Sensitivity of mitochondrial peptidyl-prolyl cis-trans isomerase, pyridine nucleotide hydrolysis and Ca2+ release to cyclosporine A and related compounds.
Prooxidants activate a specific Ca2+ release pathway from mitochondria. Here we investigate the inhibitory potency of cyclosporine A and six related compounds with respect to peptidyl-prolyl cis-trans isomerase (PPIase), pyridine nucleotide hydrolysis and Ca2+ release. Whereas the absolute inhibitory potency of the compounds varies by about three orders of magnitude, a given compound is always most effective on PPIase, followed by pyridine nucleotide hydrolysis, and least effective in Ca2+ release inhibition. The data show that pyridine nucleotide hydrolysis is a prerequisite but not a consequence of Ca2+ release. They also strongly suggest that PPIase participates in the Ca2+ release mechanism from intact mitochondria by regulating the intramitochondrial NAD+ glycohydrolase, and thereby ascribe a physiological function to the protein. Furthermore, a complete lack of correlation between the inhibitory potencies described here and the reported immunosuppressive activities of the drugs is evident.
Schweizer
M
M
Laboratory of Biochemistry 1, Swiss Federal Institute of Technology (ETH), Zürich.
Schlegel
J
J
Baumgartner
D
D
Richter
C
C
D000591:Amino Acid Isomerases / Q000037:antagonists & inhibitors*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D016572:Cyclosporine / Q000494:pharmacology*; D004533:Egtazic Acid; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000201:enzymology; D019696:Peptidylprolyl Isomerase; D010545:Peroxides; D011685:Purine Nucleotides / Q000378:metabolism*; D051381:Rats; D016559:Tacrolimus / Q000494:pharmacology*; D020122:tert-Butylhydroperoxide
D002352:Carrier Proteins; D010545:Peroxides; D011685:Purine Nucleotides; D004533:Egtazic Acid; D016572:Cyclosporine; D020122:tert-Butylhydroperoxide; D000591:Amino Acid Isomerases; D019696:Peptidylprolyl Isomerase; D002118:Calcium; D016559:Tacrolimus