Contents:
Gene and Protein Information  |
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| Species | TM | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
| Human | 8 | 461 | Xp11.23 | PORCN | porcupine O-acyltransferase | |
| Mouse | 8 | 461 | X 3.7 cM | Porcn | porcupine O-acyltransferase | |
| Rat | 8 | 461 | Xq12 | Porcn | porcupine O-acyltransferase | |
| Gene and Protein Information Comments | ||||||
| Multiple alternatively spliced transcript variants of the human and mouse genes, that encode distinct isoforms have been detected. | ||||||
| Previous and Unofficial Names |
| protein-serine O-palmitoleoyltransferase porcupine | PORC |
| Database Links |
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| BRENDA | 2.3.1.250 |
| ChEMBL Target | CHEMBL1255163 (Hs), CHEMBL1255164 (Mm) |
| Ensembl Gene | ENSG00000102312 (Hs), ENSMUSG00000031169 (Mm), ENSRNOG00000004819 (Rn) |
| Entrez Gene | 64840 (Hs), 53627 (Mm), 317368 (Rn) |
| Human Protein Atlas | ENSG00000102312 (Hs) |
| KEGG Enzyme | 2.3.1.250 |
| KEGG Gene | hsa:64840 (Hs), mmu:53627 (Mm), rno:317368 (Rn) |
| OMIM | 300651 (Hs) |
| Pharos | Q9H237 (Hs) |
| RefSeq Nucleotide | NP_982301 (Hs), NM_016913 (Mm), NM_001173355 (Rn) |
| RefSeq Protein | NM_203475 (Hs), NP_058609 (Mm), NP_001166826 (Rn) |
| UniProtKB | Q9H237 (Hs), Q9JJJ7 (Mm) |
| Wikipedia | PORCN (Hs) |
| Enzyme Reaction |
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Download all structure-activity data for this target as a CSV file 
| Inhibitors | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Inhibitor Comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Redx Pharma have two porcupine inhibitors in their development pipeline, but their chemical structures have not been formally disclosed: RXC004 has entered a cancer clinical trial (Phase1 NCT03447470) and RXC006 is a preclinical lead that is intended to treat fibrosis (out licensed to Astra Zeneca in August 2020). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clinically-Relevant Mutations and Pathophysiology
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| General Comments |
| Porcupine is a multi-transmembrane enzyme that is located in the endoplasmic reticulum where it acts to post-translationally modify Wnt ligands. Specifically, porcupine catalyses the attachment of palmitoleate (a 16-carbon monounsaturated fatty acid, C16:1) to Wnt protein serine residues. This serine palmitoleylation is essential for the secretion of, and efficient binding of Wnt ligands to frizzled receptors. Selective porcupine inhibitor compounds, that disrupt Wnt pathway activity, are being developed for clinical potential in oncology and fibrotic disease [5,12-13]. When considering Wnt pathway inhibition as a therapeutic strategy, effects on normal tissue homeostasis must be taken in to consideration, given the diverse pathways and biological functions that are impacted by Wnt signalling [9,11]. One notable toxicity arising from targeting porcupine that has already been identified is the risk of bone loss [4], although this could be managed with other drugs [10]. |
References
1. Bornholdt D, Oeffner F, König A, Happle R, Alanay Y, Ascherman J, Benke PJ, Boente Mdel C, van der Burgt I, Chassaing N et al.. (2009) PORCN mutations in focal dermal hypoplasia: coping with lethality. Hum. Mutat., 30 (5): E618-28. [PMID:19309688]
2. Cheng D, Liu J, Han D, Zhang G, Gao W, Hsieh MH, Ng N, Kasibhatla S, Tompkins C, Li J et al.. (2016) Discovery of Pyridinyl Acetamide Derivatives as Potent, Selective, and Orally Bioavailable Porcupine Inhibitors. ACS Med Chem Lett, 7 (7): 676-80. [PMID:27437076]
3. Froyen G, Govaerts K, Van Esch H, Verbeeck J, Tuomi ML, Heikkilä H, Torniainen S, Devriendt K, Fryns JP, Marynen P et al.. (2009) Novel PORCN mutations in focal dermal hypoplasia. Clin. Genet., 76 (6): 535-43. [PMID:19863546]
4. Funck-Brentano T, Nilsson KH, Brommage R, Henning P, Lerner UH, Koskela A, Tuukkanen J, Cohen-Solal M, Movérare-Skrtic S, Ohlsson C. (2018) Porcupine inhibitors impair trabecular and cortical bone mass and strength in mice. J. Endocrinol., 238 (1): 13-23. [PMID:29720540]
5. Hayashi M, Baker A, Goldstein SD, Albert CM, Jackson KW, McCarty G, Kahlert UD, Loeb DM. (2017) Inhibition of porcupine prolongs metastasis free survival in a mouse xenograft model of Ewing sarcoma. Oncotarget, 8 (45): 78265-78276. [PMID:29108227]
6. Ho SY, Keller TH. (2015) The use of porcupine inhibitors to target Wnt-driven cancers. Bioorg. Med. Chem. Lett., 25 (23): 5472-6. [PMID:26522946]
7. Leoyklang P, Suphapeetiporn K, Wananukul S, Shotelersuk V. (2008) Three novel mutations in the PORCN gene underlying focal dermal hypoplasia. Clin. Genet., 73 (4): 373-9. [PMID:18325042]
8. Liu J, Pan S, Hsieh MH, Ng N, Sun F, Wang T, Kasibhatla S, Schuller AG, Li AG, Cheng D et al.. (2013) Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974. Proc. Natl. Acad. Sci. U.S.A., 110 (50): 20224-9. [PMID:24277854]
9. Lum L, Clevers H. (2012) Cell biology. The unusual case of Porcupine. Science, 337 (6097): 922-3. [PMID:22923569]
10. Madan B, McDonald MJ, Foxa GE, Diegel CR, Williams BO, Virshup DM. (2018) Bone loss from Wnt inhibition mitigated by concurrent alendronate therapy. Bone Res, 6: 17. [PMID:29844946]
11. Mirabelli CK, Nusse R, Tuveson DA, Williams BO. (2019) Perspectives on the role of Wnt biology in cancer. Sci Signal, 12 (589). [PMID:31289213]
12. Torres VI, Godoy JA, Inestrosa NC. (2019) Modulating Wnt signaling at the root: Porcupine and Wnt acylation. Pharmacol. Ther., 198: 34-45. [PMID:30790642]
13. Wang X, Moon J, Dodge ME, Pan X, Zhang L, Hanson JM, Tuladhar R, Ma Z, Shi H, Williams NS et al.. (2013) The development of highly potent inhibitors for porcupine. J. Med. Chem., 56 (6): 2700-4. [PMID:23477365]
14. Wang X, Reid Sutton V, Omar Peraza-Llanes J, Yu Z, Rosetta R, Kou YC, Eble TN, Patel A, Thaller C, Fang P et al.. (2007) Mutations in X-linked PORCN, a putative regulator of Wnt signaling, cause focal dermal hypoplasia. Nat. Genet., 39 (7): 836-8. [PMID:17546030]
How to cite this page
Membrane bound O-acyltransferases: porcupine O-acyltransferase. Last modified on 07/08/2020. Accessed on 01/03/2021. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=3145.
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