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Information on EC 3.1.1.89 - protein phosphatase methylesterase-1 and Organism(s) Homo sapiens and UniProt Accession Q9Y570

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     3 Hydrolases
         3.1 Acting on ester bonds
             3.1.1 Carboxylic-ester hydrolases
                3.1.1.89 protein phosphatase methylesterase-1
IUBMB Comments
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.
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Homo sapiens
UNIPROT: Q9Y570
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Word Map
The taxonomic range for the selected organisms is: Homo sapiens
The enzyme appears in selected viruses and cellular organisms
Reaction Schemes
[phosphatase 2A protein]-leucine methyl ester
+
=
[phosphatase 2A protein]-leucine
+
Synonyms
ppme1, pp2a methylesterase, protein phosphatase methylesterase-1, phosphatase methylesterase-1, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
protein phosphatase methylesterase-1
-
PP2A methylesterase
-
-
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.
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
[protein phosphatase 2A catalytic subunit]-leucine methyl ester + H2O
[protein phosphatase 2A catalytic subunit]-leucine + methanol
show the reaction diagram
-
-
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
-
r
additional information
?
-
-
spliced isoform PP2Acalpha2 (lacking exon 5) does not interact with PME-1. Only the longer isoform of PP2A interacts with PME-1
-
-
?
NATURAL SUBSTRATE
NATURAL 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
additional information
?
-
-
spliced isoform PP2Acalpha2 (lacking exon 5) does not interact with PME-1. Only the longer isoform of PP2A interacts with PME-1
-
-
?
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
ABL127
aza-beta-lactum inhibitor
AMZ30
sulfonyl acrylonitrile inhibitor
okadaic acid
-
(E)-2-(4-fluorophenylsulfonyl)-3-(1-(3-nitrophenylsulfonyl)-1H-pyrrol-2-yl)acrylonitrile
-
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
-
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
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.00001
ABL127
Homo sapiens
pH and temperature not specified in the publication
0.0005
AMZ30
Homo sapiens
pH and temperature not specified in the publication
0.0006
(E)-2-(4-fluorophenylsulfonyl)-3-(1-(3-nitrophenylsulfonyl)-1H-pyrrol-2-yl)acrylonitrile
Homo sapiens
-
pH 7.5, 37°C
pI VALUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
5.8
calculated
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
in human glioma cell, high PME-1 expression correlates with tumor progression and kinase inhibitor resistance
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
-
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
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
malfunction
PME-1 knockdown by siRNA or shRNA inhibits cancer cell growth not only in in vitro but also in in vivo endometrial cancer xenograft models
metabolism
physiological function
-
overexpression of enzyme PME-1, but not of an inactive mutant, results in increased demethylation of substrate protein phosphatase PP2AC in the nucleus, whereas overexpression of a cytoplasmic PME-1 mutant lacking the nuclear localization signal results in increased demethylation in the cytoplasm, albeit without any obvious functional consequences. PME-1 associates with an inactive PP2A population, regardless of its esterase activity or localization. RNAi-mediated knock-down of PME-1 in HeLa cellsdoes not result in changes in substrate PP2AC methylation levels
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION?
PPME1_HUMAN
386
0
42315
Swiss-Prot
other Location (Reliability: 5)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
42000
x * 42000, calculated, x * 44000, SDS-PAGE
44000
x * 42000, calculated, x * 44000, SDS-PAGE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
?
x * 42000, calculated, x * 44000, SDS-PAGE
additional information
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
phosphoprotein
-
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
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
K38A
-
mutation does not abolish nuclear localization of enzyme
R271A
-
mutation abolishes nuclear localization of enzyme
R37A
-
mutation does not abolish nuclear localization of enzyme
R39A
-
mutation does not abolish nuclear localization of enzyme
S156A
-
mutation abolishes the methylesterase activity, residue S156 is a functional active site serine
additional information
-
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
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
there is no statistical difference in expression of enzyme in ischemic and non-ischemic human heart failure samples compared with non-failing heart tissue
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
medicine
in a xenograft model of endometrial cancer, covalent PME-1 inhibitors decrease cell proliferation and invasive growth in vitro but have no effect in vivo at the concentrations tested. Depletion of PME-1 with shRNA in an endometrial cancer xenograft model significantly reduces tumor growth
pharmacology
RNAi and pharmacologic inhibition of PME-1 in vitro leads to decreased cell proliferation and invasive growth in endometrial cancer cells. Discovery of more potent PME-1 inhibitors may be beneficial for the treatment of endometrial cancer
medicine
-
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
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Longin, S.; Zwaenepoel, K.; Martens, E.; Louis, J.; Rondelez, E.; Goris, J.; Janssens, V.
Spatial control of protein phosphatase 2A (de)methylation
Exp. Cell Res.
314
68-81
2008
Homo sapiens
Manually annotated by BRENDA team
Ikehara, T.; Ikehara, S.; Imamura, S.; Shinjo, F.; Yasumoto, T.
Methylation of the C-terminal leucine residue of the PP2A catalytic subunit is unnecessary for the catalytic activity and the binding of regulatory subunit (PR55/B)
Biochem. Biophys. Res. Commun.
354
1052-1057
2007
Homo sapiens
Manually annotated by BRENDA team
Xing, Y.; Li, Z.; Chen, Y.; Stock, J.; Jeffrey, P.; Shi, Y.
Structural mechanism of demethylation and inactivation of protein phosphatase 2A
Cell
133
154-163
2008
Homo sapiens (Q9Y570)
Manually annotated by BRENDA team
Ogris, E.; Du, X.; Nelson, K.; Mak, E.; Yu, X.; Lane, W.; Pallas, D.
A protein phosphatase methylesterase (PME-1) is one of several novel proteins stably associating with two inactive mutants of protein phosphatase 2A
J. Biol. Chem.
274
14382-14391
1999
Homo sapiens (Q9Y570), Homo sapiens
Manually annotated by BRENDA team
DeGrande, S.; Little, S.; Nixon, D.; Wright, P.; Snyder, J.; Dun, W.; Murphy, N.; Kilic, A.; Higgins, R.; Binkley, P.; Boyden, P.; Carnes, C.; Anderson, M.; Hund, T.; Mohler, P.
Molecular mechanisms underlying cardiac protein phosphatase 2A regulation in heart
J. Biol. Chem.
288
1032-1046
2013
Homo sapiens
Manually annotated by BRENDA team
Bachovchin, D.A.; Zuhl, A.M.; Speers, A.E.; Wolfe, M.R.; Weerapana, E.; Brown, S.J.; Rosen, H.; Cravatt, B.F.
Discovery and optimization of sulfonyl acrylonitriles as selective, covalent inhibitors of protein phosphatase methylesterase-1
J. Med. Chem.
54
5229-5236
2011
Homo sapiens
Manually annotated by BRENDA team
Bachovchin, D.A.; Mohr, J.T.; Speers, A.E.; Wang, C.; Berlin, J.M.; Spicer, T.P.; Fernandez-Vega, V.; Chase, P.; Hodder, P.S.; Schuerer, S.C.; Nomura, D.K.; Rosen, H.; Fu, G.C.; Cravatt, B.F.
Academic cross-fertilization by public screening yields a remarkable class of protein phosphatase methylesterase-1 inhibitors
Proc. Natl. Acad. Sci. USA
108
6811-6816
2011
Homo sapiens
Manually annotated by BRENDA team
Migueleti, D.; Smetana, J.; Nunes, H.; Kobarg, J.; Zanchin, N.
Identification and characterization of an alternatively spliced isoform of the human protein phosphatase 2Aalpha catalytic subunit
J. Biol. Chem.
287
4853-4862
2012
Homo sapiens
Manually annotated by BRENDA team
Lee, C.W.; Yang, F.C.; Chang, H.Y.; Chou, H.; Tan, B.C.; Lee, S.C.
Interaction between salt-inducible kinase 2 and protein phosphatase 2A regulates the activity of calcium/calmodulin-dependent protein kinase I and protein phosphatase methylesterase-1
J. Biol. Chem.
289
21108-21119
2014
Homo sapiens
Manually annotated by BRENDA team
Kaur, A.; Westermarck, J.
Regulation of protein phosphatase 2A (PP2A) tumor suppressor function by PME-1
Biochem. Soc. Trans.
44
1683-1693
2016
Mus musculus (Q8BVQ5), Homo sapiens (Q9Y570), Homo sapiens
Manually annotated by BRENDA team
Pusey, M.; Bail, S.; Xu, Y.; Buiakova, O.; Nestor, M.; Yang, J.J.; Rice, L.M.
Inhibition of protein methylesterase 1 decreased cancerous phenotypes in endometrial adenocarcinoma cell lines and xenograft tumor models
Tumour Biol.
37
11835-11842
2016
Homo sapiens (Q9Y570)
Manually annotated by BRENDA team