Cyclophilins

Activation of immunophilin receptors in the CNS is thought to be involved in certain aspects of AIDS dementia and the CNS side effects seen with the immunosupressants, FK 506 and cyclophilin. FK 506 and related compounds also have antiischemic effects. 

Kallen, J., et al. Structure of human cyclophilin and its binding site for cyclosporin A determined by x-ray crystallography and NMR spectroscopy. Nature 353 276-279, 1991. 

Takahashi, N., Hayano, T., Suzuki, M. Peptidyl-prolyl cis-trans isomerase is the cyclosporin A binding protein cyclophilin. Nature 337 473-475, 1989. 

Immunophillins are abundant proteins that catalyze the cis-trans isomerization of proline residues within proteins, generally to aid in protein folding. Immunophillins are not essential proteins, are the intracellular binding proteins of several immunosuppressive drugs. Cyclosporin A exerts its action after binding to cyclophilin. Tacrolimus and sirolimus predominantly bind to the protein FKBP-12 (FK binding protein-12). 

Cyclosporine A (CsA) is a water-insoluble cyclic peptide from a fungus composed of 11 amino acids. CsA binds to its cytosolic receptor cyclophilin. The CsA/cyclophilin complex reduces the activity of the protein phosphatase calcineurin. Inhibition of this enzyme activity interrupts antigen receptor-induced activation and translocation of the transcription factor NEAT to the nucleus which is essential for the induction of cytokine synthesis in T-lymphocytes. 

Liu S, Asparuhova M, Brondani V, Ziekau I, Klimkait T, Schumperh D (2004) Inhibition of HlV-1 multiplication by antisense U7 snRNAs and siRNAs targeting cyclophilin A, Nucleic Acids Res 32 3752-3759... 

Wu YQ, Belyakov S, Chi Choi, Limburg D, Thomas BE IV, Vaal M, Wei L, Wilkinson DE, Holmes A, Fuller M, McCormick J, Connolly M, Moeller T, Steiner J, Hamilton, GS. Synthesis and biological evaluation of non-peptidic cyclophilin ligands. J Med Chem 2003 46 1112-15. 

Peptidyl-prolyl cis-trans isomerase (PPI, cyclophilins/FKBPs) (EC5.3.4.1)... 

Colley, N., Baker, E., Stamnes, M. and Zuker, C. (1991) The cyclophilin homolog ninaA is required in the secretory pathway. Cell 67, 255-263. 

Dornan, J., Page, A.P., Taylor, P., Wu, S., Winter, A.D., Husi, H. and Walkinshaw, M.D. (1999) Biological, biochemical and structural characterisation of a divergent loop cyclophilin from Caenorhabditis elegans. Journal of Biological Chemistry 274, 34877—34883. 

Hong, X., Ma, D. and Carlow, K.S.C. (1998a) Cloning expression and characterisation of a new filarial cyclophilin. Molecular and Biochemical Parasitology 91,... 

Hong, X.Q., Ma, D., Page, A.P., Kumar, S. and Carlow, C.KS. (1998b) Highly conserved large molecular weight cyclophilin of filarial parasites. Experimental Parasitology 88, 246—251. 

Ma, D., Hong, X., Raghavan, N., Scott, A.L., McCarthy, J.S., Nutman, T.B., Williams, S.A. and Carlow, C.K.S. (1996) A cyclosporin A-sensitive small molecular weight cyclophilin of filarial parasites. Molecular and Biochemical Parasitology 79, 235-241. 

Page, A.P. (1997) Cyclophilin and protein disulphide isomerase genes are co-transcribed in a functionally related manner in Caenorhabditis elegans. DNA and CellBiology 16, 1335-1343. 

Page, A.P. and Winter, A.D. (1998) A divergent multi-domain cyclophilin is highly conserved between parasitic and free-living nematode species and is important in larval muscle development. Molecular and Biochemical Parasitology 95, 215-227. 

Page, A.P., Landry, D., Wilson, G.G. and Carlow, C.K.S. (1995b) Molecular characterization of a cyclosporin A-insensitive cyclophilin from the parasitic nematode Brugia malayi. Biochemistry 34, 11545-11550. 

Page, A.P., MacNiven, K. and Hengartner, M.O. (1996) Cloning and biochemical characterisation of the cyclophilin homologues from the free-living nematode Caenorhabditis elegans. BiochemicalJournal 317, 179-185. 

Smith, T., Ferreira, L.R., Herbert, C., Norris, K. and Sauk, J.J. (1995) Hsp47 and cyclophilin B traverse the endoplasmic reticulum with procollagen into pre-golgi intermediate vesicles a role for Hsp47 and cyclophilin B in the export of procollagen from the endoplasmic reticulum. Journal of Biological Chemistry 270,18323-18328. 

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