Pharmacological targeting of catalyzed protein folding: the example of peptide bond cis/trans isomerases.
Peptide bond isomerases are involved in important physiological processes that can be targeted in order to treat neurodegenerative disease, cancer, diseases of the immune system, allergies, and many others. The folding helper enzyme class of Peptidyl-Prolyl-cis/trans Isomerases (PPIases) contains the three enzyme families of cyclophilins (Cyps), FK506 binding proteins (FKBPs), and parvulins (Pars). Although they are structurally unrelated, all PPIases catalyze the cis/trans isomerization of the peptide bond preceding the proline in a polypeptide chain. This process not only plays an important role in de novo protein folding, but also in isomerization of native proteins. The native state isomerization plays a role in physiological processes by influencing receptor ligand recognition or isomer-specific enzyme reaction or by regulating protein function by catalyzing the switch between native isomers differing in their activity, e.g., ion channel regulation. Therefore elucidating PPIase involvement in physiological processes and development of specific inhibitors will be a suitable attempt to design therapies for fatal and deadly diseases.
Edlich
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Max-Planck Research Unit for Enzymology of Protein Folding, Halle/Saale, Germany.
Fischer
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D000818:Animals; D002318:Cardiovascular Diseases / Q000188:drug therapy; D002384:Catalysis; D021983:Cyclophilins / Q000037:antagonists & inhibitors* / Q000502:physiology; D016572:Cyclosporine / Q000494:pharmacology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009369:Neoplasms / Q000188:drug therapy; D019696:Peptidylprolyl Isomerase / Q000037:antagonists & inhibitors* / Q000502:physiology; D017510:Protein Folding; D015427:Reperfusion Injury / Q000188:drug therapy; D012871:Skin Diseases / Q000188:drug therapy; D022061:Tacrolimus Binding Protein 1A / Q000037:antagonists & inhibitors* / Q000502:physiology
D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; C437224:cyclophilin hCyp-18; D016572:Cyclosporine; D021983:Cyclophilins; D022061:Tacrolimus Binding Protein 1A; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase