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Information on EC 3.9.1.3 - phosphohistidine phosphatase and Organism(s) Homo sapiens and UniProt Accession Q9H008

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IUBMB Comments
This eukaryotic enzyme dephosphorylates phosphorylated histidine residues within proteins and peptides. The enzyme acts on phosphate groups attached to both the pros- and tele-nitrogen atoms, but the pros- position is somewhat preferred (by a factor of two at the most) . The substrate specificity depends on the amino acid sequence or structural context of the phosphohistidine in a phosphoprotein. The enzyme is also active on free phosphoramidate [1,4] and peptide-bound phospholysine .
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Homo sapiens
UNIPROT: Q9H008
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Word Map
The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
Synonyms
phpt1, php14, protein histidine phosphatase, phosphohistidine phosphatase, protein histidine phosphatase 1, phpti, phpt-1, 14-kda phosphohistidine phosphatase, phosphohistidine phosphatase 1, phospho-histidine phosphatase, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
14 kDa phosphohistidine phosphatase
-
-
14-kDa phosphohistidine phosphatase
16 kDa protein histidine phosphatase
-
-
phosphohistidine phosphatase
-
phosphohistidine phosphatase 1
phosphohistidine phosphatase I
-
-
PHP14
PHPT-1
-
-
PHPT1
PHPTI
-
-
protein histidine phosphatase
protein histidine phosphatase 1
-
-
SYSTEMATIC NAME
IUBMB Comments
[protein]-N-phospho-L-histidine phosphohydrolase
This eukaryotic enzyme dephosphorylates phosphorylated histidine residues within proteins and peptides. The enzyme acts on phosphate groups attached to both the pros- and tele-nitrogen atoms, but the pros- position is somewhat preferred (by a factor of two at the most) [4]. The substrate specificity depends on the amino acid sequence or structural context of the phosphohistidine in a phosphoprotein. The enzyme is also active on free phosphoramidate [1,4] and peptide-bound phospholysine [5].
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
4-nitrophenylphosphate + H2O
4-nitrophenol + phosphate
show the reaction diagram
-
-
-
?
6,8-difluoromethylumbelliferyl phosphate + H2O
6,8-difluoromethylumbelliferone + phosphate
show the reaction diagram
-
-
-
?
a [protein]-N-phospho-L-histidine + H2O
a [protein]-L-histidine + phosphate
show the reaction diagram
AKR-N-phospho-HKV + H2O
AKRHKV + phosphate
show the reaction diagram
-
-
-
-
?
succinyl-L-Ala-N-phospho-L-His-L-Pro-L-Phe 4-nitroanilide + H2O
succinyl-L-Ala-L-His-L-Pro-L-Phe 4-nitroanilide + phosphate
show the reaction diagram
VIFIE-N-phospho-HAKRKG + H2O
VIFIEHAKRKG + phosphate
show the reaction diagram
-
-
-
-
?
[ATP-citrate lyase]-N-phospho-L-histidine + H2O
[ATP-citrate lyase]-L-histidine + phosphate
show the reaction diagram
[KCa3.1 channel protein]-N-phospho-L-histidine + H2O
[KCa3.1 channel protein]-L-histidine + phosphate
show the reaction diagram
-
the enzyme directly binds and inhibits KCa3.1 by dephosphorylating histidine 358
-
-
?
[peptide]-N-phospho-L-histidine + H2O
[peptide]-L-histidine + phosphate
show the reaction diagram
H2O2 exposure induces selective oxidation of hPHPT1 at Met95, a residue within the substrate binding region. H2O2-induced oxidation does not impact hPHPT1 function negatively
-
-
?
[protein]-N-phospho-L-histidine + H2O
[protein]-L-histidine + phosphate
show the reaction diagram
-
-
-
-
?
additional information
?
-
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
a [protein]-N-phospho-L-histidine + H2O
a [protein]-L-histidine + phosphate
show the reaction diagram
[ATP-citrate lyase]-N-phospho-L-histidine + H2O
[ATP-citrate lyase]-L-histidine + phosphate
show the reaction diagram
[KCa3.1 channel protein]-N-phospho-L-histidine + H2O
[KCa3.1 channel protein]-L-histidine + phosphate
show the reaction diagram
-
the enzyme directly binds and inhibits KCa3.1 by dephosphorylating histidine 358
-
-
?
[protein]-N-phospho-L-histidine + H2O
[protein]-L-histidine + phosphate
show the reaction diagram
-
-
-
-
?
additional information
?
-
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
bovine serum albumin
minimal effects on activity with the exception of a 35% activity decrease in Tris/HCl
-
CaCl2
1 mM, 40% decrease of activity in HEPES and a 15% decrease in Tris/HCl buffer
CuCl2
1 mM, almost completely inhibits enzyme activity
EDTA
2 mM, negative effect on activity
MgCl2
1 mM, 10-20% decrease in all buffers except HEPES
NaCl
100 mM, 30-60% decrease in activity. 50 mM, reductions of 10-25% of activity. 10 mM, 5-15% reduction of activity
ZnCl2
1 mM, almost completely inhibits enzyme activity. Biphasic curve with IC50 values of 0.025 and 0.49 mM, indicating that there may be two zinc binding sites in the enzyme
additional information
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
7.4
4-nitrophenylphosphate
pH 8.0, 37°C, HEPES buffer (50 mM at pH 8.0) with 10 mM NaCl, 0.01% w/v Brij 35 and 0.5 mM DTT as additives
0.22
6,8-difluoromethylumbelliferyl phosphate
pH 8.0, 37°C, HEPES buffer (50 mM at pH 8.0) with 10 mM NaCl, 0.01% w/v Brij 35 and 0.5 mM DTT as additives
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.35
4-nitrophenylphosphate
pH 8.0, 37°C, HEPES buffer (50 mM at pH 8.0) with 10 mM NaCl, 0.01% w/v Brij 35 and 0.5 mM DTT as additives
0.39
6,8-difluoromethylumbelliferyl phosphate
pH 8.0, 37°C, HEPES buffer (50 mM at pH 8.0) with 10 mM NaCl, 0.01% w/v Brij 35 and 0.5 mM DTT as additives
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.047
4-nitrophenylphosphate
pH 8.0, 37°C, HEPES buffer (50 mM at pH 8.0) with 10 mM NaCl, 0.01% w/v Brij 35 and 0.5 mM DTT as additives
1.8
6,8-difluoromethylumbelliferyl phosphate
pH 8.0, 37°C, HEPES buffer (50 mM at pH 8.0) with 10 mM NaCl, 0.01% w/v Brij 35 and 0.5 mM DTT as additives
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.5
CuCl2
pH 8.0, 37°C
0.025 - 0.49
ZnCl2
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
0.06
cell lysate, mutant enzyme R45A, pH and temperature not specified in the publication
0.2
purified mutant enzyme R45A, pH and temperature not specified in the publication
0.3
cell lysate, mutant enzyme R78A, pH and temperature not specified in the publication
0.9
purified mutant enzyme R78A, pH and temperature not specified in the publication
1.4
purified mutant enzyme H81A, pH and temperature not specified in the publication
1.8
purified wild type enzyme, pH and temperature not specified in the publication
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
8
good activity with Tris/HCl buffer, bicine buffer, bis-Tris propane buffer, and HEPES buffer. Bicine buffer and bis-Tris propane buffer giving slightly higher activity than Tris·HCl and bicine buufer
pH RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
5.6 - 9
at pH 5.6, the activity is 2% of that at pH 7.5, and no activity is detected at pH 9.0
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
TEMPERATURE RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
23 - 37
significantly more active at 37 °C than at 23°C
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
cf. EC 3.6.1.1
SwissProt
Manually annotated by BRENDA team
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
in patients with hepatocellular carcinoma, low expression of LHPP correlated with increased tumour severity and reduced overall survival
Manually annotated by BRENDA team
colocalization of the enzyme (PHP14) with Arp3 and F-actin at the leading edge of migrating cells. PHP14 is recruited to the actin remodeling sites in parallel with Arp3 during lamellipodia formation
Manually annotated by BRENDA team
enzyme (PHP14) expression is upregulated in fibrotic liver and mainly in hepatic stellate cells
Manually annotated by BRENDA team
-
expressed in normal kidney proximal tubuli
Manually annotated by BRENDA team
enzyme (PHP14) expression is upregulated in fibrotic liver and mainly in hepatic stellate cells
Manually annotated by BRENDA team
colocalization of the enzyme (PHP14) with Arp3 and F-actin at the leading edge of migrating cells. PHP14 is recruited to the actin remodeling sites in parallel with Arp3 during lamellipodia formation
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
metabolism
LHPP is a protein histidine phosphatase and tumour suppressor, suggesting that deregulated histidine phosphorylation is oncogenic
malfunction
metabolism
physiological function
additional information
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION?
LHPP_HUMAN
270
0
29165
Swiss-Prot
-
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
113000
-
gel filtration
13700
13701
x * 13701, calculated from amino acid sequence
14000
16000
-
x * 16000, MALDI-TOF mass spectrometry or SDS-PAGE, the enzyme forms multimers consisting of up to more than 35 protein molecules
16300
1 * 16300, recombinant enzyme, SDS-PAGE
209000
-
gel filtration
600000
-
gel filtration
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
monomer
multimer
-
x * 16000, MALDI-TOF mass spectrometry or SDS-PAGE, the enzyme forms multimers consisting of up to more than 35 protein molecules
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
free enzyme and in phosphate-bound state
hanging drop vapor diffusion method, using 2.0 M ammonium sulfate and 0.1 M Bis-tris, pH 5.5
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
C69A
-
the mutation does not affect enzyme activity
C69A/C71A
-
the mutations do not affect enzyme activity
C69A/C71A/C73A
-
the mutations do not affect enzyme activity
C69A/C73A
-
the mutation s do not affect enzyme activity
C71A
-
the mutation does not affect enzyme activity
C71A/C73A
-
the mutations do not affect enzyme activity
C73A
-
the mutation does not affect enzyme activity
G75A
-
inacvtive
G75A/G77A/S80A
-
inactive
G77A
-
inacvtive
H102A
inactive
H81A
the mutant shows wild type activity
R45A
the specific activity of the mutant is decreased by one order of magnitude compared to the wild type enzyme
R78A
the specific activity of the mutant is decreased by about 30% compared to the wild type enzyme
additional information
-
deletion of 9 N-terminal amino acids results in inactive enzyme, while 4 C-terminal residues can be deleted without losing enzyme activity
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
DEAE-cellulose column chromatography, Sephadex G-200 gel filtration, Mono-Q column chromatography, and Superose 12 gel filtration
HiTrap column chromatography and Superdex 75 gel filtration
Mono Q column chromatography
Ni-NTA agarose column chromatography, and gel filtration
-
Ni-NTA column chromatography
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expressed in CHO cells
-
expressed in Escherichia coli BL21(DE3) cells
-
expressed in Escherichia coli Top10 cells
expressed in SH-SY5Y cells and in primary cultures of cortical neurons from embryonic (E19) rats
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
downregulated specifically in tumours
PHP14 expression is upregulated in fibrotic liver and mainly in hepatic stellate cells. TGF-beta1 can induce PHP14 expression in hepatic stellate cells accompanied with the activation of hepatic stellate cells
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
medicine
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Ma, R.; Kanders, E.; Sundh, U.B.; Geng, M.; Ek, P.; Zetterqvist, O.; Li, J.P.
Mutational study of human phosphohistidine phosphatase: effect on enzymatic activity
Biochem. Biophys. Res. Commun.
337
887-891
2005
Homo sapiens (Q9NRX4), Homo sapiens
Manually annotated by BRENDA team
Gong, W.; Li, Y.; Cui, G.; Hu, J.; Fang, H.; Jin, C.; Xia, B.
Solution structure and catalytic mechanism of human protein histidine phosphatase 1
Biochem. J.
418
337-344
2009
Homo sapiens (Q9NRX4), Homo sapiens
Manually annotated by BRENDA team
Attwood, P.V.; Ludwig, K.; Bergander, K.; Besant, P.G.; Adina-Zada, A.; Krieglstein, J.; Klumpp, S.
Chemical phosphorylation of histidine-containing peptides based on the sequence of histone H4 and their dephosphorylation by protein histidine phosphatase
Biochim. Biophys. Acta
1804
199-205
2010
Homo sapiens
Manually annotated by BRENDA team
Klumpp, S.; Ma, N.T.; Baeumer, N.; Bechmann, G.; Krieglstein, J.
Relevance of glycine and cysteine residues as well as N- and C-terminals for the activity of protein histidine phosphatase
Biochim. Biophys. Acta
1804
206-211
2010
Homo sapiens
Manually annotated by BRENDA team
Klumpp, S.; Faber, D.; Fischer, D.; Litterscheid, S.; Krieglstein, J.
Role of protein histidine phosphatase for viability of neuronal cells
Brain Res.
1264
7-12
2009
Homo sapiens
Manually annotated by BRENDA team
Seeger, A.; Rose, K.; Ma, N.T.; Kremmer, E.; Klumpp, S.; Krieglstein, J.
Influence of protein histidine phosphatase overexpression and down-regulation on human umbilical-vein endothelial cell viability
Cell Biol. Int.
36
245-249
2012
Homo sapiens (Q9NRX4), Homo sapiens
Manually annotated by BRENDA team
Ek, P.; Pettersson, G.; Ek, B.; Gong, F.; Li, J.P.; Zetterqvist, O.
Identification and characterization of a mammalian 14-kDa phosphohistidine phosphatase
Eur. J. Biochem.
269
5016-5023
2002
Homo sapiens (Q9NRX4), Homo sapiens, Sus scrofa
Manually annotated by BRENDA team
Busam, R.D.; Thorsell, A.G.; Flores, A.; Hammarstroem, M.; Persson, C.; Hallberg, B.M.
First structure of a eukaryotic phosphohistidine phosphatase
J. Biol. Chem.
281
33830-33834
2006
Homo sapiens (Q9NRX4)
Manually annotated by BRENDA team
Shen, H.; Yang, P.; Liu, Q.; Tian, Y.
Nuclear expression and clinical significance of phosphohistidine phosphatase 1 in clear-cell renal cell carcinoma
J. Int. Med. Res.
43
747-757
2015
Homo sapiens
Manually annotated by BRENDA team
Xu, A.; Hao, J.; Zhang, Z.; Tian, T.; Jiang, S.; Hao, J.; Liu, C.; Huang, L.; Xiao, X.; He, D.
14-kDa phosphohistidine phosphatase and its role in human lung cancer cell migration and invasion
Lung Cancer
67
48-56
2010
Homo sapiens (Q9NRX4), Homo sapiens
Manually annotated by BRENDA team
Han, S.X.; Wang, L.J.; Zhao, J.; Zhang, Y.; Li, M.; Zhou, X.; Wang, J.; Zhu, Q.
14-kDa phosphohistidine phosphatase plays an important role in hepatocellular carcinoma cell proliferation
Oncol. Lett.
4
658-664
2012
Homo sapiens
Manually annotated by BRENDA team
Ludwig, K.; Habbach, S.; Krieglstein, J.; Klumpp, S.; Koenig, S.
MALDI-TOF high mass calibration up to 200 kDa using human recombinant 16 kDa protein histidine phosphatase aggregates
PLoS ONE
6
e23612
2011
Homo sapiens
Manually annotated by BRENDA team
Srivastava, S.; Zhdanova, O.; Di, L.; Li, Z.; Albaqumi, M.; Wulff, H.; Skolnik, E.Y.
Protein histidine phosphatase 1 negatively regulates CD4 T cells by inhibiting the K+ channel KCa3.1
Proc. Natl. Acad. Sci. USA
105
14442-14446
2008
Homo sapiens
Manually annotated by BRENDA team
Ek, P.; Ek, B.; Zetterqvist, O.e.
Phosphohistidine phosphatase 1 (PHPT1) also dephosphorylates phospholysine of chemically phosphorylated histone H1 and polylysine
Ups. J. Med. Sci.
120
20-27
2015
Homo sapiens
Manually annotated by BRENDA team
McCullough, B.S.; Barrios, A.M.
Facile, fluorogenic assay for protein histidine phosphatase activity
Biochemistry
57
2584-2589
2018
Homo sapiens (Q9NRX4)
Manually annotated by BRENDA team
Xu, A.; Li, X.; Li, S.; Sun, L.; Wu, S.; Zhang, B.; Huang, J.
A novel role for 14-kDa phosphohistidine phosphatase in lamellipodia formation
Cell Adh. Migr.
11
488-495
2017
Homo sapiens (Q9NRX4)
Manually annotated by BRENDA team
Xu, A.; Li, Y.; Zhao, W.; Hou, F.; Li, X.; Sun, L.; Chen, W.; Yang, A.; Wu, S.; Zhang, B.; Yao, J.; Wang, H.; Huang, J.
PHP14 regulates hepatic stellate cells migration in liver fibrosis via mediating TGF-beta1 signaling to PI3Kgama/AKT/Rac1 pathway
J. Mol. Med.
96
119-133
2018
Homo sapiens (Q9NRX4)
Manually annotated by BRENDA team
Hindupur, S.K.; Colombi, M.; Fuhs, S.R.; Matter, M.S.; Guri, Y.; Adam, K.; Cornu, M.; Piscuoglio, S.; Ng, C.K.Y.; Betz, C.; Liko, D.; Quagliata, L.; Moes, S.; Jenoe, P.; Terracciano, L.M.; Heim, M.H.; Hunter, T.; Hall, M.N.
The protein histidine phosphatase LHPP is a tumour suppressor
Nature
555
678-682
2018
Homo sapiens (Q9H008), Homo sapiens, Mus musculus (Q9D7I5), Mus musculus
Manually annotated by BRENDA team
Martin, D.R.; Dutta, P.; Mahajan, S.; Varma, S.; Stevens, S.M.
Structural and activity characterization of human PHPT1 after oxidative modification
Sci. Rep.
6
23658
2016
Homo sapiens (Q9NRX4), Homo sapiens
Manually annotated by BRENDA team