Inhibition of Na+, K+-ATPase activity by the metabolites accumulating in homocystinuria.
Homocystinuria is an inborn error of sulfur amino acid metabolism characterized predominantly by vascular and nervous system dysfunction. In this study we determined the in vitro effects of homocysteine and methionine, metabolites which accumulate in homocystinuria, on Na+, K+-ATPase, and Mg2+-ATPase activities in synaptic membranes from the hippocampus of rats. The results showed that both metabolites significantly inhibit Na+, K+-ATPase but not Mg2+-ATPase activity at concentrations usually observed in plasma of homocystinuric patients. Furthermore, incubation of hippocampal homogenates with homocysteine also elicited an inhibition of the enzyme activity which was however prevented by the simultaneous addition of cysteine to the medium. In addition, cysteine or methionine per se did not modify the two enzymatic activities. These findings indicate that oxidation of critical groups in the enzyme may possibly be involved in homocysteine inhibitory effect. Moreover, kinetic studies performed to investigate the interaction between homocysteine and methionine on Na+, K+-ATPase inhibition suggested a common site for the two amino acids in the enzyme. Considering the critical role exerted by Na+, K+-ATPase in brain, it is proposed that the inhibition provoked by homocysteine and methionine on the enzyme activity may be possibly related to the brain dysfunction characteristic of homocystinuria.
Streck
Emilio L
EL
Departamento de Bioquímica, Instituto de Ciências Básicas de Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Zugno
Alexandra I
AI
Tagliari
Barbara
B
Wannmacher
Clovis
C
Wajner
Moacir
M
Wyse
Angela T S
AT
D000818:Animals; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology*; D006710:Homocysteine / Q000378:metabolism* / Q000494:pharmacology; D006712:Homocystinuria / Q000201:enzymology* / Q000503:physiopathology; D008715:Methionine / Q000378:metabolism* / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D051381:Rats; D017208:Rats, Wistar; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013347:Subcellular Fractions; D013570:Synaptic Membranes / Q000187:drug effects / Q000201:enzymology*
D004791:Enzyme Inhibitors; D006710:Homocysteine; D008715:Methionine; D000254:Sodium-Potassium-Exchanging ATPase