title: Kinetic studies on the inhibition of creatine kinase activity by branched-chain alpha-amino acids in the brain cortex of rats.
abstract: Maple syrup urine disease (MSUD) is a metabolic disorder biochemically characterized by the accumulation of branched-chain alpha-amino acids (BCAA) and their branched-chain alpha-keto acids (BCKA) in blood and tissues. Neurological dysfunction is usually present in the patients, but the mechanisms of brain damage in this disease are far from be understood. The main objective of this study was to investigate the mechanisms by which BCAA inhibit creatine kinase activity, a key enzyme of energy homeostasis, in the brain cortex of 21-day-old Wistar rats. For the kinetic studies, Lineweaver-Burk and a modification of the Chevillard et al. plots were used to characterize the mechanisms of enzyme inhibition. The results indicated that BCAA inhibit creatine kinase by competition with the substrates phosphocreatine and ADP at the active site. Considering the crucial role creatine kinase plays in energy homeostasis in brain, if these effects also occur in the brain of MSUD patients, it is possible that inhibition of this enzyme activity may contribute to the brain damage found in this disease. In this case, it is possible that creatine supplementation to the diet might benefit MSUD patients.
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, UFRGS, Rua Ramiro Barcelos 2600, CEP 90.035-003 Porto Alegre, RS, Brazil.
authors.forename: Carmen
authors.initials: C
authors.lastname: Pilla
authors.forename: Rui Felipe de Oliveira
authors.initials: RF
authors.lastname: Cardozo
authors.forename: Paula Karine Barcelos
authors.initials: PK
authors.lastname: Dornelles
authors.forename: Carlos Severo
authors.initials: CS
authors.lastname: Dutra-Filho
authors.forename: Angela Terezinha de Souza
authors.initials: AT
authors.lastname: Wyse
authors.forename: Moacir
authors.initials: M
authors.lastname: Wajner
authors.forename: Clóvis Milton Duval
authors.initials: CM
authors.lastname: Wannmacher
mesh_terms: D000596:Amino Acids / Q000737:chemistry / Q000494:pharmacology*; D000597:Amino Acids, Branched-Chain / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D002540:Cerebral Cortex; D003402:Creatine Kinase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D004789:Enzyme Activation; D007532:Isoleucine / Q000737:chemistry / Q000494:pharmacology; D007651:Keto Acids / Q000378:metabolism; D007700:Kinetics; D007930:Leucine / Q000737:chemistry / Q000494:pharmacology; D008375:Maple Syrup Urine Disease / Q000201:enzymology* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012016:Reference Values; D014633:Valine / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000596:Amino Acids; D000597:Amino Acids, Branched-Chain; D007651:Keto Acids; D007532:Isoleucine; D003402:Creatine Kinase; D007930:Leucine; D014633:Valine