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Information on EC 3.1.1.98 - [Wnt protein] O-palmitoleoyl-L-serine hydrolase
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EC Tree
3.1.1.98 [Wnt protein] O-palmitoleoyl-L-serine hydrolaseIUBMB Comments
The enzyme removes the palmitoleate modification that is introduced to specific L-serine residues in Wnt proteins by EC 2.3.1.250, [Wnt protein]-O-palmitoleoyl transferase.
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Word Map
- 3.1.1.98
- drosophila
- wing
- disc
- imaginal
-
bristle
-
wingless
-
proneural
- thorax
-
achaete-scute
-
iroquois
- macrochaetes
-
achaete
-
mesothorax
-
mesothoracic
-
prepatterning
-
dally
-
pannier
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glypicans
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notal
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dally-like
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halter
-
apterous
- drug development
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dorsocentral
The enzyme appears in viruses and cellular organisms
Reaction Schemes
[Wnt]-O-(9Z)-hexadec-9-enoyl-L-serine
+
=
[Wnt]-L-serine
+
Synonyms
Notum, Notum 1a, palmitoleoyl-protein carboxylesterase notum1, 
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
Notum
Notum
-
-
-
-
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
[Wnt]-O-(9Z)-hexadec-9-enoyl-L-serine + H2O = [Wnt]-L-serine + (9Z)-hexadec-9-enoate
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-
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SYSTEMATIC NAME
IUBMB Comments
[Wnt]-O-(9Z)-hexadec-9-enoyl-L-serine acylhydrolase
The enzyme removes the palmitoleate modification that is introduced to specific L-serine residues in Wnt proteins by EC 2.3.1.250, [Wnt protein]-O-palmitoleoyl transferase.
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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
[Wnt]-O-(9Z)-hexadec-9-enoyl-L-serine + H2O
[Wnt]-L-serine + (9Z)-hexadec-9-enoate
-
Notum is a carboxylesterase that removes an essential palmitoleate moiety from Wnt proteins
-
?
[Wnt]-O-(9Z)-hexadec-9-enoyl-L-serine + H2O
[Wnt]-L-serine + (9Z)-hexadec-9-enoate
-
-
-
?
[Wnt]-O-(9Z)-hexadec-9-enoyl-L-serine + H2O
[Wnt]-L-serine + (9Z)-hexadec-9-enoate
-
Notum is a carboxylesterase that removes an essential palmitoleate moiety from Wnt proteins
-
?
[Wnt]-O-(9Z)-hexadec-9-enoyl-L-serine + H2O
[Wnt]-L-serine + (9Z)-hexadec-9-enoate
the enzyme removes the palmitoleate modification that is introduced to specific L-serine residues in Wnt proteins by [Wnt protein]-O-palmitoleoyl transferase
-
-
?
[Wnt]-O-(9Z)-hexadec-9-enoyl-L-serine + H2O
[Wnt]-L-serine + (9Z)-hexadec-9-enoate
-
notum is responsible for depalmitoleoylation of Wnt protein
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?
additional information
?
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no measurable activity on representative sulfatase, phosphatase, phospholipase C or amidase/protease substrates
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-
?
additional information
?
-
-
no measurable activity on representative sulfatase, phosphatase, phospholipase C or amidase/protease substrates
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-
?
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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
[Wnt]-O-(9Z)-hexadec-9-enoyl-L-serine + H2O
[Wnt]-L-serine + (9Z)-hexadec-9-enoate
the enzyme removes the palmitoleate modification that is introduced to specific L-serine residues in Wnt proteins by [Wnt protein]-O-palmitoleoyl transferase
-
-
?
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
2-[(2,3-dihydro-4H-1,4-benzoxazine-4-carbonyl)oxy]-7-[(6-phenoxypyridin-3-yl)methyl]tetrahydroimidazo[1,5-a]pyrazine-1,3(2H,5H)-dione
-
7-(4-chlorobenzoyl)-2-[(2,3-dihydro-4H-1,4-benzoxazine-4-carbonyl)oxy]tetrahydroimidazo[1,5-a]pyrazine-1,3(2H,5H)-dione
-
7-(4-chlorobenzyl)-1,3-dioxohexahydroimidazo[1,5-a]pyrazin-2(3H)-yl 2,3-dihydro-4Hbenzo[b][1,4]oxazine-4-carboxylate
i.e. ABC99, selective irreversible inhibitor. The optimized -hydroxyhydantoin carbamate inhibitor preserves Wnt-mediated cell signaling in the presence of NOTUM and is also converted into an ABPP probe for visualizing NOTUM in native biological systems
7-[(2-chlorophenyl)methyl]-2-([4-(4-methoxyphenyl)piperazine-1-carbonyl]oxy)tetrahydroimidazo[1,5-a]pyrazine-1,3(2H,5H)-dione
-
7-[(3-chlorophenyl)methyl]-2-([4-(4-methoxyphenyl)piperazine-1-carbonyl]oxy)tetrahydroimidazo[1,5-a]pyrazine-1,3(2H,5H)-dione
-
7-[(4-bromophenyl)methyl]-2-[[4-(4-methoxyphenyl)piperazine-1-carbonyl]oxy]tetrahydroimidazo[1,5-a]pyrazine-1,3(2H,5H)-dione
-
7-[(4-chlorophenyl)methyl]-2-([4-(4-methoxyphenyl)piperazine-1-carbonyl]oxy)tetrahydroimidazo[1,5-a]pyrazine-1,3(2H,5H)-dione
-
7-[(4-chlorophenyl)methyl]-2-[(2,3-dihydro-4H-1,4-benzoxazine-4-carbonyl)oxy]tetrahydroimidazo[1,5-a]pyrazine-1,3(2H,5H)-dione
the optimized N-hydroxyhydantoin carbamate inhibitor preserves Wnt-mediated cell signaling in the presence of NOTUM and is also converted into an activity-based protein profiling (ABPP) probe for visualizing NOTUM in native biological systems. NOTUM inhibitors have potential for treating degenerative diseases
Phenylmethanesulfonylfluoride
strong inhibition of 4-nitrophenylacetate hydrolysis
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DISEASE
TITLE OF PUBLICATION
LINK TO PUBMED
Carcinoma, Hepatocellular
Human homolog of NOTUM, overexpressed in hepatocellular carcinoma, is regulated transcriptionally by beta-catenin/TCF.
Colorectal Neoplasms
Novel insights into Notum and glypicans regulation in colorectal cancer.
Diabetes Mellitus, Type 2
Generation of Mice with Hepatocyte-Specific Conditional Deletion of Notum.
Hepatitis C
Multi?layered prevention and treatment of chronic inflammation, organ fibrosis and cancer associated with canonical WNT/??catenin signaling activation (Review).
Infections
Multi?layered prevention and treatment of chronic inflammation, organ fibrosis and cancer associated with canonical WNT/??catenin signaling activation (Review).
Liver Cirrhosis
Notum attenuates HBV-related liver fibrosis through inhibiting Wnt 5a mediated non-canonical pathways.
Neoplasms
Induction of tumor clones in D. melanogaster wts/+ heterozygotes with chemical carcinogens.
Neoplasms
Slow-Cycling Cancer Stem Cells Regulate Progression and Chemoresistance in Colon Cancer.
Pulmonary Fibrosis
Multi?layered prevention and treatment of chronic inflammation, organ fibrosis and cancer associated with canonical WNT/??catenin signaling activation (Review).
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IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.001506
2-[(2,3-dihydro-4H-1,4-benzoxazine-4-carbonyl)oxy]-7-[(6-phenoxypyridin-3-yl)methyl]tetrahydroimidazo[1,5-a]pyrazine-1,3(2H,5H)-dione
Homo sapiens
IC50 value is determined by competitive gel-based activity-based protein profiling, pH and temperature not specified in the publication
0.01
7-(4-chlorobenzoyl)-2-[(2,3-dihydro-4H-1,4-benzoxazine-4-carbonyl)oxy]tetrahydroimidazo[1,5-a]pyrazine-1,3(2H,5H)-dione
Homo sapiens
above 0.01 mM, IC50 value is determined by competitive gel-based activity-based protein profiling, pH and temperature not specified in the publication
0.000013
7-(4-chlorobenzyl)-1,3-dioxohexahydroimidazo[1,5-a]pyrazin-2(3H)-yl 2,3-dihydro-4Hbenzo[b][1,4]oxazine-4-carboxylate
Homo sapiens
pH and temperature not specified in the publication
0.0002
7-[(2-chlorophenyl)methyl]-2-([4-(4-methoxyphenyl)piperazine-1-carbonyl]oxy)tetrahydroimidazo[1,5-a]pyrazine-1,3(2H,5H)-dione
Homo sapiens
IC50 value is determined by competitive gel-based activity-based protein profiling, pH and temperature not specified in the publication
0.01
7-[(3-chlorophenyl)methyl]-2-([4-(4-methoxyphenyl)piperazine-1-carbonyl]oxy)tetrahydroimidazo[1,5-a]pyrazine-1,3(2H,5H)-dione
Homo sapiens
above 0.01 mM, IC50 value is determined by competitive gel-based activity-based protein profiling, pH and temperature not specified in the publication
0.000677
7-[(4-bromophenyl)methyl]-2-[[4-(4-methoxyphenyl)piperazine-1-carbonyl]oxy]tetrahydroimidazo[1,5-a]pyrazine-1,3(2H,5H)-dione
Homo sapiens
IC50 value is determined by competitive gel-based activity-based protein profiling, pH and temperature not specified in the publication
0.00029
7-[(4-chlorophenyl)methyl]-2-([4-(4-methoxyphenyl)piperazine-1-carbonyl]oxy)tetrahydroimidazo[1,5-a]pyrazine-1,3(2H,5H)-dione
Homo sapiens
IC50 value is determined by competitive gel-based activity-based protein profiling, pH and temperature not specified in the publication
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
expression of Notum1a first appears around the blastoderm margin prior to the onset of gastrulation
brenda
at 24 h post fertilization, expression is particularly pronounced in the central nervous system, including the dorsal neural tube and the midbrain-hindbrain boundary
brenda
Notum1a is expressed in the lateral edges and midline of the posterior neural plate. During segmentation, it is expressed in stripes at the lateral edges and adjacent to the midline of the neural plate
brenda
Notum is expressed dynamically during Xenopus embryogenesis, expression is required for head formation and neural induction. Notum functions in the prostective ectoderm
brenda
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LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
metabolism
the enzyme removes the palmitoleate modification that is introduced to specific L-serine residues in Wnt proteins by [Wnt protein]-O-palmitoleoyl transferase
physiological function
physiological function
Notum hydrolyzes the Wnt palmitoleoylate adduct extracellularly, resulting in inactivated Wnt proteins that form oxidized oligomers incapable of receptor binding. Notum is a Wnt deacylase, and palmitoleoylation is obligatory for the Wnt structure that maintains its active monomeric conformation. Notum is critical for neural and head induction by acting within the presumptive neuroectoderm
physiological function
Notum requires glypicans to suppress Wnt signalling, but does not cleave their glycophosphatidylinositol anchor. Glycosaminoglycan binding sites on Notum probably help to co-localize with Wnt proteins. A large hydrophobic pocket at the active site accommodates palmitoleate
physiological function
Notum requires glypicans to suppress Wnt signalling, but does not cleave their glycophosphatidylinositol anchor. Glycosaminoglycan binding sites on Notum probably help to co-localize with Wnt proteins. A large hydrophobic pocket at the active site accommodates palmitoleate
physiological function
Notum1a contributes to a self-regulatory loop that restricts Wnt/betA-catenin signaling. Notum 1a does not interact with Glypican 4, an essential component of the Wnt/planar cell polarity pathway, but plays specific role in the developing vertebrate embryo. In cultured cells, Notum1a inhibits Wnt/beta-catenin signaling
physiological function
notum has a role in promoting brain cell numbers during conditions of brain cell loss through tissue remodeling. Notum inhibits wnt11-6 to control brain size in regenerative degrowth and growth. Notum and wnt11-6 antagonism acts in an essentially constitutive process to control brain cell number, potentially through the determination and maintenance of a size set-point for the planarian brain. Notum and wnt11-6 regulate neoblast differentiation to influence brain size. Inhibition of notum does not significantly alter the density of neurons within the brain or average neuronal cell size, indicating that notum is likely to regulate brain:body proportion principally through the regulation of brain cell number
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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). NOTU2_XENLA
486
0
55452
Swiss-Prot
Secretory Pathway (Reliability: 4)
NOTUM_DROME
671
0
76937
Swiss-Prot
other Location (Reliability: 3)
NOTUM_HUMAN
496
0
55699
Swiss-Prot
Secretory Pathway (Reliability: 4)
NOTUM_MOUSE
503
0
56584
Swiss-Prot
Secretory Pathway (Reliability: 1)
NOTUM_SCHMD
527
0
60852
Swiss-Prot
Secretory Pathway (Reliability: 2)
NOT1_XENLA
488
0
54784
Swiss-Prot
Secretory Pathway (Reliability: 2)
NOT1A_DANRE
500
1
56715
Swiss-Prot
Secretory Pathway (Reliability: 2)
NOT1P_XENLA
488
0
54991
Swiss-Prot
Secretory Pathway (Reliability: 2)
A0A6J8A3J1_MYTCO
558
0
64238
TrEMBL
other Location (Reliability: 1)
A0A6J8B4F5_MYTCO
369
1
41214
TrEMBL
other Location (Reliability: 3)
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PDB
SCOP
CATH
UNIPROT
ORGANISM
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MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
nine crystal forms at resolutions between 1.4 and 2.8 A. The catalytic triad comprises Ser232, Asp340 and His389
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
Notum is expressed dynamically during Xenopus embryogenesis, expression is required for head formation and neural induction. Notum functions in the prostective ectoderm
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
drug development
NOTUM inhibitors have potential for treating degenerative diseases
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REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Zhang, X.; Cheong, S.M.; Amado, N.G.; Reis, A.H.; MacDonald, B.T.; Zebisch, M.; Jones, E.Y.; Abreu, J.G.; He, X.
Notum is required for neural and head induction via Wnt deacylation, oxidation, and inactivation
Dev. Cell
32
719-730
2015
Xenopus laevis (A0A0D3QS99)
brenda
Flowers, G.P.; Topczewska, J.M.; Topczewski, J.
A zebrafish Notum homolog specifically blocks the Wnt/beta-catenin signaling pathway
Development
139
2416-2425
2012
Danio rerio (C5H5C4), Danio rerio
brenda
Kakugawa, S.; Langton, P.F.; Zebisch, M.; Howell, S.A.; Chang, T.H.; Liu, Y.; Feizi, T.; Bineva, G.; OReilly, N.; Snijders, A.P.; Jones, E.Y.; Vincent, J.P.
Notum deacylates Wnt proteins to suppress signalling activity
Nature
519
187-192
2015
Homo sapiens (Q6P988), Homo sapiens, Drosophila melanogaster (Q9VUX3)
brenda
Suciu, R.M.; Cognetta, A.B.; Potter, Z.E.; Cravatt, B.F.
Selective irreversible inhibitors of the Wnt-deacylating enzyme NOTUM developed by activity-based protein profiling
ACS Med. Chem. Lett.
9
563-568
2018
Homo sapiens, Homo sapiens (Q6P988)
brenda
Hill, E.M.; Petersen, C.P.
Wnt/Notum spatial feedback inhibition controls neoblast differentiation to regulate reversible growth of the planarian brain
Development
142
4217-4229
2015
Schmidtea mediterranea (F8U830)
brenda
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