Information on EC 3.1.1.89 - protein phosphatase methylesterase-1

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The enzyme appears in viruses and cellular organisms

EC NUMBER
COMMENTARY hide
3.1.1.89
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RECOMMENDED NAME
GeneOntology No.
protein phosphatase methylesterase-1
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REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
[phosphatase 2A protein]-leucine methyl ester + H2O = [phosphatase 2A protein]-leucine + methanol
show the reaction diagram
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SYSTEMATIC NAME
IUBMB Comments
[phosphatase 2A protein]-leucine ester acylhydrolase
A key regulator of protein phosphatase 2A. The methyl ester is formed by EC 2.1.1.233 (leucine carboxy methyltransferase-1). Occurs mainly in the nucleus.
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
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Manually annotated by BRENDA team
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Manually annotated by BRENDA team
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Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
malfunction
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knockdown of PME-1 downregulates the elevated dmL307-PP2A level induced by GSK-3 activation
physiological function
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
[phosphatase 2A protein]-leucine methyl ester + H2O
[phosphatase 2A protein]-leucine + methanol
show the reaction diagram
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?
[protein phosphatase 2A catalytic subunit]-leucine methyl ester + H2O
[protein phosphatase 2A catalytic subunit]-leucine + methanol
show the reaction diagram
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reversible methylation and demethylation at C-terminal residue Leu309. The activity of protein phosphatase 2A is largely unaffected by the addition of enzyme. Mutant versions of substrate protein phosphatase 2A containing an alanine residue in place of Leu309, and a deletion of Leu309 both exhibit phosphatase activity
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r
additional information
?
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NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
additional information
?
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INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
(E)-2-(4-fluorophenylsulfonyl)-3-(1-(3-nitrophenylsulfonyl)-1H-pyrrol-2-yl)acrylonitrile
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compound inhibits PME-1 with more than100fold selectivity relative to other serine hydrolases in human cells. Application reduces the demethylated form of substrate protein phosphatase 2A in living cells
dimethyl 3-cyclopentyl-4-oxo-3-phenylcyclobutane-1,2-dicarboxylate
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in both MDA-MB-231 and HEK-293T cells, highly potent and selective inhibition of the enzyme with IC50 values of 11.1 nM and 6.4 nM. Analysis reveals complete and selective in situ inhibition of PME-1 with no activity against more than 50 other serine hydrolases detected in MDA-MB-231 and HEK-293T cells. In both cell lines, inhibition results in significant reductions in the levels of demethylated PP2A
okadaic acid
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IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0006
(E)-2-(4-fluorophenylsulfonyl)-3-(1-(3-nitrophenylsulfonyl)-1H-pyrrol-2-yl)acrylonitrile
Homo sapiens
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pH 7.5, 37°C
pI VALUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
5.8
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calculated
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
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Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
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PME-1 is localised in the cytoplasm of adult rat ventricular myocytes
Manually annotated by BRENDA team
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enzyme is predominantly localized in the nucleus and harbors a functional nuclear localization signal. This is in good correlation with the methylation status of its substrate protein phosphates PP2AC, demethylated PP2AC being substantially nuclear
Manually annotated by BRENDA team
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negligible localisation in the soluble membrane
Manually annotated by BRENDA team
PDB
SCOP
CATH
ORGANISM
UNIPROT
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
42000
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x * 42000, calculated, x * 44000, SDS-PAGE
44000
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x * 42000, calculated, x * 44000, SDS-PAGE
45000
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x * 45000, SDS-PAGE
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
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enzyme forms stable complexes with catalytically inactive mutants of the C subunit of its substrate protein phosphatase 2A. The carboxyl terminus of protein phosphatase 2A C subunit mutant H59Q is important, but not essential, for complex formation
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
phosphoprotein
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PME-1 is phosphorylated in vitro by active CaMKI and dephosphorylated by salt-inducible kinase 2 (SIK2)/protein phosphatase 2 (PP2A)
Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
crystal structures of methylesterase PME-1 by itself and in complex with a protein phosphatase PP2A heterodimeric core enzyme, to 2.0 and 2.7 A resolution. PME-1 directly binds to the active site of protein phosphatase PP2A and this interaction results in the activation of PME-1 by rearranging the catalytic triad into an active conformation. These interactions also lead to inactivation of protein phosphatase PP2A by evicting the manganese ions that are required for the phosphatase activity of PP2A. PME-1 fdisplays a dual role that regulates protein phosphatase PP2A activation, methylation, and holoenzyme assembly in cells
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Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
inhibition of GSK-3 decreases PME-1 expression
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pharmacological activation of glycogen synthase kinase-3beta (GSK-3) by wortmannin (WO) increases PME-1 expression
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there is no statistical difference in expression of enzyme in ischemic and non-ischemic human heart failure samples compared with non-failing heart tissue
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ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
K38A
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mutation does not abolish nuclear localization of enzyme
R271A
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mutation abolishes nuclear localization of enzyme
R37A
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mutation does not abolish nuclear localization of enzyme
R39A
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mutation does not abolish nuclear localization of enzyme
S156A
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mutation abolishes the methylesterase activity, residue S156 is a functional active site serine
additional information
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construction of deletion mutants and expression in HeLa cells. Domain 1 of the enzyme extends from amino acids 1 to 233, domain 2 from amino acids 234 to 284 and domain 3 includes amino acids 285 to 378. Domain 1 of PME-1 does not migrate into the nucleus and domain 3 shows a speckled cytoplasmic distribution, whereas domain 2 is targeted to the nucleus
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
medicine
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no difference in methylation of substrate PP2A catalytic subunit at residue Leu-309 in nonischemic heart failure samples compared with non-failing heart, and no statistical difference in expression of enzyme in ischemic and non-ischemic human heart failure samples compared with non-failing heart tissue