Synaptic plasma membrane Na(+), K (+)-ATPase activity is significantly reduced by the alpha-keto acids accumulating in maple syrup urine disease in rat cerebral cortex.
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(+), K(+)-ATPase activity in synaptic plasma membranes from cerebral cortex of 35-day-old rats. All keto acids significantly inhibited Na(+), K(+)-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(+), K(+)-ATPase activity, but totally prevented the branched-chain alpha-keto acids-induced Na(+), K(+)-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(+) K(+)-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(+), K(+)-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.
Wajner
André
A
Departamento de Bioquímica, Institute de Ciências Básicas da Saúde, UFRGS, Rua Ramiro Barcelos, 2600-Anexo, CEP: 90035-003, Porto Alegre, RS, Brazil.
Bürger
Cristiane
C
Dutra-Filho
Carlos Severo
CS
Wajner
Moacir
M
de Souza Wyse
Angela Terezinha
AT
Wannmacher
Clóvis Milton Duval
CM
D000409:Alanine / Q000494:pharmacology; D000818:Animals; D002462:Cell Membrane / Q000201:enzymology; D002540:Cerebral Cortex / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D045782:Hemiterpenes; D007651:Keto Acids / Q000378:metabolism*; D008375:Maple Syrup Urine Disease / Q000378:metabolism*; D010649:Phenylalanine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D013569:Synapses / Q000201:enzymology*
D045782:Hemiterpenes; D007651:Keto Acids; C016211:alpha-keto-beta-methylvaleric acid; D010649:Phenylalanine; C001505:alpha-ketoisovalerate; C013082:alpha-ketoisocaproic acid; D000254:Sodium-Potassium-Exchanging ATPase; D000409:Alanine