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Information on EC 2.1.1.233 - [phosphatase 2A protein]-leucine-carboxy methyltransferase and Organism(s) Homo sapiens
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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: Homo sapiens
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, leucine carboxyl methyl transferase 1, 
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topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
LCMT-1
LCMT1
leucine carboxyl 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 + [phosphatase 2A protein]-leucine309
S-adenosyl-L-homocysteine + [phosphatase 2A protein]-leucine309 methyl ester
additional information
?
-
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no activity changes are observed upon methylation of dimeric and trimeric phosphatase 2A protein
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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]-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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the enzyme exclusively methylates the carboxyl group of the C-terminal leucine residue of the catalytic subunit of protein phosphatase 2A (Leu309)
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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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the enzyme LCMT1 methylates the terminal carboxyl group of the leucine 309 residue of protein phosphatase 2A protein
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-
?
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]-leucine309
S-adenosyl-L-homocysteine + [phosphatase 2A protein]-leucine309 methyl ester
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absolut specific methylation of Leu309 in the C subunit of phosphatase 2A protein, no activity with Leu309DELTA PPA2 mutant
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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
-
-
-
?
S-adenosyl-L-methionine + [phosphatase 2A protein]-leucine309
S-adenosyl-L-homocysteine + [phosphatase 2A protein]-leucine309 methyl ester
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-
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0018
[phosphatase 2A protein]-leucine
pH and temperature not specified in the publication
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IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
pI VALUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
immunohistochemic analysis of LCMT-1 content in human postmortem brain sections, brain from humans with disease, such as progressive supranuclear palsy and Alzheimer's disease, clinical and neuropathological characteristics, overview
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
-
the enzyme is underrepresented in the nucleus and mainly localized to the cytoplasm, Golgi region and late endosomes
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the enzyme is underrepresented in the nucleus and mainly localized to the cytoplasm, Golgi region and late endosomes
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the enzyme is underrepresented in the nucleus and mainly localized to the cytoplasm, Golgi region and late endosomes
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the enzyme is underrepresented in the nucleus and mainly localized to the cytoplasm, Golgi region and late endosomes
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LCMT1 and methylated phosphatase 2A protein are concentrated in rafts, whereas demethylated phosphatase 2A protein and small amounts of PME-1 are preferentially distributed in non-raft membrane microdomains
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
metabolism
physiological function
malfunction
-
a dominant-negative leucine carboxyl methyltransferase 1 mutant attenuates the cell cycle without causing cell death, likely by inhibiting uncontrolled phosphatase activity
malfunction
-
leucine carboxyl methyltransferase-1 (LCMT-1) knockdown reduces the formation of protein phosphatase 2A heterotrimers containing the Balpha regulatory subunit and, in a subset of the cells, induces apoptosis, characterized by caspase activation, nuclear condensation/fragmentation, and membrane blebbing. LCMT-1 knockdown cells are more sensitive to the spindle-targeting drug nocodazole
malfunction
-
decreased phosphatase 2A protein catalytic subunit methylation is linked with decreased LCMT-1 expression causing human heart failure, overview
malfunction
-
depletion of leucine carboxyl methyltransferase-1, LCMT1, or overexpression of protein phosphatase methylesterase-1, PME-1, lead to long spindles. In contrast, depletion of PME-1, pharmacological inhibition of PME-1 or overexpression of LCMT1 lead to short spindles. Perturbation of the LCMT1-PME-1 methylation equilibrium leads to mitotic arrest, spindle assembly checkpoint activation, defective cell divisions, induction of apoptosis and reduced cell viability, phenotype, overview
malfunction
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reduced methylation of phosphatase 2A protein through enzyme LCMT1, a major Tau phosphatase, occurs in Alzheimer disease. Altered phosphatase 2A protein and Tau membrane distribution can promote neuronal dysfunction and phospho-Tau pathology in Alzheimer disease. Methylation-incompetent L309DELTA mutant of PP2A C subunit is excluded from membrane rafts. Expression of the inactive LCMT1 mutant inhibits the accumulation of dephosphorylated and total Tau at the plasma membrane, whereas concomitantly enhancing Tau phosphorylation at the Ser422 phospho-epitope. Partial knockdown of LCMT1 in Neuro2a cells is associated with a 42-45% decrease in total amounts of membrane-associated Tau pools relative to controls
malfunction
increased expression of NNMT selectively affects LCMT1 resulting in lower PP2A activation. Decreased LCMT1 expression or SAH concentration decreases endogenous activated PP2A
malfunction
Protein phosphatase 2A and its methylation modulating enzymes LCMT-1 and PME-1 are dysregulated in tauopathies of progressive supranuclear palsy and Alzheimer's disease, pathologic phenotype, overview. Analyses shows a decrease of methyl-PP2A and an increase of demethyl-PP2A with a concomitant reduction in the methyl/demethyl PP2A ratio in both PSP (74%) and AD (76%) brains. This is associated with a decrease in LCMT-1 and an increase in the demethylating enzyme, protein phosphatase methylesterase (PME-1), in both diseases. State of PP2A regulation in tauopathies, overview
metabolism
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past global read-outs of cellular PP2A activity more appropriately represent the collective activity of numerous individual PP2A holoenzymes, each displaying a specific subcellular localization (dictated by select PP2A regulatory subunits) as well as local specific post-translational catalytic subunit methylation and phosphorylation events that regulate local and rapid holoenzyme assembly/disassembly via leucine carboxymethyltransferase 1/phosphatase methylesterase 1 (LCMT-1/PME-1), PP2A regulation system involving nine different PP2A regulatory subunits (PPP2R2A, PPP2R2B, PPP2R3A, PPP2R4, PPP2R5A, PPP2R5B, PPP2R5C, PPP2R5D, and PPP2R5E) in the heart. LCMT-1 and PME-1 show cell-type and disease-linked expressional regulation, overview
metabolism
nicotinamide-N-methyltransferase (NNMT, EC 2.1.1.1) outcompetes leucine carboxyl methyl transferase 1 (LCMT1) for methyl transfer from principal methyl donor SAM in biological systems, because NNMT has a higher affinity for SAM as compared to LCMT1. Inhibiting NNMT increases the availability of methyl groups for LCMT1 to methylate protein phosphatase 2A (PP2A) resulting in the inhibition of oncogenic serine/threonine kinases (STKs, EC 2.7.11.). Even if there are methylated products in the system by LCMT1, which is a O-methylating enzyme, they can potentially be reversed to unmethylated form due to their reversible nature and availability of demethylases such as PME1. In contrast, N-methylating NNMT enzyme product MNA which is stable and acts as methylation sink further favoring methyl transfer by NNMT compared to LCMT1. The NNMT-PME1-LCMT1 signaling axis is one mechanism by which the activity of the MAPK/Akt pathways are maintained in cancer cells
physiological function
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leucine carboxyl methyltransferase-1 (LCMT-1) is necessary for normal progression through mitosis and cell survival. LCMT-1 is important for spindle checkpoint
physiological function
-
the enzyme tightly controls phosphatase 2A protein function, important for the cell cycle and cell survival
physiological function
-
leucine carboxyl methyltransferase 1-dependent methylation regulates the association of protein phosphatase 2A and Tau protein with plasma membrane microdomains in neuroblastoma cells
physiological function
-
leucine carboxyl methyltransferase-1, LCMT1, and protein phosphatase methylesterase-1, PME-1, are essential enzymes that regulate the methylation of the protein phosphatase 2A catalytic subunit. The two enzymes have been linked to the regulation of cell growth and proliferation, and a role of LCMT1-PME-1 methylation equilibrium in controlling mitotic spindle size. The LCMT1-PME-1 methylation equilibrium is critical for regulating mitotic spindle size and thereby proper cell division
physiological function
methylation of protein phosphatase 2A (PP2A) activates PP2A activity
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). LCMT1_HUMAN
334
0
38379
Swiss-Prot
other Location (Reliability: 2)
I3L4A2_HUMAN
158
0
18163
TrEMBL
other Location (Reliability: 2)
I3L2E3_HUMAN
93
0
10595
TrEMBL
Secretory Pathway (Reliability: 3)
I3L2Q8_HUMAN
119
0
13740
TrEMBL
other Location (Reliability: 1)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
enzyme in isolation and in complex with phosphatase 2A protein stabilized by a cofactor mimic, hanging drop vapor diffusion method, using 17-19% (w/v) PEG2000 monomethyl ether, 150 mM triethylamine N-oxide, and 5 mM dithiothreitol
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in complex with the cofactor S-adenosylmethionine, hanging drop vapor diffusion method
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
D303R
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the mutant shows less than 10% activity compared to the wild type enzyme
F237D
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the mutant shows less than 10% activity compared to the wild type enzyme
N244A
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the mutant shows less than 40% activity compared to the wild type enzyme
additional information
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generation of LCMT1-R71DELTA, a catalytically inactive mutant of LCMT1
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
phenyl Sepharose column chromatography, DEAE cellulose column chromatography, Poros ion exchange column chromatography, DEAE Sephacelcolumn chromatography, and Sephadex G-75 gel filtration
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant expression of HA-tagged enzyme LCMT1 in Neuro-2a cells, coepression with Myc-tagged PME-1
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REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Tsai, M.; Cronin, N.; Djordjevic, S.
The structure of human leucine carboxyl methyltransferase 1 that regulates protein phosphatase PP2A
Acta Crystallogr. Sect. D
67
14-24
2011
Homo sapiens
De Baere, I.; Derua, R.; Janssens, V.; Van Hoof, C.; Waelkens, E.; Merlevede, W.; Goris, J.
Purification of porcine brain protein phosphatase 2A leucine carboxyl methyltransferase and cloning of the human homologue
Biochemistry
38
16539-16547
1999
Homo sapiens, Sus scrofa
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
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
Stanevich, V.; Jiang, L.; Satyshur, K.; Li, Y.; Jeffrey, P.; Li, Z.; Menden, P.; Semmelhack, M.; Xing, Y.
The structural basis for tight control of PP2A methylation and function by LCMT-1
Mol. Cell.
41
331-342
2011
Homo sapiens
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
Xia, X.; Gholkar, A.; Senese, S.; Torres, J.Z.
A LCMT1-PME-1 methylation equilibrium controls mitotic spindle size
Cell Cycle
14
1938-1947
2015
Homo sapiens
Sontag, J.M.; Nunbhakdi-Craig, V.; Sontag, E.
Leucine carboxyl methyltransferase 1 (LCMT1)-dependent methylation regulates the association of protein phosphatase 2A and Tau protein with plasma membrane microdomains in neuroblastoma cells
J. Biol. Chem.
288
27396-27405
2013
Homo sapiens
Palanichamy, K.; Kanji, S.; Gordon, N.; Thirumoorthy, K.; Jacob, J.R.; Litzenberg, K.T.; Patel, D.; Chakravarti, A.
NNMT silencing activates tumor suppressor PP2A, inactivates oncogenic STKs, and inhibits tumor forming ability
Clin. Cancer Res.
23
2325-2334
2017
Homo sapiens (Q9UIC8)
Park, H.J.; Lee, K.W.; Oh, S.; Yan, R.; Zhang, J.; Beach, T.G.; Adler, C.H.; Voronkov, M.; Braithwaite, S.P.; Stock, J.B.; Mouradian, M.M.
Protein phosphatase 2A and its methylation modulating enzymes LCMT-1 and PME-1 are dysregulated in tauopathies of progressive supranuclear palsy and Alzheimer disease
J. Neuropathol. Exp. Neurol.
77
139-148
2018
Homo sapiens (Q9UIC8)
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