Synaptic Plasma Membrane Na super(+), K super(+)-ATPase Activity is Significantly Reduced by the alpha -Keto Acids Accumulating in Maple Syrup Urine Disease in Rat Cerebral Cortex

• Published in: Metabolic brain disease Vol. 22; no. 1; pp. 77 - 88
• Main Authors: Wajner, Andre, Buerger, Cristiane, Dutra-Filho, Carlos Severo, Wajner, Moacir, de Souza Wyse, Angela Terezinha, Wannmacher, Clovis Milton Duval
• Format: Journal Article
• Language: English
• Published: 01.03.2007
• ISSN: 0885-7490
• DOI: 10.1007/s11011-007-9046-5

The objective of the present study was to investigate the in vitro effects of the branched-chain alpha -keto acids accumulating in maple syrup urine disease, namely L-2-ketoisocaproic acid, L-2-keto-3-methylvaleric acid and L-2-ketoisovaleric acid on Na super(+), K super(+)-ATPase activity in synaptic plasma membranes from cerebral cortex of 35-day-old rats. All keto acids significantly inhibited Na super(+), K super(+)-ATPase activity at concentrations similar (1 mM) or even lower (0.5 mM) than those found in blood and cerebrospinal fluid of maple syrup urine disease patients. We also tested the effects of alanine on this enzyme activity. Alanine per se did not alter Na super(+), K super(+)-ATPase activity, but totally prevented the branched-chain alpha -keto acids-induced Na super(+), K super(+)-ATPase inhibition, indicating that alanine and the keto acids may possibly bind to the same site on the enzyme. We also observed that the branched-chain amino acids leucine, isoleucine and valine also inhibited Na super(+) K super(+)-ATPase activity to a similar degree as that of the branched-chain alpha -keto acids and that alanine was able to fully prevent these effects. Considering that Na super(+), K super(+)-ATPase is a critical enzyme for normal brain development and functioning, it is presumed that these findings may be involved in the pathophysiology of the neurological dysfunction of maple syrup urine disease.