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Information on EC 3.1.3.95 - phosphatidylinositol-3,5-bisphosphate 3-phosphatase and Organism(s) Homo sapiens and UniProt Accession Q96EF0
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EC Tree
3.1.3.95 phosphatidylinositol-3,5-bisphosphate 3-phosphataseIUBMB Comments
The enzyme is found in both plants and animals. It also has the activity of EC 3.1.3.64 (phosphatidylinositol-3-phosphatase).
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Word Map
- 3.1.3.95
- mtmr14
- 3-phosphate
- phosphoinositide
-
lupus
-
erythematosus
- medicine
-
caribbean
- tacrolimus
- mycophenolate
-
belimumab
-
hispanic
- corticosteroids
- mofetil
-
pleckstrin
- rituximab
- mizoribine
- azathioprine
-
flares
-
10-year
-
mtm-related
-
infection-related
-
nephritis
- cyclophosphamide
-
myopathy
The taxonomic range for the selected organisms is: Homo sapiens
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Reaction Schemes
Synonyms
myotubularin-related protein 3, myotubularin-related protein 14, myotubularin-related protein-4, myotubularin-related protein 1, myotubularin related protein-2, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
MTMR1
MTMR3
myotubularin-related protein 1
myotubularin-related protein 3
SYSTEMATIC NAME
IUBMB Comments
1-phosphatidyl-1D-myo-inositol-3,5-bisphosphate 3-phosphohydrolase
The enzyme is found in both plants and animals. It also has the activity of EC 3.1.3.64 (phosphatidylinositol-3-phosphatase).
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
1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 5-phosphate + phosphate
presence of catalytically inactive MTMR9 increases the enzymatic activity of isoform MTMR8 toward 1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate by 1.4fold
-
-
?
1-phosphatidyl-1D-myo-inositol 3-phosphate + H2O
1-phosphatidyl-1D-myo-inositol + phosphate
presence of catalytically inactive MTMR9 increases the enzymatic activity of isoform MTMR8 toward 1-phosphatidyl-1D-myo-inositol 3-phosphate by 4fold
-
-
?
1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 5-phosphate + phosphate
1-phosphatidyl-1D-myo-inositol 3-phosphate + H2O
1-phosphatidyl-1D-myo-inositol + phosphate
1-phosphatidyl-1D-myo-inositol 5-phosphate + H2O
1-phosphatidyl-1D-myo-inositol + phosphate
-
-
-
?
1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 5-phosphate + phosphate
-
-
-
-
?
1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 5-phosphate + phosphate
-
-
-
?
1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 5-phosphate + phosphate
-
isoform MTM1 can hydrolyze phosphatidylinositol 3,5-bisphosphate both in vitro and in mammalian cells
-
?
1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 5-phosphate + phosphate
-
product causes myotubularin MTM1 to form a heptameric ring that is 12.5 nm in diameter, and it is a specific allosteric activator of myotubularin MTM1, and myotubularin-related proteins MTMR3 and MTMR6
-
?
1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 5-phosphate + phosphate
-
-
product stimulates cell migration
-
?
1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 5-phosphate + phosphate
the enzyme also has the activity of EC 3.1.3.64 (phosphatidylinositol-3-phosphatase)
-
-
?
1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 5-phosphate + phosphate
presence of catalytically inactive MTMR9 increases the enzymatic activity of isoform MTMR6 toward 1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate by over 30fold
-
-
?
1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 5-phosphate + phosphate
-
substrate binds most strongly to the GRAM domain of isoform MTMR2
-
-
?
1-phosphatidyl-1D-myo-inositol 3-phosphate + H2O
1-phosphatidyl-1D-myo-inositol + phosphate
-
-
-
-
?
1-phosphatidyl-1D-myo-inositol 3-phosphate + H2O
1-phosphatidyl-1D-myo-inositol + phosphate
-
-
-
?
1-phosphatidyl-1D-myo-inositol 3-phosphate + H2O
1-phosphatidyl-1D-myo-inositol + phosphate
presence of catalytically inactive MTMR9 increases the enzymatic activity of isoform MTMR6 toward 1-phosphatidyl-1D-myo-inositol 3-phosphate by 2fold
-
-
?
additional information
?
-
isoform MTM1 additionally hydrolyzes 1-phosphatidyl-1D-myo-inositol 3-phosphate, reaction of EC 3.1.3.64
-
-
?
additional information
?
-
isoform MTMR6 shows similar activity with substrates 1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate and 1-phosphatidyl-1D-myo-inositol 3-phosphate
-
-
?
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
1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 5-phosphate + phosphate
1-phosphatidyl-1D-myo-inositol 3-phosphate + H2O
1-phosphatidyl-1D-myo-inositol + phosphate
-
-
-
-
?
1-phosphatidyl-1D-myo-inositol 5-phosphate + H2O
1-phosphatidyl-1D-myo-inositol + phosphate
-
-
-
?
1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 5-phosphate + phosphate
-
-
-
-
?
1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 5-phosphate + phosphate
-
-
-
?
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
1-phosphatidyl-1D-myo-inositol 5-phosphate
reaction product, acts as a specific allosteric activator of myotubularin MTM1, and myotubularin-related proteins MTMR3 and MTMR6
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
isoform MTMR2 and myotubularin-related protein MTMR13 cofractionate in both a light membrane fraction and a cytosolic fraction. MTMR13 membrane association is mediated by the segment of the protein which contains the pseudophosphatase domain
isoform MTMR2 and myotubularin-related protein MTMR13 cofractionate in both a light membrane fraction and a cytosolic fraction
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
physiological function
complex formation between the active isoform MTMR6 and catalytically inactive MTMR9 increases its catalytic activity and alters its substrate specificity. The MTMR6/MTMR9 complex prefers 1-phosphatidyl-1D-myo-inositol 3-phosphate as substrate. Presence of MTMR9 increases the enzymatic activity of MTMR8 toward 1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate by 1.4fold, and enhances the activity toward 1-phosphatidyl-1D-myo-inositol 3-phosphate by 4fold. In cells, the MTMR8/R9 complex reduces the cellular levels of 1-phosphatidyl-1D-myo-inositol 3-phosphate
malfunction
metabolism
-
enzyme levels control Piezo2 ion channels-mediated rapidly adapting mechanically activated currents
physiological function
malfunction
-
both depletion and overexpression of either myotubularin-related protein 3 or myotubularin-related protein 4 results in abnormal midbody morphology and cytokinesis failure
malfunction
-
enzyme knockdown markedly suppresses the motility, fusion, and fission of phosphatidylinositol 3-phosphate-enriched structures, resulting in decreases in late endosomes, autophagosomes, and lysosomes, and enlargement of phosphatidylinositol 3-phosphate-enriched early and late endosomes. Enzyme knockdown impairs starvation-induced transcription factor-EB nuclear translocation and lysosome biogenesis
physiological function
complex formation between the active isoform MTMR6 and catalytically inactive MTMR9 increases its catalytic activity and alters its substrate specificity. The MTMR6/MTMR9 complex prefers 1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate as substrate. Presence of MTMR9 increases the enzymatic activity of MTMR6 toward 1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate by over 30fold, and enhances the activity toward 1-phosphatidyl-1D-myo-inositol 3-phosphate by only 2fold. In cells, the MTMR6/R9 complex significantly increases the cellular levels of 1-phosphatidyl-1D-myo-inositol 3-phosphate, the product of 1-phosphatidyl-1D-myo-inositol 3-phosphate dephosphorylation
physiological function
endogenous isoform MTMR2 and myotubularin-related protein MTMR13 proteins are associated in human embryonic kidney 293 cells. MTMR2-MTMR13 association is mediated by coiled-coil sequences present in each protein. Loss of MTMR13 function in Charcot-Marie-Tooth disease type 4B patients may lead to alterations in MTMR2 function and subsequent alterations in 3-phosphoinositide signaling
physiological function
in L6 myotubes overexpressing isoform MTM1, hyperosmotic shock induces an increase in the mass level of 1-phosphatidyl-1D-myo-inositol 5-phosphate that is reduced by 50% upon overexpression of the MTM1 inactive mutant D278A
physiological function
-
on depletion of isoform MTMR3 by RNAi, BJ cells are unable to migrate into the wound and show a significant decrease in velocity of about 60% and a decrease in persistence. While 80% of control cells present actin fibres perpendicular to the wound, only 52% of the cells show this on MTMR3 depletion
physiological function
-
myotubularin-related proteins 3 and 4 interact with polo-like kinase 1 and centrosomal protein of 55000 Da to ensure proper abscission
physiological function
-
overexpression of isoform MTMR3 inhibits the activity of the serine/threonine kinase complex mTORC1. Thus the enzyme regulates autophagy via its effect on mTORC1 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). MTMR8_HUMAN
704
0
78919
Swiss-Prot
other Location (Reliability: 2)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
monomer
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
isoform MTMR8 phosphatase domain, hanging drop vapor diffusion method, using 10 mM N-(2-acetamido)iminodiacetic acid, 1.0 M ammonium phosphate dibasic pH 6.5 at 20°C
-
sitting drop vapor diffusion method, using 100 mM Na HEPES pH 7.0, 15% (w/v) polyethylene glycol 20000
-
sitting drop vapor diffusion method, using 100 mM Na-HEPES (pH 7.0) and 15% (w/v) polyethylene glycol 20000
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
A253K
-
the mutation enhances the kcat/Km value by 49% compared to the wild type enzyme
C413S
K255A
-
the mutation reduces the kcat/Km value by 66% compared to the wild type enzyme
K285A
the mutation has little effect on the phosphatase activity compared to the wild type enzyme
R480A
the mutant shows slightly reduced phosphatase activity compared to the wild type enzyme
C413S
catalytically inactive mutant. Overexpression of a catalytically dead MTMR3 (C413S) in mammalian cells induces a striking formation of vacuolar compartments that enclose membranous structures that are highly concentrated in mutant proteins
C413S
-
mutant without catalytic activity, mutant is unable to rescue the RNAi-knockdown phenotype, indicating that isoform MTMR3 acts enzymatically on phosphoinositides during cell migration
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
medicine
loss of myotubularin-related protein MTMR13 function in Charcot-Marie-Tooth disease type 4B patients may lead to alterations in isoform MTMR2 function and subsequent alterations in 3-phosphoinositide signaling
medicine
mutations in the MTM1 gene are associated with theX-linked myotubular myopathy
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Schaletzky, J.; Dove, S.K.; Short, B.; Lorenzo, O.; Clague, M.J.; Barr, F.A.
Phosphatidylinositol-5-phosphate activation and conserved substrate specificity of the myotubularin phosphatidylinositol 3-phosphatases
Curr. Biol.
13
504-509
2003
Homo sapiens (Q9Y217)
Tronchere, H.; Laporte, J.; Pendaries, C.; Chaussade, C.; Liaubet, L.; Pirola, L.; Mandel, J.L.; Payrastre, B.
Production of phosphatidylinositol 5-phosphate by the phosphoinositide 3-phosphatase myotubularin in mammalian cells
J. Biol. Chem.
279
7304-7312
2004
Homo sapiens (Q13496)
Robinson, F.L.; Dixon, J.E.
The phosphoinositide-3-phosphatase MTMR2 associates with MTMR13, a membrane-associated pseudophosphatase also mutated in type 4B Charcot-Marie-tooth disease
J. Biol. Chem.
280
31699-31707
2005
Homo sapiens (Q13614)
Walker, D.M.; Urbe, S.; Dove, S.K.; Tenza, D.; Raposo, G.; Clague, M.J.
Characterization of MTMR3. an inositol lipid 3-phosphatase with novel substrate specificity
Curr. Biol.
11
1600-1605
2001
Homo sapiens (Q13615)
Oppelt, A.; Lobert, V.H.; Haglund, K.; Mackey, A.M.; Rameh, L.E.; Liest?l, K.; Schink, K.O.; Pedersen, N.M.; Wenzel, E.M.; Haugsten, E.M.; Brech, A.; Rusten, T.E.; Stenmark, H.; Wesche, J.
Production of phosphatidylinositol 5-phosphate via PIKfyve and MTMR3 regulates cell migration
EMBO Rep.
14
57-64
2013
Homo sapiens
Tsujita, K.; Itoh, T.; Ijuin, T.; Yamamoto, A.; Shisheva, A.; Laporte, J.; Takenawa, T.
Myotubularin regulates the function of the late endosome through the gram domain-phosphatidylinositol 3,5-bisphosphate interaction
J. Biol. Chem.
279
13817-13824
2004
Homo sapiens
Zou, J.; Zhang, C.; Marjanovic, J.; Kisseleva, M.V.; Majerus, P.W.; Wilson, M.P.
Myotubularin-related protein (MTMR) 9 determines the enzymatic activity, substrate specificity, and role in autophagy of MTMR8
Proc. Natl. Acad. Sci. USA
109
9539-9544
2012
Homo sapiens (Q96EF0), Homo sapiens (Q9Y217)
Yoo, K.Y.; Son, J.Y.; Lee, J.U.; Shin, W.; Im, D.W.; Kim, S.J.; Ryu, S.E.; Heo, Y.S.
Structure of the catalytic phosphatase domain of MTMR8 implications for dimerization, membrane association and reversible oxidation
Acta Crystallogr. Sect. D
71
1528-1539
2015
Homo sapiens
Bong, S.M.; Yang, S.W.; Choi, J.W.; Kim, S.J.; Lee, B.I.
Crystallization and preliminary X-ray crystallographic analysis of human myotubularin-related protein 1
Acta Crystallogr. Sect. F
71
261-265
2015
Homo sapiens
Narayanan, P.; Huette, M.; Kudryasheva, G.; Taberner, F.J.; Lechner, S.G.; Rehfeldt, F.; Gomez-Varela, D.; Schmidt, M.
Myotubularin related protein-2 and its phospholipid substrate PIP2 control Piezo2-mediated mechanotransduction in peripheral sensory neurons
eLife
7
e32346
2018
Homo sapiens
Hao, F.; Itoh, T.; Morita, E.; Shirahama-Noda, K.; Yoshimori, T.; Noda, T.
The PtdIns3-phosphatase MTMR3 interacts with mTORC1 and suppresses its activity
FEBS Lett.
590
161-173
2016
Homo sapiens
Pham, H.Q.; Yoshioka, K.; Mohri, H.; Nakata, H.; Aki, S.; Ishimaru, K.; Takuwa, N.; Takuwa, Y.
MTMR4, a phosphoinositide-specific 3-phosphatase, regulates TFEB activity and the endocytic and autophagic pathways
Genes Cells
23
670-687
2018
Homo sapiens
St-Denis, N.; Gupta, G.D.; Lin, Z.Y.; Gonzalez-Badillo, B.; Pelletier, L.; Gingras, A.C.
Myotubularin-related proteins 3 and 4 interact with polo-like kinase 1 and centrosomal protein of 55 kDa to ensure proper abscission
Mol. Cell. Proteomics
14
946-960
2015
Homo sapiens
Bong, S.M.; Son, K.B.; Yang, S.W.; Park, J.W.; Cho, J.W.; Kim, K.T.; Kim, H.; Kim, S.J.; Kim, Y.J.; Lee, B.I.
Crystal structure of human myotubularin-related protein 1 provides insight into the structural basis of substrate specificity
PLoS ONE
11
e0152611
2016
Homo sapiens (Q13613), Homo sapiens
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