4tot

Structural highlights

Function

[PPIF_RAT] PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides. Involved in regulation of the mitochondrial permeability transition pore (mPTP). It is proposed that its association with the mPTP is masking a binding site for inhibiting inorganic phosphate (Pi) and promotes the open probability of the mPTP leading to apoptosis or necrosis; the requirement of the PPIase activity for this function is debated. In cooperation with mitochondrial TP53 is involved in activating oxidative stress-induced necrosis. Involved in modulation of mitochondrial membrane F(1)F(0) ATP synthase activity and regulation of mitochondrial matrix adenine nucleotide levels. Has anti-apoptotic activity independently of mPTP and in cooperation with BCL2 inhibits cytochrome c-dependent apoptosis.^{[1] [2] [3]}

References

1. ↑ Nicolli A, Basso E, Petronilli V, Wenger RM, Bernardi P. Interactions of cyclophilin with the mitochondrial inner membrane and regulation of the permeability transition pore, and cyclosporin A-sensitive channel. J Biol Chem. 1996 Jan 26;271(4):2185-92. PMID:8567677
2. ↑ Scorrano L, Nicolli A, Basso E, Petronilli V, Bernardi P. Two modes of activation of the permeability transition pore: the role of mitochondrial cyclophilin. Mol Cell Biochem. 1997 Sep;174(1-2):181-4. PMID:9309684
3. ↑ Woodfield K, Ruck A, Brdiczka D, Halestrap AP. Direct demonstration of a specific interaction between cyclophilin-D and the adenine nucleotide translocase confirms their role in the mitochondrial permeability transition. Biochem J. 1998 Dec 1;336 ( Pt 2):287-90. PMID:9820802
4. ↑ Fu J, Tjandra M, Becker C, Bednarczyk D, Capparelli M, Elling R, Hanna I, Fujimoto R, Furegati M, Karur S, Kasprzyk T, Knapp M, Leung K, Li X, Lu P, Mergo W, Miault C, Ng S, Parker D, Peng Y, Roggo S, Rivkin A, Simmons RL, Wang M, Wiedmann B, Weiss AH, Xiao L, Xie L, Xu W, Yifru A, Yang S, Zhou B, Sweeney ZK. Potent nonimmunosuppressive cyclophilin inhibitors with improved pharmaceutical properties and decreased transporter inhibition. J Med Chem. 2014 Oct 23;57(20):8503-16. doi: 10.1021/jm500862r. Epub 2014 Oct 13. PMID:25310383 doi:http://dx.doi.org/10.1021/jm500862r