FK506

Figure 4.49 reprinted with permission from Pranata J and W L Jorgensen. Computational Studies on FK506 Conformational Search and Molecular Dynamics Simulations in Water. The Journal of the American Chemical Society 113 9483-9493. 1991 American Chemical Society. 

A secondary metabolite produced by Tolypocladium inflation. This fungus was initially isolated in a soil sample collected in Norway. Cyclosporin A is a cyclic undecapeptide. Inside cells, cyclosporine A binds its immunophillin receptor known as cyclophillin. Like the FK506-FKBP12 complex, cyclosporin A-cyclophillin binds and inhibits the protein phosphatase calcineurin. 

FKBP12 is a member of immunophilin family that has prolyl isomerase activity and is related to the cyclophi-lins in function. FKBP12 binds immunosuppressant molecule FK506 (tacrolimus). The FBKP-FK506 complex inhibits calcineurin, a protein phosphatase, thus blocking signal transduction in the T-lymphocyte... 

Tacrolimus (TRL), in the past also named FK506, belongs to the group of macrolides and is produced by a special actinomycete species. TRL binds to its cytosolic receptor FKBP-12, however, it also blocks calcineurin activity and subsequently cytokine synthesis. 

The introduction of PP2B (calcinemin) inhibitors revolutionized kidney transplantation. Cyclosporine A and tacrolimus (FK506) are the principal immunosuppressants prescribed for adult and pediatric renal transplantation. Cyclosporine A was in use clinically long before its mechanism of action was elucidated. 

Keswani SC, Chander B et al (2003a) FK506 is neuroprotective in a model of antiretroviral toxic neuropathy. Ann Neurol 53(l) 57-64... 

Playfair J.H.L. 992) Immunology at a Glance, 5th edn. Oxford Blackwell Scientific Publications. Roitt I.M. 99A) Essential Immunology, 8th edn. Oxford Blackwell Scientific Publications. Schreiber S.L. Crabtree G.R (1992) The mechanisms of action of cyclosporin A and FK506. Immunol Today, 13, 136-142. 

Fe-TPAA Fe(III)-tris[N-(2-pyridylmethyl)-2-aminoethyl] amine Fe-TPEN Fe(II)-tetrakis-N,N,N, N -(2-pyridyl methyl-2-aminoethyl)amine FFA Free fatty acids FGF Fibroblast growth factor FID Flame ionization detector FITC Fluorescein isothiocyanate FKBP FK506-binding protein FLAP 5-lipoxygenase-activating protein... 

Petros AM, Kawai M, Luly JR, Fesik SW. Conformation of two nonimmunosuppressive FK506 analogs when bound to FKBP by isotope-filtered NMR. FEBS Lett 1992 308 309-314. 

Davis, E.C., Broekelmann, T.J., Ozawa, Y. and Mecham, R.P. (1998) Identification of tropoelastin as a ligand for the 65-kD FK506-binding protein, FKBP65, in the secretory pathway. Journal of Cell Biology 140, 295-303. 

Zeng, B.F., MacDonald, J.R., Bann, J.G., Reck, K., Gambee, J.E., Boswell, B.A. and Bachinger, H.P. (1998) Chicken FK506-binding protein, FKBP65, a member of the FKBP family of peptidylprolyl cis-lrans isomerases, is only partially inhibited by FK506. BiochemicalJournal 330, 109-114. 

Wulfing, C., Lombardero, J. and Pluckthun, A. (1994) An Escherichia coli protein consisting of a domain homologous to FK506-binding proteins (FKBP) and a new metal binding motif. Journal of Biological Chemistry 269, 2895-2901. 

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