Article

Inhibition of creatine kinase activity by lysine in rat cerebral cortex

Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS Brazil; Universidade luterana do Brasil, Canoas, RS Brazil
Metabolic Brain Disease (Impact Factor: 2.33). 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.

0 Bookmarks
 · 
87 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Infantile spasms (IS) are an age-dependent epileptic encephalopathy with severe cognitive dysfunction. Prenatal stress (PS) has been reported to increase the risk for IS through clinical and animal studies. We aim to investigate the mechanism of brain damage caused by IS and the effect of PS. Animals were divided into 4 groups: PS-spasm model, PS-saline control, NS-spasm model, and saline control. N-methyl-d-aspartate (NMDA) was used to induce spasm and swimming in cold water was used to induce PS. A proteomics-based approach was used to compare the NS-spasm model vs. saline control, and PS-spasm model vs. NS-spasm model. Gel image analysis was followed by mass spectrometric protein identification and bioinformatics analysis. We observed an increased spasm frequency (t = 8.65, P < 0.001), and a shorter latency period (t = 3.96, P < 0.001) in the PS-spasm model vs. the NS-spasm model. In the NS-spasm model vs. saline control, the main differentially expressed proteins were CFL1, PKM2, PRPS2, DLAT, CKB, DPYSL3, and SNAP25. In the PS-spasm model vs. NS-spasm model, MDH1 and YWHAZ were differentially expressed. YWHAZ was directly connected with CFL1 in protein networks. YWHAZ and CFL1 were further validated by western blot analysis. The biological function of differentially expressed proteins indicate the pathogenesis of IS maybe relevant to energy metabolism, brain development, and neural remodeling. PS aggravated seizures in the NMDA-induced spasm model, YWHAZ, and CFL1 may be involved.
    Epilepsy Research. 01/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Phenylketonuria (PKU) is the most frequent inborn error of metabolism. It is caused by deficiency in the activity of phenylalanine hydroxylase, leading to accumulation of phenylalanine and its metabolites. Untreated maternal PKU or hyperphenylalaninemia may result in nonphenylketonuric offspring with low birth weight and neonatal sequelae, especially microcephaly and intellectual disability. The mechanisms underlying the neuropathology of brain injury in maternal PKU syndrome are poorly understood. In the present study, we evaluated the possible preventive effect of the co-administration of creatine plus pyruvate on the effects elicited by phenylalanine administration to female Wistar rats during pregnancy and lactation on some enzymes involved in the phosphoryltransfer network in the brain cortex and hippocampus of the offspring at 21 days of age. Phenylalanine administration provoked diminution of body, brain cortex an hippocampus weight and decrease of adenylate kinase, mitochondrial and cytosolic creatine kinase activities. Co-administration of creatine plus pyruvate was effective in the prevention of those alterations provoked by phenylalanine, suggesting that altered energy metabolism may be important in the pathophysiology of maternal PKU. If these alterations also occur in maternal PKU, it is possible that pyruvate and creatine supplementation to the phenylalanine-restricted diet might be beneficial to phenylketonuric mothers.
    Neurochemical Research 06/2014; · 2.13 Impact Factor
  • [Show abstract] [Hide abstract]
    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.
    Neurochemical Research 10/2010; 36(2):205-14. · 2.13 Impact Factor