RESUMO
FKBP51 and FKBP52 are two iconic members of the family of peptidyl-prolyl-(cis/trans)-isomerases (EC: 5.2.1.8), which comprises proteins that catalyze the cis/trans isomerization of peptidyl-prolyl peptide bonds in unfolded and partially folded polypeptide chains and native state proteins. Originally, both proteins have been studied as molecular chaperones belonging to the steroid receptor heterocomplex, where they were first discovered. In addition to their expected role in receptor folding and chaperoning, FKBP51 and FKBP52 are also involved in many biological processes, such as signal transduction, transcriptional regulation, protein transport, cancer development, and cell differentiation, just to mention a few examples. Recent studies have revealed that both proteins are subject of post-translational modifications such as phosphorylation, SUMOlyation, and acetylation. In this work, we summarize recent advances in the study of these immunophilins portraying them as scaffolding proteins capable to organize protein heterocomplexes, describing some of their antagonistic properties in the physiology of the cell, and the putative regulation of their properties by those post-translational modifications.
Assuntos
Processamento de Proteína Pós-Traducional , Proteínas de Ligação a Tacrolimo/fisiologia , Acetilação , Humanos , Fosforilação , Ligação Proteica , Transporte Proteico , Sumoilação , Proteínas de Ligação a Tacrolimo/metabolismo , Fatores de Transcrição/metabolismoRESUMO
FK506 (tacrolimus) and polyketide macrolides such as rapamycin and its derivates bind to FK506-binding proteins (FKBPs). These proteins display a peptidyl-prolyl rotamase function that is believed to catalyze protein folding and they are well-validated anti-proliferative drug targets in certain pathogenic microorganisms, and their functions have been characterized in parasitic protozoa. However, much less is known in helminths and trials with rapalogs on cestoda have not yet been reported. Due to a growing need for new treatment options for human cystic echinococcosis, the in vitro efficacy of rapalogs in Echinococcus granulosus was investigated. We determined the effect of ramapycin, FK506 and everolimus against this cestode, demonstrating their protoscolicidal ability. Also, we observed synergic scolicidal actions during combined therapy with rapalogs plus cyclosporine A, proposing dual administration of drugs to improve pharmacological effects in vivo. We have identified an E. granulosus (Eg)-fkb1 gene that encodes Eg-FKBP, an archetypal protein of the FKBP family, which includes all residues implicated in the binding of pharmacological ligands, in the enzymatic activity and in interactions with possible target proteins. Levels of Eg-fkb1 mRNA are over-expressed by acid but not rapalog treatment. We also described the presence of receptor-operated calcium channels in the larval stage, suggesting that exogenous ligands may dissociate the interaction of Eg-FKBP from these intracellular channels, enhancing the activity of the Ca(2+) release and interfering with their normal regulatory functions. As rapamycin sensitivity is the major criterion used to detect targets of rapamycin kinase, we identified and analyzed in silico critical residues of putative homologs in the Echinococcus genome. These preliminary results will allow us to continue subsequent studies that could reveal the precise intracellular functions of Eg-FKBP, providing greater knowledge for further identification of downstream target proteins, a promising target for chemotherapy of cystic echinococcosis.
Assuntos
Anti-Helmínticos/farmacologia , Cálcio/metabolismo , Echinococcus granulosus/efeitos dos fármacos , Echinococcus granulosus/fisiologia , Proteínas de Helminto/fisiologia , Sirolimo/farmacologia , Proteínas de Ligação a Tacrolimo/fisiologia , Sequência de Aminoácidos , Animais , Bovinos , Ciclosporina/farmacologia , DNA de Helmintos/química , DNA de Helmintos/genética , Sinergismo Farmacológico , Echinococcus granulosus/genética , Echinococcus granulosus/metabolismo , Everolimo , Perfilação da Expressão Gênica , Proteínas de Helminto/genética , Homeostase , Humanos , Dados de Sequência Molecular , Alinhamento de Sequência , Análise de Sequência de DNA , Sirolimo/análogos & derivados , Análise de Sobrevida , Tacrolimo/farmacologia , Proteínas de Ligação a Tacrolimo/genética , Estados UnidosRESUMO
Atopic dermatitis is a common allergic disease, in which the treatment is extremely complex; even when several immunological abnormalities have been described in atopic dermatitis, the immune response to drugs remains unclear for both: conventional and unconventional therapies. The present review is centered on clinical efficacy and safety of tacrolimus, one of the immunomodulators proposed to treat atopic dermatitis. There are clinical evidences to support that tacrolimus have considerable impact on expression of inflammatory markers, despite of clinical assays could be necessary to demonstrate its profiles of toxicity and efficacy, during long-time periods.