Article

Inhibition of creatine kinase activity by lysine in rat cerebral cortex

Universidade luterana do Brasil, Canoas, RS Brazil
Metabolic Brain Disease (Impact Factor: 2.4). 06/2009; 24(2):349-360. DOI: 10.1007/s11011-009-9131-z

ABSTRACT 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 14CO2 production from [U-14C] glucose (aerobic glycolytic pathway) and [1-14C] 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 5.0mM. 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.

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    • "Indeed it is currently unknown whether lysine or lysine-derived metabolites are toxic. In vitro, high concentrations of lysine (5 mM) induced oxidative damage to proteins and lipids, decreased oxidized glutathione and inhibited cytosolic creatine kinase activity [16,17]. Intrastriatal injection of lysine in rats did not affect creatine kinase, but inhibited synaptic Na+,K+-ATPase activity, induced lipid peroxidation and decreased glutathione level [18]. "
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    ABSTRACT: Background Hyperlysinemia is an autosomal recessive inborn error of L-lysine degradation. To date only one causal mutation in the AASS gene encoding α-aminoadipic semialdehyde synthase has been reported. We aimed to better define the genetic basis of hyperlysinemia. Methods We collected the clinical, biochemical and molecular data in a cohort of 8 hyperlysinemia patients with distinct neurological features. Results We found novel causal mutations in AASS in all affected individuals, including 4 missense mutations, 2 deletions and 1 duplication. In two patients originating from one family, the hyperlysinemia was caused by a contiguous gene deletion syndrome affecting AASS and PTPRZ1. Conclusions Hyperlysinemia is caused by mutations in AASS. As hyperlysinemia is generally considered a benign metabolic variant, the more severe neurological disease course in two patients with a contiguous deletion syndrome may be explained by the additional loss of PTPRZ1. Our findings illustrate the importance of detailed biochemical and genetic studies in any hyperlysinemia patient.
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    ABSTRACT: Lysine (Lys) accumulation in tissues and biological fluids is the biochemical hallmark of patients affected by familial hyperlysinemia (FH) and other inherited metabolic disorders. In the present study we investigated the effects of acute administration of Lys on relevant parameters of energy metabolism and oxidative stress in striatum of young rats. We verified that Lys in vivo intrastriatal injection did not change the citric acid cycle function and creatine kinase activity, but, in contrast, significantly inhibited synaptic Na(+),K(+)-ATPase activity in striatum prepared 2 and 12 h after injection. Moreover, Lys induced lipid peroxidation and diminished the concentrations of glutathione 2 h after injection. These effects were prevented by the antioxidant scavengers melatonin and the combination of α-tocopherol and ascorbic acid. Lys also inhibited glutathione peroxidase activity 12 h after injection. Therefore it is assumed that inhibition of synaptic Na(+),K(+)-ATPase and oxidative damage caused by brain Lys accumulation may possibly contribute to the neurological manifestations of FH and other neurometabolic conditions with high concentrations of this amino acid.
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    ABSTRACT: Pristanic acid (Prist) accumulates in some peroxisomal disorders characterized by neurologic dysfunction and brain abnormalities. The present work investigated the in vitro effects of Prist on important parameters of energy metabolism in brain cortex of young rats. CO(2) production from labeled acetate and the activities of the respiratory chain complexes I-IV, creatine kinase and synaptic Na(+), K(+)-ATPase were measured. Prist decreased CO(2) production and the activities of complexes I, II and II-III. Prist also reduced Na(+), K(+)-ATPase activity, but did not affect the activity of creatine kinase. Considering the importance of the citric acid cycle and the electron flow through the respiratory chain for brain energy production and of Na(+), K(+)-ATPase for the maintenance of membrane potential, the present data indicate that Prist compromises brain bioenergetics and neurotransmission. It is presumed that these pathomechanisms may be involved in the neurological damage found in patients affected by disorders in which Prist accumulates.
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