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Information on EC 2.3.1.250 - [Wnt protein] O-palmitoleoyl transferase and Organism(s) Homo sapiens and UniProt Accession Q9H237
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2.3.1.250 [Wnt protein] O-palmitoleoyl transferaseIUBMB Comments
The enzyme, found in animals, modifies a specific serine residue in Wnt proteins, e.g. Ser209 in human Wnt3a and Ser224 in chicken WNT1 [2,3]. The enzyme can accept C13 to C16 fatty acids in vitro, but only (9Z)-hexadecenoate modification is observed in vivo . cf. EC 3.1.1.98, [Wnt protein]-O-palmitoleoyl-L-serine hydrolase.
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The taxonomic range for the selected organisms is: Homo sapiens
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Reaction Schemes
+
[Wnt]-L-serine
=
+
[Wnt]-O-(9Z)-hexadec-9-enoyl-L-serine
Synonyms
porcupine, porcn, mom-1, mporc, mporcd, xporc, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
PORCN
-
-
-
-
SYSTEMATIC NAME
IUBMB Comments
(9Z)-hexadec-9-enoyl-CoA:[Wnt]-L-serine O-hexadecenoyltransferase
The enzyme, found in animals, modifies a specific serine residue in Wnt proteins, e.g. Ser209 in human Wnt3a and Ser224 in chicken WNT1 [2,3]. The enzyme can accept C13 to C16 fatty acids in vitro, but only (9Z)-hexadecenoate modification is observed in vivo [1]. cf. EC 3.1.1.98, [Wnt protein]-O-palmitoleoyl-L-serine hydrolase.
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
decanoyl-CoA + [Wnt]-L-serine
CoA + [Wnt]-O-decanoyl-L-serine
about 30% of the activity as compared to (9Z)-hexadec-9-enoyl-CoA. There is an increase in the catalytic activity from hexanoyl-CoA to decanoyl-CoA, after which there is an abrupt drop for dodecanoyl-CoA. Upon further increase in fatty acyl chain length, the activity stays at approximately the same level until the unsaturated palmitoleoyl-CoA, which is the best substrate
-
-
?
dodecanoyl-CoA + [Wnt]-L-serine
CoA + [Wnt]-O-dodecanoyl-L-serine
about 15% of the activity as compared to (9Z)-hexadec-9-enoyl-CoA. There is an increase in the catalytic activity from hexanoyl-CoA to decanoyl-CoA, after which there is an abrupt drop for dodecanoyl-CoA. Upon further increase in fatty acyl chain length, the activity stays at approximately the same level until the unsaturated palmitoleoyl-CoA, which is the best substrate
-
-
?
hexanoyl-CoA + [Wnt]-L-serine
CoA + [Wnt]-O-hexanoyl-L-serine
about 20% of the activity as compared to (9Z)-hexadec-9-enoyl-CoA. There is an increase in the catalytic activity from hexanoyl-CoA to decanoyl-CoA, after which there is an abrupt drop for dodecanoyl-CoA. Upon further increase in fatty acyl chain length, the activity stays at approximately the same level until the unsaturated palmitoleoyl-CoA, which is the best substrate
-
-
?
octanoyl-CoA + [Wnt]-L-serine
CoA + [Wnt]-O-octanoyl-L-serine
about 25% of the activity as compared to (9Z)-hexadec-9-enoyl-CoA. There is an increase in the catalytic activity from hexanoyl-CoA to decanoyl-CoA, after which there is an abrupt drop for dodecanoyl-CoA. Upon further increase in fatty acyl chain length, the activity stays at approximately the same level until the unsaturated palmitoleoyl-CoA, which is the best substrate
-
-
?
tetradecanoyl-CoA + [Wnt]-L-serine
CoA + [Wnt]-O-tetradecanoyl-L-serine
about 10% of the activity as compared to (9Z)-hexadec-9-enoyl-CoA. There is an increase in the catalytic activity from hexanoyl-CoA to decanoyl-CoA, after which there is an abrupt drop for dodecanoyl-CoA. Upon further increase in fatty acyl chain length, the activity stays at approximately the same level until the unsaturated palmitoleoyl-CoA, which is the best substrate
-
-
?
(9Z)-hexadec-9-enoyl-CoA + [Wnt1]-L-serine
CoA + [Wnt1]-O-(9Z)-hexadec-9-enoyl-L-serine
-
-
-
?
(9Z)-hexadec-9-enoyl-CoA + [Wnt1]-L-serine
CoA + [Wnt1]-O-(9Z)-hexadec-9-enoyl-L-serine
chick WNT1 protein, the enzyme is an O-acyl transferase for WNT1 protein, WNT1 residues 214-234 are sufficient for PORCN-dependent palmitoylation of Ser224. Substitution of Ser224 with Thr, but not Cys, is tolerated in palmitoylation and biological assays. Transiently transfection of HEK-293T cells with WNT1. WNT1 mutant S224T is accepted as substrate, while mutants S224A and S224C are inactive
-
-
?
(9Z)-hexadec-9-enoyl-CoA + [Wnt1]-L-serine
CoA + [Wnt1]-O-(9Z)-hexadec-9-enoyl-L-serine
chicken substrate, and chimeric recombinant substrate containing amino acids 1-63 from mouse Wnt1 (-EPSLQL) and amino acids 64-370 from chicken Wnt1 (LSRKQ-)
-
-
?
(9Z)-hexadec-9-enoyl-CoA + [Wnt3a]-L-serine
CoA + [Wnt3a]-O-(9Z)-hexadec-9-enoyl-L-serine
-
-
-
?
(9Z)-hexadec-9-enoyl-CoA + [Wnt3a]-L-serine
CoA + [Wnt3a]-O-(9Z)-hexadec-9-enoyl-L-serine
the enzyme catalyzes the palmitoylation of the serine corresponding to Ser209 of Wnt3a
-
-
?
(9Z)-hexadec-9-enoyl-CoA + [Wnt3a]-L-serine
CoA + [Wnt3a]-O-(9Z)-hexadec-9-enoyl-L-serine
Wnt3a is palmitoylated in the endoplasmic reticulum and targeted to exosomes, palmitoylated Wnt3a proteins are found throughout the cytosol and at the plasma membrane but not in the nucleus, overview
-
-
?
(9Z)-hexadec-9-enoyl-CoA + [Wnt3a]-L-serine
CoA + [Wnt3a]-O-(9Z)-hexadec-9-enoyl-L-serine
chicken substrate, and substrate from Mus musculus
-
-
?
(9Z)-hexadec-9-enoyl-CoA + [Wnt3a]-L-serine
CoA + [Wnt3a]-O-(9Z)-hexadec-9-enoyl-L-serine
Wnt3a is palmitoylated by fatty acids 13-16 carbons in length at Ser209 but not at Cys77, consistent with a slow turnover rate, glycosylation is not required for Wnt3a palmitoylation, which is necessary but not sufficient for Wnt3a secretion
-
-
?
(9Z)-hexadec-9-enoyl-CoA + [Wnt5a]-L-serine
CoA + [Wnt5a]-O-(9Z)-hexadec-9-enoyl-L-serine
-
-
-
?
(9Z)-hexadec-9-enoyl-CoA + [Wnt5a]-L-serine
CoA + [Wnt5a]-O-(9Z)-hexadec-9-enoyl-L-serine
palmitoylation of Wnt-5a at Cys104
-
-
?
(9Z)-hexadec-9-enoyl-CoA + [Wnt]-L-serine
CoA + [Wnt]-O-(9Z)-hexadec-9-enoyl-L-serine
-
-
-
?
(9Z)-hexadec-9-enoyl-CoA + [Wnt]-L-serine
CoA + [Wnt]-O-(9Z)-hexadec-9-enoyl-L-serine
the enzyme catalyzes posttranslational modification of Wnts with palmitoleic acid. PORCN is necessary and sufficient for Wnt acylation. PORCN intimately recognizes the local structure of Wnt around the site of acylation
-
-
?
(9Z)-hexadec-9-enoyl-CoA + [Wnt]-L-serine
CoA + [Wnt]-O-(9Z)-hexadec-9-enoyl-L-serine
there is an increase in the catalytic activity from hexanoyl-CoA to decanoyl-CoA, after which there is an abrupt drop for dodecanoyl-CoA. Upon further increase in fatty acyl chain length, the activity stays at approximately the same level until the unsaturated palmitoleoyl-CoA, which is the best substrate
-
-
?
additional information
?
-
PORCN splice variants differ globally in signaling activity
-
-
?
additional information
?
-
generation of a fusion protein that is palmitoylated in a PORCN-dependent manner, overview
-
-
?
additional information
?
-
no activity with palmitoylation-defective Wnt3aS209A mutant
-
-
?
additional information
?
-
-
no activity with palmitoylation-defective Wnt3aS209A mutant
-
-
?
additional information
?
-
vertebrate Wnt1 and Wnt3a possess at least one additional site for porcupine-mediated lipid-modification
-
-
?
additional information
?
-
-
vertebrate Wnt1 and Wnt3a possess at least one additional site for porcupine-mediated lipid-modification
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
(9Z)-hexadec-9-enoyl-CoA + [Wnt1]-L-serine
CoA + [Wnt1]-O-(9Z)-hexadec-9-enoyl-L-serine
-
-
-
?
(9Z)-hexadec-9-enoyl-CoA + [Wnt5a]-L-serine
CoA + [Wnt5a]-O-(9Z)-hexadec-9-enoyl-L-serine
-
-
-
?
additional information
?
-
PORCN splice variants differ globally in signaling activity
-
-
?
(9Z)-hexadec-9-enoyl-CoA + [Wnt3a]-L-serine
CoA + [Wnt3a]-O-(9Z)-hexadec-9-enoyl-L-serine
-
-
-
?
(9Z)-hexadec-9-enoyl-CoA + [Wnt3a]-L-serine
CoA + [Wnt3a]-O-(9Z)-hexadec-9-enoyl-L-serine
the enzyme catalyzes the palmitoylation of the serine corresponding to Ser209 of Wnt3a
-
-
?
(9Z)-hexadec-9-enoyl-CoA + [Wnt3a]-L-serine
CoA + [Wnt3a]-O-(9Z)-hexadec-9-enoyl-L-serine
Wnt3a is palmitoylated in the endoplasmic reticulum and targeted to exosomes, palmitoylated Wnt3a proteins are found throughout the cytosol and at the plasma membrane but not in the nucleus, overview
-
-
?
(9Z)-hexadec-9-enoyl-CoA + [Wnt]-L-serine
CoA + [Wnt]-O-(9Z)-hexadec-9-enoyl-L-serine
-
-
-
?
(9Z)-hexadec-9-enoyl-CoA + [Wnt]-L-serine
CoA + [Wnt]-O-(9Z)-hexadec-9-enoyl-L-serine
the enzyme catalyzes posttranslational modification of Wnts with palmitoleic acid. PORCN is necessary and sufficient for Wnt acylation. PORCN intimately recognizes the local structure of Wnt around the site of acylation
-
-
?
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
2-(4-(2-methylpyridin-4-yl)phenyl)-N-(4-(pyridin-3-yl)phenyl)acetamide
i.e. C59
2-[5-methyl-6-(2-methylpyridin-4-yl)pyridin-3-yl]-N-(5-pyrazin-2-ylpyridin-2-yl)acetamide
i.e. LGK-974
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
glycosylation is not required for substrate Wnt3a palmitoylation, which is necessary but not sufficient for Wnt3a secretion
-
additional information
-
glycosylation is not required for substrate Wnt3a palmitoylation, which is necessary but not sufficient for Wnt3a secretion
-
additional information
substrate glycosylation promotes, but is not absolutely required for Wnt1 palmitoylation
-
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
additional information
endoplasmic reticulum-resident integral membrane enzyme
integral membrane protein, enzyme structure and topology model with cytoplasmic and endoplasmic reticulum luman parts, overview
the enzyme has multiple transmembrane domains
additional information
palmitoylated Wnt3a proteins are found throughout the cytosol and at the plasma membrane but not in the nucleus
-
additional information
-
palmitoylated Wnt3a proteins are found throughout the cytosol and at the plasma membrane but not in the nucleus
-
additional information
the enzyme is predicted to palmitoylate Wnt either co-translationally or post-translationally, so that in either case, the catalytic site is likely to be in the membrane or in the lumen of the endoplasmic reticulum
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
malfunction
metabolism
the enzyme catalyzes posttranslational modification of Wnts with palmitoleic acid. This unique form of lipidation with palmitoleic acid is a vital step in the biogenesis and secretion of Wnt
physiological function
evolution
the enzyme belongs to the membrane-bound O-acyltransferase family
evolution
the enzyme is a member of the membrane-bound O-acyl transferase (MBOAT) superfamily
malfunction
enzyme mutation, with a 219-kb deletion in Xp11.23 in two affected females, causes focal dermal hypoplasia is an X-linked dominant disorder characterized by patchy hypoplastic skin and digital, ocular and dental malformations
malfunction
mutations in gene PORCN are associated with focal dermal hypoplasia. PORCN null cells are completely incapable of autocrine Wnt signaling
physiological function
palmitoylation of Wnt-5a is important for the triggering of signalling at the cell surface level, the lipid-unmodified form of Wnt-5a cannot activate intracellular signal cascades. The palmitoylation is not essential for the secretion of Wnt-5a, but is necessary for its ability to suppress Wnt-3a-dependent T-cell factor transcriptional activity and to stimulate cell migration. Wnt-5a activates focal adhesion kinase and this activation also requires palmitoylation. Palmitoylation enables Wnt5a to induces the internalization of Fz5 and to promote cell migration by stimulating focal adhesion turnover
physiological function
porcupine-mediated lipid-modification regulates the activity and distribution of Wnt proteins, and promotes their activity in 293T cells, porcupine is required for Wnt activity in 293T cells, and porcupine/palmitoylation regulates the activity of Wnt1 and Wnt3a in 293T cells
physiological function
the enzyme is a membrane-bound O-acyltransferase and is a key non-redundant node for the regulation of global Wnt signaling, essential regulatory role of PORCN in shaping Wnt signaling gradients. All Wnt activity absolutely requires posttranslational modification by the O-acyltransferase PORCN, whose abundance or activity modulates signaling tightly and over a large dynamic range, the enzyme activity is a key modulator of all Wnt ligand activity
physiological function
the enzyme is critical for Wnt acylation and maintaining its hydrophobic nature, palmitoylation of the enzyme protein itself partially regulates Wnt palmitoylation and signaling, loss of palmitoylation of PORCN results in a modest increase in Wnt signaling, suggesting a negative regulatory role for PORCN Cys187 fatty acylation. Overexpression of PORCN promoted glycan processing of wild-type Wnt3a and the Ser209 (and Cys77) mutant, suggesting an additional acylation-independent role for the enzyme PORCN in maturation of Wnt3a
physiological function
the enzyme is enzyme responsible for palmitoylating Wnt proteins, importance of enzyme catalyzed palmitoylation for WNT1 activity and Wnt signaling
physiological function
the enzyme is involved in secretion of Wnt proteins
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). PORCN_HUMAN
461
7
52318
Swiss-Prot
Secretory Pathway (Reliability: 3)
PDB
SCOP
CATH
UNIPROT
ORGANISM
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
lipoprotein
primate-specific S-palmitoylation of PORCN at Cys187, fatty acylation of PORCN is not due to autopalmitoylation. The palmitoylation of the enzyme, a membrane-bound O-acyltransferase or MBOAT protein, partially regulates Wnt palmitoylation and signaling, overview. Loss of palmitoylation of PORCN results in a modest increase in Wnt signaling, suggesting a negative regulatory role for PORCN Cys187 fatty acylation
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
C187A
site-directed mutagenesis, increase in Wnt signaling activity of about 1.5fold upon expression of PORCNC187A compared to wild-type PORCN
C375X
site-directed mutagenesis, mutations introduced in PORCN at either Cys375, Cys381 or Cys385, all situated on a predicted luminal loop projecting from transmembrane domain VII that contains the catalytic His341 residue, have detrimental effects on Wnt3a palmitoylation and signaling that are comparable to that of the catalytically dead H341A mutant
C381X
site-directed mutagenesis, mutations introduced in PORCN at either Cys375, Cys381 or Cys385, all situated on a predicted luminal loop projecting from transmembrane domain VII that contains the catalytic His341 residue, have detrimental effects on Wnt3a palmitoylation and signaling that are comparable to that of the catalytically dead H341A mutant
C385X
site-directed mutagenesis, mutations introduced in PORCN at either Cys375, Cys381 or Cys385, all situated on a predicted luminal loop projecting from transmembrane domain VII that contains the catalytic His341 residue, have detrimental effects on Wnt3a palmitoylation and signaling that are comparable to that of the catalytically dead H341A mutant
H341A
additional information
H341A
site-directed mutagenesis, the mutation reduces Wnt signaling relative to wild-type PORCN
additional information
identification of enzyme mutants with a 219-kb deletion in Xp11.23, heterozygous and mosaic mutations in gene PORCN, genotyping, overview
additional information
-
identification of enzyme mutants with a 219-kb deletion in Xp11.23, heterozygous and mosaic mutations in gene PORCN, genotyping, overview
additional information
overexpression of HA-tagged human PORC to confirm the ability of hPORC RNAi constructs to knockdown hPORC expression
additional information
-
overexpression of HA-tagged human PORC to confirm the ability of hPORC RNAi constructs to knockdown hPORC expression
additional information
the cysteine mutations might be detrimental to the enzyme's tertiary structure and its catalytic activity
additional information
-
the cysteine mutations might be detrimental to the enzyme's tertiary structure and its catalytic activity
additional information
zinc finger nuclease-mediated PORCN gene deletion in HT1080 cells. Mutation or skipping of PORCN exon 9 creates cells null for PORCN catalytic activity
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
gene MG61, DNA and amino acid sequence determination and analysis, sequence comparisons
gene PORCN, DNA and amino acid sequence determination and analysis, genotyping
gene PORCN, quantitative RT-PCR enzyme expression analysis. PORCN splice variants differ globally in signaling activity in HT-1080 cells
overexpression of HA-tagged human PORC to confirm the ability of hPORC RNAi constructs to knockdown hPORC expression
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
drug development
PORCN is a prominent target for developing inhibitors for various cancers
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Kurayoshi, M.; Yamamoto, H.; Izumi, S.; Kikuchi, A.
Post-translational palmitoylation and glycosylation of Wnt-5a are necessary for its signalling
Biochem. J.
402
515-523
2007
Homo sapiens (Q9H237)
Galli, L.; Barnes, T.; Secrest, S.; Kadowaki, T.; Burrus, L.
Porcupine-mediated lipid-modification regulates the activity and distribution of Wnt proteins in the chick neural tube
Development
134
3339-3348
2007
Gallus gallus, Homo sapiens (Q9H237), Homo sapiens, Mus musculus (Q9JJJ7)
Tanaka, K.; Okabayashi, K.; Asashima, M.; Perrimon, N.; Kadowaki, T.
The evolutionarily conserved porcupine family is involved in the processing of the Wnt family
Eur. J. Biochem.
267
4300-4311
2000
Drosophila melanogaster, Drosophila melanogaster (Q9VWV9), Caenorhabditis elegans (Q22329), Homo sapiens (Q9H237), Xenopus laevis (Q9I935), Mus musculus (Q9JJJ7), Mus musculus
Miranda, M.; Galli, L.M.; Enriquez, M.; Szabo, L.A.; Gao, X.; Hannoush, R.N.; Burrus, L.W.
Identification of the WNT1 residues required for palmitoylation by Porcupine
FEBS Lett.
588
4815-4824
2014
Homo sapiens (Q9H237)
Proffitt, K.D.; Virshup, D.M.
Precise regulation of porcupine activity is required for physiological Wnt signaling
J. Biol. Chem.
287
34167-34178
2012
Homo sapiens (Q9H237), Mus musculus (Q9JJJ7)
Gao, X.; Hannoush, R.N.
Single-cell imaging of Wnt palmitoylation by the acyltransferase porcupine
Nat. Chem. Biol.
10
61-68
2014
Homo sapiens (Q9H237), Homo sapiens, Mus musculus (Q9JJJ7)
Wang, X.; Reid Sutton, V.; Omar Peraza-Llanes, J.; Yu, Z.; Rosetta, R.; Kou, Y.C.; Eble, T.N.; Patel, A.; Thaller, C.; Fang, P.; Van den Veyver, I.B.
Mutations in X-linked PORCN, a putative regulator of Wnt signaling, cause focal dermal hypoplasia
Nat. Genet.
39
836-838
2007
Homo sapiens (Q9H237), Homo sapiens
EXTERNAL LINKS (specific for EC-Number 2.3.1.250)
Transporter Classification Database (TCDB): 2.A.50.3.2, 2.A.50.3.1
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