. Furthermore, the inhibitory effect of Lys on tCK activity was totally prevented by reduced glutathione, suggesting a possible role of reactive species oxidizing critical thiol groups of the enzyme. In contrast, Lys did not affect (14)CO(2) production from [U-(14)C] glucose (aerobic glycolytic pathway) and [1-(14)C] acetic acid (citric acid cycle activity) neither the various activities of the electron transfer chain and synaptic Na(+)K(+)-ATPase at concentrations as high as 5.0 mM. Considering the importance of creatine kinase (CK) activity for brain energy metabolism homeostasis and especially ATP transfer and buffering, our results suggest that inhibition of this enzyme by Lys may contribute to the neurological signs presented by symptomatic patients affected by FH and other neurodegenerative disorders in which Lys accumulates.