title: Inhibition of creatine kinase activity in vitro by ethylmalonic acid in cerebral cortex of young rats.
abstract: Short-chain acyl-CoA dehydrogenase deficiency is an inherited metabolic disorder biochemically characterized by tissue accumulation of ethylmalonic (EMA) and methylsuccinic (MSA) acids and clinically by severe neurological symptoms. In the present study we investigated the in vitro effects of EMA and MSA on the activity of creatine kinase (CK) in homogenates from cerebral cortex, skeletal and cardiac muscle of rats. EMA significantly inhibited CK activity from cerebral cortex, but did not affect this activity in skeletal and cardiac muscle. Furthermore, MSA had no effect on this enzyme in all tested tissues. Glutathione (GSH), ascorbic acid and alpha-tocopherol, and the nitric oxide synthase inhibitor L-NAME, did not affect the enzyme activity per se, but GSH fully prevented the inhibitory effect of EMA when co-incubated with EMA. In contrast, alpha-tocopherol, ascorbic acid and L-NAME did not influence the inhibitory effect of the acid. The data suggest that inhibition of brain CK activity by EMA is possibly mediated by oxidation of essential groups of the enzyme, which are protected by the potent intracellular, endogenous, naturally occurring antioxidant GSH.
authors.affiliation: Laboratório de Erros Inatos do Metabolismo, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, UFRGS, Porto Alegre, RS, Brazil.
authors.forename: Patrícia F
authors.initials: PF
authors.lastname: Schuck
authors.forename: Guilhian
authors.initials: G
authors.lastname: Leipnitz
authors.forename: César A J
authors.initials: CA
authors.lastname: Ribeiro
authors.forename: Karina B
authors.initials: KB
authors.lastname: Dalcin
authors.forename: Dênis R
authors.initials: DR
authors.lastname: Assis
authors.forename: Alethea G
authors.initials: AG
authors.lastname: Barschak
authors.forename: Vânia
authors.initials: V
authors.lastname: Pulrolnik
authors.forename: Clóvis M D
authors.initials: CM
authors.lastname: Wannmacher
authors.forename: Angela T S
authors.initials: AT
authors.lastname: Wyse
authors.forename: Moacir
authors.initials: M
authors.lastname: Wajner
mesh_terms: D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects* / Q000201:enzymology; D003402:Creatine Kinase / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005978:Glutathione / Q000494:pharmacology; D066298:In Vitro Techniques; D008314:Malonates / Q000494:pharmacology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D051381:Rats; D017208:Rats, Wistar; D024502:alpha-Tocopherol / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D008314:Malonates; C038080:ethylmalonic acid; D019001:Nitric Oxide Synthase; D003402:Creatine Kinase; D005978:Glutathione; D024502:alpha-Tocopherol; D001205:Ascorbic Acid; D019331:NG-Nitroarginine Methyl Ester