Interaction of tacrolimus(FK506) and its metabolites with FKBP and calcineurin.
Tacrolimus(FK506) is a strong immuno-suppressant and shows its activity through inhibiting IL-2 mRNA transcription by forming pentameric complex with intracellular receptor(FK506 binding protein 12 kDa or FKBP12), Ca2+, calmodulin, and calcineurin. Here, we report the binding activity to FKBP12, the pentameric complex formation and Con-A response inhibiting activities of 7 metabolites. C15-demethylated metabolite(M-3) needed higher quantity to compete in Con-A assay and in pentamer formation assay, although it binds more strongly to FKBP12. The result suggests that the ability to form a pentameric complex is not a two step reaction with the first binding to FKBP12, but a single step reaction by components for the pentamer formation.
Tamura
K
K
Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
Fujimura
T
T
Iwasaki
K
K
Sakuma
S
S
Fujitsu
T
T
Nakamura
K
K
Shimomura
K
K
Kuno
T
T
Tanaka
C
C
Kobayashi
M
M
D000818:Animals; D019703:Calcineurin; D002148:Calmodulin-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D002417:Cattle; D002478:Cells, Cultured; D003208:Concanavalin A; D004797:Enzyme-Linked Immunosorbent Assay; D006360:Heat-Shock Proteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008213:Lymphocyte Activation / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D046911:Macromolecular Substances; D051379:Mice; D008807:Mice, Inbred BALB C; D010749:Phosphoprotein Phosphatases / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D011994:Recombinant Proteins / Q000378:metabolism; D016559:Tacrolimus / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D022021:Tacrolimus Binding Proteins
D002148:Calmodulin-Binding Proteins; D002352:Carrier Proteins; D006360:Heat-Shock Proteins; D046911:Macromolecular Substances; D011994:Recombinant Proteins; D003208:Concanavalin A; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases; D022021:Tacrolimus Binding Proteins; D016559:Tacrolimus