Cysteamine prevents inhibition of adenylate kinase caused by cystine in rat brain cortex.
Cystinosis is a systemic genetic disease caused by a lysosomal transport deficiency accumulating cystine in the lysosomes of almost all tissues. Although tissue damage might depend on cystine accumulation, the mechanisms of tissue damage are still obscures. Adenylate kinase, along with creatine kinase, is responsible for the enzymatic phosphotransfer network, crucial for energy homeostasis. Taking into account that cystine is known to inhibit creatine kinase activity, the two enzymes have thiol groups, and the strong interaction between the two activities, our main objective was to investigate the effect of cystine on adenylate kinase activity in the brain cortex of Wistar rats. For the in vivo studies, the animals were injected twice a day with 1.6 micromol/g body weight of cystine dimethylester and/or 0.46 micromol/g body weight of cysteamine from the 25th to the 29th postpartum day and sacrificed after 12 h. Cystine inhibited the enzyme activity in vitro in a concentration dependent way, whereas cysteamine prevented the inhibition. Adenylate kinase activity was found diminished in the brain cortex of rats loaded with cystine dimethylester and co-administration of cysteamine prevented the diminution of the enzyme activity. Considering that adenylate kinase together with creatine kinase is crucial for energy homeostasis, the release of cystine from lysosomes with consequent enzymes inhibition could impair energy homeostasis, contributing to tissue damage in patients with cystinosis.
Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, UFRGS, Rua Ramiro Barcelos 2600, Porto Alegre, RS, CEP 90.035-003, Brazil.
Vandré Casagrande
VC
Figueiredo
Luciane Rosa
LR
Feksa
Clovis Milton Duval
CM
Wannmacher
D000262:Adenylyl Cyclases / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology; D001928:Brain Diseases, Metabolic / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism*; D003402:Creatine Kinase / Q000737:chemistry / Q000378:metabolism; D003543:Cysteamine / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D003553:Cystine / Q000031:analogs & derivatives / Q000378:metabolism* / Q000633:toxicity; D003554:Cystinosis / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D003553:Cystine; D003543:Cysteamine; D003402:Creatine Kinase; D000262:Adenylyl Cyclases; C034582:cystine dimethyl ester