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porcupine O-acyltransferase

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Target not currently curated in GtoImmuPdb

Target id: 3145

Nomenclature: porcupine O-acyltransferase

Family: Membrane bound O-acyltransferases

Contents:

Gene and Protein Information Click here for help
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 Click here for help
protein-serine O-palmitoleoyltransferase porcupine | PORC
Database Links Click here for help
Alphafold Q9H237 (Hs), Q9JJJ7 (Mm)
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 Click here for help
EC Number: 2.3.1.250 (9Z)-hexadecenoyl-CoA + [Wnt protein]-L-serine = [Wnt protein]-O-(9Z)-hexadecenoyl-L-serine + CoA

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Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
Wnt-C59 Small molecule or natural product Hs Inhibition 10.1 pIC50 6
⤷ pIC50 10.1 (IC50 7.4x10-11 M) [6]
Description: Measuring inhibition of PORCN activity expressed in human HT1080 cells in a Wnt3A-driven luciferase production assay
GNF-6231 Small molecule or natural product Hs Inhibition 9.1 pIC50 2
⤷ pIC50 9.1 (IC50 8x10-10 M) [2]
LGK974 Small molecule or natural product Ligand has a PDB structure Hs Inhibition 9.0 pIC50 8
⤷ pIC50 9.0 (IC50 1x10-9 M) [8]
Description: Displacement of [3H]-GNF-1331 in a hPORCN radioligand binding assay.
ETC-1922159 Small molecule or natural product Hs Inhibition 8.5 pIC50 6
⤷ pIC50 8.5 (IC50 2.9x10-9 M) [6]
GNF-1331 Small molecule or natural product Hs Inhibition 8.1 pIC50 2
⤷ pIC50 8.1 (IC50 8x10-9 M) [2]
Description: Measuring displacement of radio-labelled GNF-1331 from hPORCN
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) [12] and RXC006 is intended to treat fibrosis (out licensed to Astra Zeneca in August 2020, and re-named AZD5055) that has been progressed to Phase 1 evaluation for anti-fibrotic efficacy in idiopathic pulmonary fibrosis (NCT05134727).
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  focal dermal hypoplasia
Description: FDH is an X-linked dominant disorder. It is characterised by patchy hypoplastic skin and digital, ocular, and dental malformations.
OMIM: 305600
Comments:  Mutations in the PORCN gene have been identified as the cause of FDH.
References:  1,3,7,15
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 [5,12-14]. 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

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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 USA, 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. Shah K, Panchal S, Patel B. (2021) Porcupine inhibitors: Novel and emerging anti-cancer therapeutics targeting the Wnt signaling pathway. Pharmacol Res, 167: 105532. [PMID:33677106]

13. Torres VI, Godoy JA, Inestrosa NC. (2019) Modulating Wnt signaling at the root: Porcupine and Wnt acylation. Pharmacol Ther, 198: 34-45. [PMID:30790642]

14. 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]

15. 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 01/06/2022. Accessed on 05/12/2022. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=3145.