Literature summary for 3.1.3.48 extracted from

Hjortness, M.; Riccardi, L.; Hongdusit, A.; Ruppe, A.; Zhao, M.; Kim, E.; Zwart, P.; Sankaran, B.; Arthanari, H.; Sousa, M.; De Vivo, M.; Fox, J.
Abietane-type diterpenoids inhibit protein tyrosine phosphatases by stabilizing an inactive enzyme conformation (2018), Biochemistry, 57, 5886-5896 .

No PubMed abstract available

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Cloned(Commentary)

Cloned (Comment)	Organism
gene PTP1B, recombinant expression of C-terminally His-tagged wild-type and mutant enzymes (PTP1B residues 1-321) in Escherichia coli strain BL21(DE3)	Homo sapiens

Protein Variants

Protein Variants	Comment	Organism
A122F	site-directed mutagenesis, affects inhibition by abietic acid and 2-[(carboxycarbonyl)amino]-4,5,6,7-tetrahydro-thieno[2,3-c]-pyridine-3-carboxylic acid	Homo sapiens
A122S	site-directed mutagenesis, affects inhibition by abietic acid	Homo sapiens
A189S	site-directed mutagenesis, affects inhibition by 3-(3,5-dibromo-4-hydroxybenzoyl)-2-ethylbenzofuran-6-sulfonic acid-[4-(thiazol-2-ylsulfamyl)phenyl]-amide and 2-[(carboxycarbonyl)amino]-4,5,6,7-tetrahydro-thieno[2,3-c]-pyridine-3-carboxylic acid	Homo sapiens
C92A	site-directed mutagenesis, affects inhibition by abietic acid and 2-[(carboxycarbonyl)amino]-4,5,6,7-tetrahydro-thieno[2,3-c]-pyridine-3-carboxylic acid	Homo sapiens
F135Y	site-directed mutagenesis, affects inhibition by abietic acid, 3-(3,5-dibromo-4-hydroxybenzoyl)-2-ethylbenzofuran-6-sulfonic acid-[4-(thiazol-2-ylsulfamyl)phenyl]-amide, and 2-[(carboxycarbonyl)amino]-4,5,6,7-tetrahydro-thieno[2,3-c]-pyridine-3-carboxylic acid	Homo sapiens
F182Y	site-directed mutagenesis, affects inhibition by abietic acid and 2-[(carboxycarbonyl)amino]-4,5,6,7-tetrahydro-thieno[2,3-c]-pyridine-3-carboxylic acid	Homo sapiens
F196Y	site-directed mutagenesis, affects inhibition by abietic acid and 2-[(carboxycarbonyl)amino]-4,5,6,7-tetrahydro-thieno[2,3-c]-pyridine-3-carboxylic acid	Homo sapiens
F280Y	site-directed mutagenesis, does not affect abietane-type diterpenoids as inhibitors	Homo sapiens
G259S	site-directed mutagenesis, affects inhibition by 2-[(carboxycarbonyl)amino]-4,5,6,7-tetrahydro-thieno[2,3-c]-pyridine-3-carboxylic acid	Homo sapiens
H175A	site-directed mutagenesis, affects inhibition by abietic acid and 2-[(carboxycarbonyl)amino]-4,5,6,7-tetrahydro-thieno[2,3-c]-pyridine-3-carboxylic acid	Homo sapiens
R112A	site-directed mutagenesis, affects inhibition by abietic acid, 3-(3,5-dibromo-4-hydroxybenzoyl)-2-ethylbenzofuran-6-sulfonic acid-[4-(thiazol-2-ylsulfamyl)phenyl]-amide, and 2-[(carboxycarbonyl)amino]-4,5,6,7-tetrahydro-thieno[2,3-c]-pyridine-3-carboxylic acid	Homo sapiens
V113T	site-directed mutagenesis, does not affect abietane-type diterpenoids as inhibitors	Homo sapiens
Y152A/Y153A	site-directed mutagenesis, the mutation attenuates allosteric communication between the C-terminus and the WPD loop, affects inhibition by abietic acid, 3-(3,5-dibromo-4-hydroxybenzoyl)-2-ethylbenzofuran-6-sulfonic acid-[4-(thiazol-2-ylsulfamyl)phenyl]-amide, and 2-[(carboxycarbonyl)amino]-4,5,6,7-tetrahydro-thieno[2,3-c]-pyridine-3-carboxylic acid	Homo sapiens

Inhibitors

Inhibitors	Comment	Organism	Structure
2-[(carboxycarbonyl)amino]-4,5,6,7-tetrahydro-thieno[2,3-c]-pyridine-3-carboxylic acid	i.e. TCS401, binds to the active site	Homo sapiens
3-(3,5-dibromo-4-hydroxybenzoyl)-2-ethylbenzofuran-6-sulfonic acid-[4-(thiazol-2-ylsulfamyl)phenyl]-amide	i.e. BBR	Homo sapiens
abietic acid	a nonpolar inhibitor and weak mixed-type inhibitor of PTP1B, inhibits the enzyme by binding to its active site in a nonsubstrate-like manner that stabilizes the catalytically essential WPD loop in an inactive conformation, modelling of enzyme binding. Upon binding to the active site, abietic acid forms a hydrogen bond with R221 that weakens a bond between R221 and E115 and prevents the formation of a hydrogen bond between W179 and R221 that forms when the WPD loop closes	Homo sapiens
continentalic acid	modelling of enzyme binding	Homo sapiens
dehydroabietic acid	modelling of enzyme binding	Homo sapiens
dihydroabietic acid	modelling of enzyme binding	Homo sapiens
isopimaric acid	modelling of enzyme binding	Homo sapiens
additional information	abietane-type diterpenoids inhibit protein tyrosine phosphatases by stabilizing an inactive enzyme conformation. Abietane-type diterpenoids, a biologically active class of phytometabolites with largely nonpolar structures, are used for the development of pharmaceutically relevant PTP inhibitors. Minor changes in the structures of abietane-type diterpenoids (e.g. the addition of hydrogens) can improve potency (i.e. lower IC50) by several fold. Trodusquemine and benzofuran derivatives bind to C-terminal allosteric sites that attenuate WPD loop dynamics. Mechanisms of inhibition, dynamic docking, modelling, overview	Homo sapiens

KM Value [mM]

KM Value [mM]	KM Value Maximum [mM]	Substrate	Comment	Organism	Structure
additional information	-	additional information	Michaelis-Menten kinetic modeling	Homo sapiens

Natural Substrates/ Products (Substrates)

Natural Substrates	Organism	Comment (Nat. Sub.)	Natural Products	Comment (Nat. Pro.)	Rev.	Reac.
[a protein]-tyrosine phosphate + H2O	Homo sapiens	-	[a protein]-tyrosine + phosphate	-	?

Organism

Organism	UniProt	Comment	Textmining
Homo sapiens	P18031	-	-

Purification (Commentary)

Purification (Comment)	Organism
recombinant His-tagged wild-type and mutant enzymes from Escherichia coli strain BL21(DE3) by nickel affinity chromatography	Homo sapiens

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.	Reac.
4-nitrophenyl phosphate + H2O	-	Homo sapiens	4-nitrophenol + phosphate	-	?
[a protein]-tyrosine phosphate + H2O	-	Homo sapiens	[a protein]-tyrosine + phosphate	-	?

Synonyms

Synonyms	Comment	Organism
protein tyrosine phosphatase	-	Homo sapiens
protein tyrosine phosphatase 1B	-	Homo sapiens
PTP	-	Homo sapiens
PTP1B	-	Homo sapiens

General Information

General Information	Comment	Organism
physiological function	protein tyrosine phosphatase 1B is a negative regulator of insulin signaling	Homo sapiens

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Release 2023.1 (January 2023)