peptidylprolyl isomerase D
Target not currently curated in GtoImmuPdb
Target id: 3179
Nomenclature: peptidylprolyl isomerase D
Abbreviated Name: Cyclophilin D
Contents:
Gene and Protein Information  |
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| Species | TM | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
| Human | - | 370 | 4q32.1 | PPID | peptidylprolyl isomerase D | |
| Mouse | - | 370 | 3 E3 | Ppid | peptidylprolyl isomerase D (cyclophilin D) | |
| Rat | - | 370 | 2q33 | Ppid | peptidylprolyl isomerase D | |
| Database Links |
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| Alphafold | Q08752 (Hs), Q9CR16 (Mm), Q6DGG0 (Rn) |
| BRENDA | 5.2.1.8 |
| ChEMBL Target | CHEMBL1697657 (Hs) |
| Ensembl Gene | ENSG00000171497 (Hs), ENSMUSG00000027804 (Mm), ENSRNOG00000027408 (Rn) |
| Entrez Gene | 5481 (Hs), 67738 (Mm), 361967 (Rn) |
| Human Protein Atlas | ENSG00000171497 (Hs) |
| KEGG Enzyme | 5.2.1.8 |
| KEGG Gene | hsa:5481 (Hs), mmu:67738 (Mm), rno:361967 (Rn) |
| OMIM | 601753 (Hs) |
| Pharos | Q08752 (Hs) |
| RefSeq Nucleotide | NM_005038 (Hs), NM_001356326 (Mm), NM_001004279 (Rn) |
| RefSeq Protein | NP_005029 (Hs), NP_080628 (Mm), NP_001004279 (Rn) |
| UniProtKB | Q08752 (Hs), Q9CR16 (Mm), Q6DGG0 (Rn) |
| Wikipedia | PPID (Hs) |
| Enzyme Reaction |
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Download all structure-activity data for this target as a CSV file 
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| Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| General Comments |
| Cyclosporin A (CsA) is the prototypical cyclophilin D (CyPD) inhibitor, but it also inhibits cyclophilin A and the calcineurin pathway, an effect that has long been used for immunosuppression in humans [11]. A number of non-immunosuppressive analogues of CsA, which do inhibit CyPD, have been developed, including NIM811 (N-methyl-4-isoleucine-cyclosporin), Alisporivir (Debio025), and MeVal-4-cyclosporin (N-methylvaline-4-cyclosporin A) [2,7-8,11,13]. In addition, mitochondrial-targeted analogues have been developed to increase the relative concentration of CsA in mitochondria [[5,10-11,14]. Additional CyPD inhibitors, not related to CsA, include Sanglifehrin A, antamanide, ER-000444793, and urea-derived compounds [1,3-4,6,11,15], while small molecule screens have identified other inhibitors of CyPD [12]. |
References
1. Azzolin L, Antolini N, Calderan A, Ruzza P, Sciacovelli M, Marin O, Mammi S, Bernardi P, Rasola A. (2011) Antamanide, a derivative of Amanita phalloides, is a novel inhibitor of the mitochondrial permeability transition pore. PLoS One, 6 (1): e16280. [PMID:21297983]
2. Biasutto L, Azzolini M, Szabò I, Zoratti M. (2016) The mitochondrial permeability transition pore in AD 2016: An update. Biochim Biophys Acta, 1863 (10): 2515-30. [PMID:26902508]
3. Briston T, Lewis S, Koglin M, Mistry K, Shen Y, Hartopp N, Katsumata R, Fukumoto H, Duchen MR, Szabadkai G et al.. (2016) Identification of ER-000444793, a Cyclophilin D-independent inhibitor of mitochondrial permeability transition, using a high-throughput screen in cryopreserved mitochondria. Sci Rep, 6: 37798. [PMID:27886240]
4. Clarke SJ, McStay GP, Halestrap AP. (2002) Sanglifehrin A acts as a potent inhibitor of the mitochondrial permeability transition and reperfusion injury of the heart by binding to cyclophilin-D at a different site from cyclosporin A. J Biol Chem, 277 (38): 34793-9. [PMID:12095984]
5. Dube H, Selwood D, Malouitre S, Capano M, Simone MI, Crompton M. (2012) A mitochondrial-targeted cyclosporin A with high binding affinity for cyclophilin D yields improved cytoprotection of cardiomyocytes. Biochem J, 441 (3): 901-7. [PMID:22035570]
6. Elkamhawy A, Park JE, Hassan AHE, Pae AN, Lee J, Park BG, Roh EJ. (2018) Synthesis and evaluation of 2-(3-arylureido)pyridines and 2-(3-arylureido)pyrazines as potential modulators of Aβ-induced mitochondrial dysfunction in Alzheimer's disease. Eur J Med Chem, 144: 529-543. [PMID:29288949]
7. Hansson MJ, Mattiasson G, Månsson R, Karlsson J, Keep MF, Waldmeier P, Ruegg UT, Dumont JM, Besseghir K, Elmér E. (2004) The nonimmunosuppressive cyclosporin analogs NIM811 and UNIL025 display nanomolar potencies on permeability transition in brain-derived mitochondria. J Bioenerg Biomembr, 36 (4): 407-13. [PMID:15377880]
8. Khaspekov L, Friberg H, Halestrap A, Viktorov I, Wieloch T. (1999) Cyclosporin A and its nonimmunosuppressive analogue N-Me-Val-4-cyclosporin A mitigate glucose/oxygen deprivation-induced damage to rat cultured hippocampal neurons. Eur J Neurosci, 11 (9): 3194-8. [PMID:10510183]
9. Kuo J, Bobardt M, Chatterji U, Mayo PR, Trepanier DJ, Foster RT, Gallay P, Ure DR. (2019) A Pan-Cyclophilin Inhibitor, CRV431, Decreases Fibrosis and Tumor Development in Chronic Liver Disease Models. J Pharmacol Exp Ther, 371 (2): 231-241. [PMID:31406003]
10. Malouitre S, Dube H, Selwood D, Crompton M. (2009) Mitochondrial targeting of cyclosporin A enables selective inhibition of cyclophilin-D and enhanced cytoprotection after glucose and oxygen deprivation. Biochem J, 425 (1): 137-48. [PMID:19832699]
11. Porter Jr GA, Beutner G. (2018) Cyclophilin D, Somehow a Master Regulator of Mitochondrial Function. Biomolecules, 8 (4). [PMID:30558250]
12. Shore ER, Awais M, Kershaw NM, Gibson RR, Pandalaneni S, Latawiec D, Wen L, Javed MA, Criddle DN, Berry N et al.. (2016) Small Molecule Inhibitors of Cyclophilin D To Protect Mitochondrial Function as a Potential Treatment for Acute Pancreatitis. J Med Chem, 59 (6): 2596-611. [PMID:26950392]
13. Waldmeier PC, Feldtrauer JJ, Qian T, Lemasters JJ. (2002) Inhibition of the mitochondrial permeability transition by the nonimmunosuppressive cyclosporin derivative NIM811. Mol Pharmacol, 62 (1): 22-9. [PMID:12065751]
14. Warne J, Pryce G, Hill JM, Shi X, Lennerås F, Puentes F, Kip M, Hilditch L, Walker P, Simone MI et al.. (2016) Selective Inhibition of the Mitochondrial Permeability Transition Pore Protects against Neurodegeneration in Experimental Multiple Sclerosis. J Biol Chem, 291 (9): 4356-73. [PMID:26679998]
15. Šileikytė J, Forte M. (2016) Shutting down the pore: The search for small molecule inhibitors of the mitochondrial permeability transition. Biochim Biophys Acta, 1857 (8): 1197-1202. [PMID:26924772]
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