Peptidyl-prolyl cis/trans isomerases | Enzymes | IUPHAR/BPS Guide to IMMUNOPHARMACOLOGY

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Peptidyl-prolyl cis/trans isomerases

Peptidyl-prolyl cis/trans isomerases C

Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).

Overview

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Peptidyl-prolyl cis/trans isomerases (PPIases) are an enzyme family which catalyse the cis/trans isomerisation of proline peptide bonds to promote the folding and re-folding of peptides and proteins. Three subfamilies have been identified: cyclophilins, FK506-binding proteins and parvulins. Individual PPIases are overexpressed in a number of cancers [17], and family members have been targetted for immunosuppressant effects.

Enzymes

Targets of relevance to immunopharmacology are highlighted in blue

FKBP12 (FKBP prolyl isomerase 1A) C Show summary »« Hide summary More detailed page go icon to follow link

Target Id

2609

Nomenclature

FKBP prolyl isomerase 1A

Common abbreviation

FKBP12

Previous and unofficial names

Genes

FKBP1A (Hs), Fkbp1a (Mm), Fkbp1a (Rn)

Ensembl ID

ENSG00000088832 (Hs), ENSMUSG00000032966 (Mm), ENSRNOG00000008822 (Rn)

UniProtKB AC

P62942 (Hs), P26883 (Mm), Q62658 (Rn)

EC number

5.2.1.8

Inhibitors

zotarolimus (Binding) pIC₅₀ 8.6 [6]

Selective inhibitors

tacrolimus pK_i 9.4 [9]

pimecrolimus pIC₅₀ 8.2 [10] - Rat

FKBP38 (FKBP prolyl isomerase 8) C Show summary »« Hide summary More detailed page go icon to follow link

Target Id

3177

Nomenclature

FKBP prolyl isomerase 8

Common abbreviation

FKBP38

Previous and unofficial names

K506 binding protein 8 | FKBP38 | FKBPr38 | K506-binding protein 8 (38kD)

Genes

FKBP8 (Hs), Fkbp8 (Mm), Fkbp8 (Rn)

Ensembl ID

ENSG00000105701 (Hs), ENSMUSG00000019428 (Mm), ENSRNOG00000058359 (Rn)

UniProtKB AC

Q14318 (Hs), O35465 (Mm), Q3B7U9 (Rn)

EC number

5.2.1.8

Inhibitors

GPI-1046 pK_i 7.3 [2]

Selective inhibitors

DM-CHX pK_i 7.1 [2]

FKBP51 (FKBP prolyl isomerase 5) C Show summary »« Hide summary More detailed page go icon to follow link

FKBP52 (FKBP prolyl isomerase 4) C Show summary »« Hide summary More detailed page go icon to follow link

FKBP prolyl isomerase like C Show summary »« Hide summary More detailed page go icon to follow link

Target Id

3178

Nomenclature

FKBP prolyl isomerase like

Previous and unofficial names

DIR1 | WAF-1/CIP1 stabilizing protein 39 | WISp39

Genes

FKBPL (Hs), Fkbpl (Mm), Fkbpl (Rn)

Ensembl ID

ENSG00000204315 (Hs), ENSMUSG00000033739 (Mm), ENSRNOG00000000432 (Rn)

UniProtKB AC

Q9UIM3 (Hs), O35450 (Mm), Q6MG81 (Rn)

EC number

5.2.1.8

Comment

Peptides based on the non-functional PPIase domain of FKBPL (e.g. AD-01 and ALM201) have potent anti-tumour activity by inhibiting angiogenesis and promoting the differentiation of cancer stem cells [1,13-14,18].

peptidylprolyl cis/trans isomerase, NIMA-interacting 1 C Show summary »« Hide summary More detailed page go icon to follow link

Target Id

3171

Nomenclature

peptidylprolyl cis/trans isomerase, NIMA-interacting 1

Previous and unofficial names

protein (peptidyl-prolyl cis/trans isomerase) NIMA-interacting 1 | peptidylprolyl cis/trans isomerase

Genes

PIN1 (Hs), Pin1 (Mm), Pin1 (Rn)

Ensembl ID

ENSG00000127445 (Hs), ENSMUSG00000032171 (Mm), ENSRNOG00000085482 (Rn)

UniProtKB AC

Q13526 (Hs), Q9QUR7 (Mm)

EC number

5.2.1.8

Inhibitors

BJP-06-005-3 pK_i 7.8 [15]

AG-17724 pK_i 7.1 [8]

Comment

PIN1 isomerises phosphorylated serine/threonine-proline bonds. It plays roles in cell cycle control, neuropathologies and the immune system [3].

Cyclophilin A (peptidylprolyl isomerase A) C Show summary »« Hide summary More detailed page go icon to follow link

Target Id

2751

Nomenclature

peptidylprolyl isomerase A

Common abbreviation

Cyclophilin A

Previous and unofficial names

CYPA | peptidylprolyl isomerase A (cyclophilin A)

Genes

PPIA (Hs), Ppia (Mm), Ppia (Rn)

Ensembl ID

ENSG00000196262 (Hs), ENSMUSG00000071866 (Mm), ENSRNOG00000027864 (Rn)

UniProtKB AC

P62937 (Hs), P17742 (Mm), P10111 (Rn)

EC number

5.2.1.8

Inhibitors

voclosporin (Binding) pK_d 7.8 [11]

cyclosporin A pIC₅₀ 8.3 (Inhibition of the phosphatase activity of calcineurin in Jurkat cells.) [4]

Cyclophilin D (peptidylprolyl isomerase D) C Show summary »« Hide summary More detailed page go icon to follow link

Target Id

3179

Nomenclature

peptidylprolyl isomerase D

Common abbreviation

Cyclophilin D

Genes

PPID (Hs), Ppid (Mm), Ppid (Rn)

Ensembl ID

ENSG00000171497 (Hs), ENSMUSG00000027804 (Mm), ENSRNOG00000027408 (Rn)

UniProtKB AC

Q08752 (Hs), Q9CR16 (Mm), Q6DGG0 (Rn)

EC number

5.2.1.8

Inhibitors

cyclosporin A pIC₅₀ 8.0 [12,16]

Comment

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 [16].

References

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1. Annett S, Moore G, Short A, Marshall A, McCrudden C, Yakkundi A, Das S, McCluggage WG, Nelson L, Harley I et al.. (2020) FKBPL-based peptide, ALM201, targets angiogenesis and cancer stem cells in ovarian cancer. Br J Cancer, 122 (3): 361-371. [PMID:31772325]

2. Edlich F, Weiwad M, Wildemann D, Jarczowski F, Kilka S, Moutty MC, Jahreis G, Lücke C, Schmidt W, Striggow F et al.. (2006) The specific FKBP38 inhibitor N-(N',N'-dimethylcarboxamidomethyl)cycloheximide has potent neuroprotective and neurotrophic properties in brain ischemia. J Biol Chem, 281 (21): 14961-70. [PMID:16547004]

3. Esnault S, Shen ZJ, Malter JS. (2008) Pinning down signaling in the immune system: the role of the peptidyl-prolyl isomerase Pin1 in immune cell function. Crit Rev Immunol, 28 (1): 45-60. [PMID:18298383]

4. Fruman DA, Klee CB, Bierer BE, Burakoff SJ. (1992) Calcineurin phosphatase activity in T lymphocytes is inhibited by FK 506 and cyclosporin A. Proc Natl Acad Sci USA, 89 (9): 3686-90. [PMID:1373887]

5. Gaali S, Kirschner A, Cuboni S, Hartmann J, Kozany C, Balsevich G, Namendorf C, Fernandez-Vizarra P, Sippel C, Zannas AS et al.. (2015) Selective inhibitors of the FK506-binding protein 51 by induced fit. Nat Chem Biol, 11 (1): 33-7. [PMID:25436518]

6. Garcia-Touchard A, Burke SE, Toner JL, Cromack K, Schwartz RS. (2006) Zotarolimus-eluting stents reduce experimental coronary artery neointimal hyperplasia after 4 weeks. Eur Heart J, 27 (8): 988-93. [PMID:16449248]

7. Gopalakrishnan R, Kozany C, Wang Y, Schneider S, Hoogeland B, Bracher A, Hausch F. (2012) Exploration of pipecolate sulfonamides as binders of the FK506-binding proteins 51 and 52. J Med Chem, 55 (9): 4123-31. [PMID:22455398]

8. Guo C, Hou X, Dong L, Marakovits J, Greasley S, Dagostino E, Ferre R, Johnson MC, Humphries PS, Li H et al.. (2014) Structure-based design of novel human Pin1 inhibitors (III): optimizing affinity beyond the phosphate recognition pocket. Bioorg Med Chem Lett, 24 (17): 4187-91. [PMID:25091930]

9. Hamilton GS, Steiner JP. (1998) Immunophilins: beyond immunosuppression. J Med Chem, 41 (26): 5119-43. [PMID:9857082]

10. Hultsch T, Müller KD, Meingassner JG, Grassberger M, Schopf RE, Knop J. (1998) Ascomycin macrolactam derivative SDZ ASM 981 inhibits the release of granule-associated mediators and of newly synthesized cytokines in RBL 2H3 mast cells in an immunophilin-dependent manner. Arch Dermatol Res, 290 (9): 501-7. [PMID:9808344]

11. Kuglstatter A, Mueller F, Kusznir E, Gsell B, Stihle M, Thoma R, Benz J, Aspeslet L, Freitag D, Hennig M. (2011) Structural basis for the cyclophilin A binding affinity and immunosuppressive potency of E-ISA247 (voclosporin). Acta Crystallogr D Biol Crystallogr, 67 (Pt 2): 119-23. [PMID:21245533]

12. 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]

13. McClements L, Annett S, Yakkundi A, O'Rourke M, Valentine A, Moustafa N, Alqudah A, Simões BM, Furlong F, Short A et al.. (2019) FKBPL and its peptide derivatives inhibit endocrine therapy resistant cancer stem cells and breast cancer metastasis by downregulating DLL4 and Notch4. BMC Cancer, 19 (1): 351. [PMID:30975104]

14. McClements L, Yakkundi A, Papaspyropoulos A, Harrison H, Ablett MP, Jithesh PV, McKeen HD, Bennett R, Donley C, Kissenpfennig A et al.. (2013) Targeting treatment-resistant breast cancer stem cells with FKBPL and its peptide derivative, AD-01, via the CD44 pathway. Clin Cancer Res, 19 (14): 3881-93. [PMID:23741069]

15. Pinch BJ, Doctor ZM, Nabet B, Browne CM, Seo HS, Mohardt ML, Kozono S, Lian X, Manz TD, Chun Y et al.. (2020) Identification of a potent and selective covalent Pin1 inhibitor. Nat Chem Biol, 16 (9): 979-987. [PMID:32483379]

16. Porter Jr GA, Beutner G. (2018) Cyclophilin D, Somehow a Master Regulator of Mitochondrial Function. Biomolecules, 8 (4). [PMID:30558250]

17. Rippmann JF, Hobbie S, Daiber C, Guilliard B, Bauer M, Birk J, Nar H, Garin-Chesa P, Rettig WJ, Schnapp A. (2000) Phosphorylation-dependent proline isomerization catalyzed by Pin1 is essential for tumor cell survival and entry into mitosis. Cell Growth Differ, 11 (7): 409-16. [PMID:10939594]

18. Valentine A, O'Rourke M, Yakkundi A, Worthington J, Hookham M, Bicknell R, McCarthy HO, McClelland K, McCallum L, Dyer H et al.. (2011) FKBPL and peptide derivatives: novel biological agents that inhibit angiogenesis by a CD44-dependent mechanism. Clin Cancer Res, 17 (5): 1044-56. [PMID:21364036]

NC-IUPHAR subcommittee and family contributors

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Concise Guide to PHARMACOLOGY citation:

Alexander SPH, Fabbro D, Gibb AJ, Kelly E, Mathie AA, Peach CJ, Veale EL, Armstrong JF, Faccenda E, Harding SD, Southan C, Davies JA et al. (2025) The Concise Guide to PHARMACOLOGY 2025/26: Enzymes. Br J Pharmacol. 182: S307-S403.