title: Cysteamine prevents and reverses the inhibition of pyruvate kinase activity caused by cystine in rat heart.
abstract: Cystinosis is a disorder associated with excessive lysosomal cystine accumulation secondary to defective cystine efflux. Patients affected by this disease develop a variable degree of symptoms depending on the involved tissues. Accumulation of cystine in myocardium may lead to heart failure. However, the mechanisms by which cystine is toxic to the tissues are not fully understood. Considering that thiolic enzymes like pyruvate kinase (PK) may be altered by disulfides like cystine, the main objective of the present study was to investigate the effect of cystine on PK activity in the heart of developing rats. We performed kinetic studies and investigated the effects of reduced glutathione (GSH), a biologically occurring thiol groups protector, and cysteamine, the drug used for cystinosis treatment, on the enzyme activity. We observed that cystine inhibited the enzyme activity non-competitively in a dose- and time-dependent way. We also observed that GSH and cysteamine fully prevented and reversed the inhibition caused by cystine, suggesting that cystine inhibits PK activity by oxidation of the sulfhydryl groups of the enzyme. Although there is no definite proof of cystine within cytoplasm, there is indirect proof t it is able to escape lysosomes and come in contact with PK. Considering that cysteamine is used in patients with cystinosis because it causes parenchymal organ cystine depletion, the present data provide a possible new effect for this drug.
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, UFRGS, Rua Ramiro Barcelos 2600-Anexo, CEP 90.035-003, Porto Alegre, RS, Brazil.
authors.forename: Tatiana Galetto
authors.initials: TG
authors.lastname: Rosa
authors.forename: Angela Terezinha
authors.initials: AT
authors.lastname: de Souza Wyse
authors.forename: Moacir
authors.initials: M
authors.lastname: Wajner
authors.forename: Clóvis Milton Duval
authors.initials: CM
authors.lastname: Wannmacher
mesh_terms: D000818:Animals; D003543:Cysteamine / Q000008:administration & dosage*; D003553:Cystine / Q000494:pharmacology*; D003554:Cystinosis / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D006321:Heart / Q000187:drug effects; D009206:Myocardium / Q000201:enzymology*; D009924:Organ Culture Techniques; D011770:Pyruvate Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D003553:Cystine; D003543:Cysteamine; D011770:Pyruvate Kinase