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Information on EC 2.1.1.233 - [phosphatase 2A protein]-leucine-carboxy methyltransferase and Organism(s) Mus musculus and UniProt Accession A2RTH5
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2.1.1.233 [phosphatase 2A protein]-leucine-carboxy methyltransferaseIUBMB Comments
Methylates the C-terminal leucine of phosphatase 2A. A key regulator of protein phosphatase 2A. The methyl ester is hydrolysed by EC 3.1.1.89 (protein phosphatase methylesterase-1). Occurs mainly in the cytoplasm, Golgi region and late endosomes.
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The taxonomic range for the selected organisms is: Mus musculus
The expected taxonomic range for this enzyme is: Eukaryota, Archaea, Bacteria
The expected taxonomic range for this enzyme is: Eukaryota, Archaea, Bacteria
Reaction Schemes
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[phosphatase 2A protein]-leucine
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[phosphatase 2A protein]-leucine methyl ester
Synonyms
pme-1, lcmt-1, lcmt1, pp2a methyltransferase, leucine carboxyl methyltransferase, leucine carboxyl methyltransferase-1, leucine carboxyl methyltransferase 1, ppm1p, pp2a-specific methyltransferase, pp2a-methyltransferase, 
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topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
LCMT-1
LCMT1
leucine carboxyl methyltransferase 1
PP2A methyltransferase
SYSTEMATIC NAME
IUBMB Comments
S-adenosyl-L-methionine:[phosphatase 2A protein]-leucine O-methyltransferase
Methylates the C-terminal leucine of phosphatase 2A. A key regulator of protein phosphatase 2A. The methyl ester is hydrolysed by EC 3.1.1.89 (protein phosphatase methylesterase-1). Occurs mainly in the cytoplasm, Golgi region and late endosomes.
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
S-adenosyl-L-methionine + [phosphatase 2A protein]-leucine
S-adenosyl-L-homocysteine + [phosphatase 2A protein]-leucine methyl ester
S-adenosyl-L-methionine + [protein phosphatase 4 catalytic subunit]-leucine
S-adenosyl-L-homocysteine + [protein phosphatase 4 catalytic subunit]-leucine methyl ester
S-adenosyl-L-methionine + [protein phosphatase 6 catalytic subunit]-leucine
S-adenosyl-L-homocysteine + [protein phosphatase 6 catalytic subunit]-leucine methyl ester
S-adenosyl-L-methionine + [phosphatase 2A protein]-leucine
S-adenosyl-L-homocysteine + [phosphatase 2A protein]-leucine methyl ester
S-adenosyl-L-methionine + [phosphatase 2A protein]-leucine309
S-adenosyl-L-homocysteine + [phosphatase 2A protein]-leucine309 methyl ester
S-adenosyl-L-methionine + [phosphatase 2A protein]-leucine
S-adenosyl-L-homocysteine + [phosphatase 2A protein]-leucine methyl ester
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-
-
?
S-adenosyl-L-methionine + [phosphatase 2A protein]-leucine
S-adenosyl-L-homocysteine + [phosphatase 2A protein]-leucine methyl ester
LCMT-1 is the major methyltransferase in embryonic fibroblasts for all three PP2A subfamily phosphatases, PP2Ac, PP4c, and PP6c
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-
?
S-adenosyl-L-methionine + [protein phosphatase 4 catalytic subunit]-leucine
S-adenosyl-L-homocysteine + [protein phosphatase 4 catalytic subunit]-leucine methyl ester
-
-
-
?
S-adenosyl-L-methionine + [protein phosphatase 4 catalytic subunit]-leucine
S-adenosyl-L-homocysteine + [protein phosphatase 4 catalytic subunit]-leucine methyl ester
LCMT-1 is the major methyltransferase in embryonic fibroblasts for all three PP2A subfamily phosphatases, PP2Ac, PP4c, and PP6c
-
-
?
S-adenosyl-L-methionine + [protein phosphatase 6 catalytic subunit]-leucine
S-adenosyl-L-homocysteine + [protein phosphatase 6 catalytic subunit]-leucine methyl ester
-
-
-
?
S-adenosyl-L-methionine + [protein phosphatase 6 catalytic subunit]-leucine
S-adenosyl-L-homocysteine + [protein phosphatase 6 catalytic subunit]-leucine methyl ester
LCMT-1 is the major methyltransferase in embryonic fibroblasts for all three PP2A subfamily phosphatases, PP2Ac, PP4c, and PP6c
-
-
?
S-adenosyl-L-methionine + [phosphatase 2A protein]-leucine
S-adenosyl-L-homocysteine + [phosphatase 2A protein]-leucine methyl ester
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-
-
-
?
S-adenosyl-L-methionine + [phosphatase 2A protein]-leucine
S-adenosyl-L-homocysteine + [phosphatase 2A protein]-leucine methyl ester
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-
-
?
S-adenosyl-L-methionine + [phosphatase 2A protein]-leucine309
S-adenosyl-L-homocysteine + [phosphatase 2A protein]-leucine309 methyl ester
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-
-
-
?
S-adenosyl-L-methionine + [phosphatase 2A protein]-leucine309
S-adenosyl-L-homocysteine + [phosphatase 2A protein]-leucine309 methyl ester
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specific for
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-
?
additional information
?
-
-
enzyme LCMT1 is a class 1 S-adenosylmethionine-dependent methyltransferase with PP2A as its only known substrate
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-
?
additional information
?
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peptides mimicking the C-terminal tail of PP2A are not substrates of LCMT1
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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
S-adenosyl-L-methionine + [phosphatase 2A protein]-leucine
S-adenosyl-L-homocysteine + [phosphatase 2A protein]-leucine methyl ester
LCMT-1 is the major methyltransferase in embryonic fibroblasts for all three PP2A subfamily phosphatases, PP2Ac, PP4c, and PP6c
-
-
?
S-adenosyl-L-methionine + [protein phosphatase 4 catalytic subunit]-leucine
S-adenosyl-L-homocysteine + [protein phosphatase 4 catalytic subunit]-leucine methyl ester
LCMT-1 is the major methyltransferase in embryonic fibroblasts for all three PP2A subfamily phosphatases, PP2Ac, PP4c, and PP6c
-
-
?
S-adenosyl-L-methionine + [protein phosphatase 6 catalytic subunit]-leucine
S-adenosyl-L-homocysteine + [protein phosphatase 6 catalytic subunit]-leucine methyl ester
LCMT-1 is the major methyltransferase in embryonic fibroblasts for all three PP2A subfamily phosphatases, PP2Ac, PP4c, and PP6c
-
-
?
S-adenosyl-L-methionine + [phosphatase 2A protein]-leucine
S-adenosyl-L-homocysteine + [phosphatase 2A protein]-leucine methyl ester
-
-
-
?
S-adenosyl-L-methionine + [phosphatase 2A protein]-leucine309
S-adenosyl-L-homocysteine + [phosphatase 2A protein]-leucine309 methyl ester
-
-
-
-
?
additional information
?
-
-
enzyme LCMT1 is a class 1 S-adenosylmethionine-dependent methyltransferase with PP2A as its only known substrate
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
alpha-synuclein
alpha-syn, negatively regulates protein phosphatase 2A (PP2A) methylation via LCMT-1 and PME-1, whilst activation of LCMT-1 and inhibition of PME-1 reverses this process
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
isolated from proximal caput, distal caput, and caudal regions of the epididymis
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
mouse embryonic fibroblasts derived from LCMT-1 knock-out mouse embryos have reduced levels of PP2A B regulatory subunit and PP4R1 relative to control mouse embryonic fibroblasts, indicating that LCMT-1 is important for maintaining normal levels of these subunits. LCMT-1 homozygous knock-out mouse embryonic fibroblasts exhibit hyperphosphorylation of HDAC3, a reported target of the methylation-dependent PP4R1-PP4c complex
physiological function
malfunction
metabolism
in vivo demethylation of sperm PP2A in the epididymis, regulation of protein phosphatase activity in sperm
physiological function
physiological function
generation of transgenic mice that overexpress the leucine carboxylmethyltransferase-1 (LCMT-1). LCMT-1 overexpression protected against behavioral and electrophysiological impairments caused by exogenous Abeta exposure
physiological function
the enzyme coordinately regulates the carboxyl methylation of PP2A-related phosphatases and, consequently, their holoenzyme assembly and function
malfunction
-
homozygous gene trap knock-out of leucine carboxyl methyltransferase-1 in mice results in embryonic lethality
malfunction
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hypomorphic Lcmt1 mice show reduced protein phosphatase 2A methyltransferase expression due to splicing around the insertion, Lcmt1 transcript and LCMT1 protein levels are reduced but not eliminated. LCMT1 activity and methylation of protein phosphatase 2A are reduced in a coordinate fashion, suggesting that LCMT1 is the only PP2A methyltransferase. The mice exhibit an insulin-resistance phenotype. Knockout of Lcmt1 in mice is lethal during embryonic development. Male Lcmt1-/- animals display increased glucose-stimulated insulin secretion, increased insulin resistance, and decreased methylation of phosphatase 2A protein
malfunction
alpha-synuclein (alpha-syn) overexpression induces increased alpha-syn phosphorylation at Ser129, and protein phosphatase 2A (PP2A) inhibition, in vitro and in vivo. alpha-Syn overexpression results in PP2A demethylation. This demethylation is mediated via downregulated leucine carboxyl methyltransferase (LCMT-1) expression, and upregulated protein phosphatase methylesterase (PME-1, EC 3.1.1.89) expression. Furthermore, LCMT-1 overexpression, or PME-1 inhibition, reverses alpha-syn-induced increases in alpha-syn phosphorylation and apoptosis
physiological function
-
leucine carboxyl methyltransferase-1 (LCMT-1) is essential for embryonic development in mice. LCMT-1 is important for spindle checkpoint
physiological function
-
regulation of protein phosphatase 2A methylation by leucine carboxy methyltransferase-1 (LCMT1) plays a critical role in differentiation of neuroblastoma cells. Enhanced expression of LCMT1 in cultured N2a neuroblastoma cells induces changes in F-actin organization. Expression of LCMT1 promotes the formation of elongated neurite-like processes
physiological function
-
protein phosphatase 2A is the major serine/threonine phosphatase in eukaryotic cells, its assembly is governed by a variety of mechanisms, one of which is carboxyl-terminal methylation of the catalytic subunit by the leucine carboxyl methyltransferase LCMT1. Protein phosphatase 2A is nearly stoichiometrically methylated in the cytosol. Role for this methyltransferase in signaling in insulin-sensitive tissues
physiological function
LCMT-1 overexpression or protein phosphatase methylesterase (PME-1, EC 3.1.1.89) inhibition protects against alpha-syn-induced protein phosphatase 2A (PP2A) inhibition, and increases in apoptosis of SK-N-SH cells
physiological function
the enzyme PP2A methyl transferase, LCMT1 responsible for transferring the methyl group from S-adenosyl methionine specifically to PP2A
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). A2RTH5_MOUSE
332
0
38192
TrEMBL
other Location (Reliability: 2)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
-
generation of hypomorphic Lcmt1 mice with reduced protein phosphatase 2A methyltransferase expression and defects in insulin signaling, circumventing embryonic lethality with Lcmt1 deficiency
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
gene lcmt1, DNA and amino acid sequence determination and analysis, quantitative expression analysis in wild-type and mutant mice
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
alpha-syn overexpression results in PP2A demethylation. This demethylation is mediated via downregulated leucine carboxyl methyltransferase (LCMT-1) expression
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Lee, J.; Pallas, D.
Leucine carboxyl methyltransferase-1 is necessary for normal progression through mitosis in mammalian cells
J. Biol. Chem.
282
30974-30984
2007
Homo sapiens, Mus musculus
Sontag, J.; Nunbhakdi-Craig, V.; Mitterhuber, M.; Ogris, E.; Sontag, E.
Regulation of protein phosphatase 2A methylation by LCMT1 and PME-1 plays a critical role in differentiation of neuroblastoma cells
J. Neurochem.
115
1455-1465
2010
Mus musculus
MacKay, K.B.; Tu, Y.; Young, S.G.; Clarke, S.G.
Circumventing embryonic lethality with Lcmt1 deficiency: generation of hypomorphic Lcmt1 mice with reduced protein phosphatase 2A methyltransferase expression and defects in insulin signaling
PLoS ONE
8
e65967
2013
Mus musculus
Tian, H.; Lu, Y.; Liu, J.; Liu, W.; Lu, L.; Duan, C.; Gao, G.; Yang, H.
Leucine carboxyl methyltransferase downregulation and protein phosphatase methylesterase upregulation contribute toward the inhibition of protein phosphatase 2A by alpha-synuclein
Front. Aging Neurosci.
10
173
2018
Mus musculus (A0A0U1RNF2), Mus musculus, Mus musculus C57BL/6N (A0A0U1RNF2)
Hwang, J.; Lee, J.A.; Pallas, D.C.
Leucine carboxyl methyltransferase 1 (LCMT-1) methylates protein phosphatase 4 (PP4) and protein phosphatase 6 (PP6) and differentially regulates the stable formation of different PP4 holoenzymes
J. Biol. Chem.
291
21008-21019
2016
Mus musculus (A2RTH5), Mus musculus
Nicholls, R.E.; Sontag, J.M.; Zhang, H.; Staniszewski, A.; Yan, S.; Kim, C.Y.; Yim, M.; Woodruff, C.M.; Arning, E.; Wasek, B.; Yin, D.; Bottiglieri, T.; Sontag, E.; Kandel, E.R.; Arancio, O.
PP2A methylation controls sensitivity and resistance to beta-amyloid-induced cognitive and electrophysiological impairments
Proc. Natl. Acad. Sci. USA
113
3347-3352
2016
Mus musculus (A2RTH5), Mus musculus
Dudiki, T.; Kadunganattil, S.; Ferrara, J.; Kline, D.; Vijayaraghavan, S.
Changes in carboxy methylation and tyrosine phosphorylation of protein phosphatase PP2A are associated with epididymal sperm maturation and motility
PLoS ONE
10
e0141961
2015
Mus musculus (A0A0U1RNF2), Bos taurus (Q3T0H0)
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