title: Cysteamine prevents and reverses the inhibition of creatine kinase activity caused by cystine in rat brain cortex.
abstract: Cystinosis is a disorder associated with lysosomal cystine accumulation caused by defective cystine efflux. Cystine accumulation provokes a variable degree of symptoms depending on the involved tissues. Adult patients may present brain cortical atrophy. However, the mechanisms by which cystine is toxic to the tissues are not fully understood. Considering that brain damage may be developed by energy deficiency, creatine kinase is a thiolic enzyme crucial for energy homeostasis, and disulfides like cystine may alter thiolic enzymes by thiol/disulfide exchange, the main objective of the present study was to investigate the effect of cystine on creatine kinase activity in total homogenate, cytosolic and mitochondrial fractions of the brain cortex from 21-day-old Wistar rats. We performed kinetic studies and investigated the effects of GSH, a biologically occurring thiol group protector, and cysteamine, the drug used for cystinosis treatment, to better understand the effect of cystine on creatine kinase activity. Results showed that cystine inhibited the enzyme activity non-competitively in a dose- and time-dependent way. GSH partially prevented and reversed CK inhibition caused by cystine and cysteamine fully prevented and reversed this inhibition, suggesting that cystine inhibits creatine kinase activity by interaction with the sulfhydryl groups of the enzyme. Considering that creatine kinase is a crucial enzyme for brain cortex energy homeostasis, these results provide a possible mechanism for cystine toxicity and also a new possible beneficial effect for the use of cysteamine in cystinotic patients.
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos 2600 - Anexo, CEP 90.035-003 Porto Alegre, RS, Brazil.
authors.forename: Rochele M Müller
authors.initials: RM
authors.lastname: Fleck
authors.forename: Valnes
authors.initials: V
authors.lastname: Rodrigues Junior
authors.forename: Juliana
authors.initials: J
authors.lastname: Giacomazzi
authors.forename: Daiana
authors.initials: D
authors.lastname: Parissoto
authors.forename: Carlos Severo
authors.initials: CS
authors.lastname: Dutra-Filho
authors.forename: Angela Terezinha
authors.initials: AT
authors.lastname: de Souza Wyse
authors.forename: Moacir
authors.initials: M
authors.lastname: Wajner
authors.forename: Clovis Milton Duval
authors.initials: CM
authors.lastname: Wannmacher
mesh_terms: D000244:Adenosine Diphosphate / Q000737:chemistry; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects* / Q000201:enzymology*; D003402:Creatine Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003543:Cysteamine / Q000494:pharmacology*; D003553:Cystine / Q000494:pharmacology*; D003554:Cystinosis / Q000150:complications / Q000201:enzymology; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D009410:Nerve Degeneration / Q000201:enzymology / Q000209:etiology; D010725:Phosphocreatine / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D013347:Subcellular Fractions / Q000187:drug effects / Q000201:enzymology
chemical_list: D004791:Enzyme Inhibitors; D010725:Phosphocreatine; D003553:Cystine; D003543:Cysteamine; D000244:Adenosine Diphosphate; D003402:Creatine Kinase; D005978:Glutathione