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bis(4-nitrophenyl) phosphate + H2O
4-nitrophenyl phosphate + 4-nitrophenol
-
-
-
?
dATP + H2O
deoxyadenosine + triphosphate
dATP + H2O
deoxyadeonsine + triphosphate
-
-
-
-
?
dCTP + H2O
deoxycytidine + triphosphate
dGTP + H2O
deoxyguanosine + triphosphate
dTTP + H2O
deoxythymidine + triphosphate
additional information
?
-
dATP + H2O
deoxyadenosine + triphosphate
-
-
-
-
?
dATP + H2O
deoxyadenosine + triphosphate
-
-
-
?
dATP + H2O
deoxyadenosine + triphosphate
-
-
-
?
dCTP + H2O
deoxycytidine + triphosphate
-
-
-
-
?
dCTP + H2O
deoxycytidine + triphosphate
-
-
-
?
dCTP + H2O
deoxycytidine + triphosphate
-
-
-
?
dGTP + H2O
deoxyguanosine + triphosphate
-
-
-
-
?
dGTP + H2O
deoxyguanosine + triphosphate
-
-
-
?
dGTP + H2O
deoxyguanosine + triphosphate
-
-
-
?
dTTP + H2O
deoxythymidine + triphosphate
-
-
-
-
?
dTTP + H2O
deoxythymidine + triphosphate
-
-
-
?
dTTP + H2O
deoxythymidine + triphosphate
-
-
-
?
additional information
?
-
enzyme EF1143 fails to hydrolyze any of the dNTPs when a sole dNTP is present in the reaction mixture. Among the four dNTPs, only dGTP can function as an activator of dATP and dCTP hydrolysis. dGTP hydrolysis is clearly enhanced by the presence of dATP or dCTP, but not dTTP, with dATP being the more potent activator. Further, dTTP hydrolysis is virtually nonexistent when any one other dNTP is combined with dTTP in the reaction mixture. With all four dNTPs present at equal concentrations, the decreasing order of dNTP hydrolysis is dGTP, dCTP, dATP, dTTP
-
-
?
additional information
?
-
-
enzyme EF1143 fails to hydrolyze any of the dNTPs when a sole dNTP is present in the reaction mixture. Among the four dNTPs, only dGTP can function as an activator of dATP and dCTP hydrolysis. dGTP hydrolysis is clearly enhanced by the presence of dATP or dCTP, but not dTTP, with dATP being the more potent activator. Further, dTTP hydrolysis is virtually nonexistent when any one other dNTP is combined with dTTP in the reaction mixture. With all four dNTPs present at equal concentrations, the decreasing order of dNTP hydrolysis is dGTP, dCTP, dATP, dTTP
-
-
?
additional information
?
-
enzyme EF1143 fails to hydrolyze any of the dNTPs when a sole dNTP is present in the reaction mixture. Among the four dNTPs, only dGTP can function as an activator of dATP and dCTP hydrolysis. dGTP hydrolysis is clearly enhanced by the presence of dATP or dCTP, but not dTTP, with dATP being the more potent activator. Further, dTTP hydrolysis is virtually nonexistent when any one other dNTP is combined with dTTP in the reaction mixture. With all four dNTPs present at equal concentrations, the decreasing order of dNTP hydrolysis is dGTP, dCTP, dATP, dTTP
-
-
?
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dATP
both dATP and dGTP are co-activators for hydrolysis of dTTP, dATP might bind at the secondary allosteric site
dCTP
allosteric activator, less potent than dGTP and dATP
dNTP
both GTP and dNTP are required for tetramer activation of the enzyme. SAMHD1 activation is regulated by the concentration of dNTP
dGTP
the tetrameric enzyme EF1143 contains four additional secondary allosteric sites adjacent to the previously identified dGTP-binding primary regulatory sites. dGTP binding to the first allosteric site, with nanomolar affinity, is a prerequisite for substrate docking and hydrolysis. Then, the presence of a particular dNTP in the second site either enhances or inhibits the dNTPase activity
dGTP
-
allosteric activator. Allosteric dGTP binding induces conformational changes at the active site, allowing a more stable interaction with the substrate and explaining the dGTP-induced isoform SAMHD1 dNTPase activity. Mutations of dGTP binding residues in the allosteric site affect tetramer formation, dNTPase activity and HIV-1 restriction
dGTP
low concentrations of either GTP or dGTP stimulate the reaction maximally, Km value for binding to allosteric site 1 is 0.00015 mM with substrate dATP
dGTP
low concentrations of either GTP or dGTP stimulate the reaction maximally, Km value for binding to allosteric site 1 is 0.0008 mM with substrate dATP
dGTP
dGTP causes ISF1 to tetramerize, activating its catalytic activity. Isoform ISF2 has dGTP-independent catalytic activity
GTP
low concentrations of either GTP or dGTP stimulate the reaction maximally, Km value for binding to allosteric site 1 is 0.00015 mM with substrate dATP. In quiescent cells where the enzyme is maximally expressed GTP binds to allosteric site 1 with very high affinity, stabilizing site 2 of the tetrameric structure. Any canonical dNTP can bind to site 2 and activate the enzyme, but in cells only dATP or dTTP are present at sufficient concentrations. Tetrameric enzyme is activated for the hydrolysis of any dNTP only after binding of a dNTP to site 2
GTP
both GTP and dNTP are required for tetramer activation of the enzyme
GTP
low concentrations of either GTP or dGTP stimulate the reaction maximally, Km value for binding to allosteric site 1 is 0.0005 mM with substrate dATP. In quiescent cells where the enzyme is maximally expressed GTP binds to allosteric site 1 with very high affinity, stabilizing site 2 of the tetrameric structure. Any canonical dNTP can bind to site 2 and activate the enzyme, but in cells only dATP or dTTP are present at sufficient concentrations. Tetrameric enzyme is activated for the hydrolysis of any dNTP only after binding of a dNTP to site 2
additional information
-
dGTP, but not the other dNTPs, is required for the formation and maintenance of the catalytically more active SAMHD1 tetramer
-
additional information
in quiescent cells where the enzyme is maximally expressed GTP binds to allosteric site 1 with very high affinity, stabilizing site 2 of the tetrameric structure. Any canonical dNTP can bind to site 2 and activate the enzyme, but in cells only dATP or dTTP are present at sufficient concentrations. Tetrameric enzyme is activated for the hydrolysis of any dNTP only after binding of a dNTP to site 2
-
additional information
-
in quiescent cells where the enzyme is maximally expressed GTP binds to allosteric site 1 with very high affinity, stabilizing site 2 of the tetrameric structure. Any canonical dNTP can bind to site 2 and activate the enzyme, but in cells only dATP or dTTP are present at sufficient concentrations. Tetrameric enzyme is activated for the hydrolysis of any dNTP only after binding of a dNTP to site 2
-
additional information
in quiescent cells where the enzyme is maximally expressed GTP binds to allosteric site 1 with very high affinity, stabilizing site 2 of the tetrameric structure. Any canonical dNTP can bind to site 2 and activate the enzyme, but in cells only dATP or dTTP are present at sufficient concentrations. Tetrameric enzyme is activated for the hydrolysis of any dNTP only after binding of a dNTP to site 2
-
additional information
-
in quiescent cells where the enzyme is maximally expressed GTP binds to allosteric site 1 with very high affinity, stabilizing site 2 of the tetrameric structure. Any canonical dNTP can bind to site 2 and activate the enzyme, but in cells only dATP or dTTP are present at sufficient concentrations. Tetrameric enzyme is activated for the hydrolysis of any dNTP only after binding of a dNTP to site 2
-
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0.0016
dATP
-
dCTP bound at allosteric site AS2, pH 7.8, temperature not specified in the publication
0.0028
dATP
-
dGTP bound at allosteric site AS2, pH 7.8, temperature not specified in the publication
0.0041
dATP
-
dATP bound at allosteric site AS2, pH 7.8, temperature not specified in the publication
0.0142
dATP
-
dTTP bound at allosteric site AS2, pH 7.8, temperature not specified in the publication
0.22
dATP
pH 7.5, 37°C, presence of 0.02 mM GTP
0.34
dATP
pH 7.5, 37°C, presence of 0.02 mM GTP
0.0016
dCTP
-
dCTP bound at allosteric site AS2, pH 7.8, temperature not specified in the publication
0.0033
dCTP
-
dGTP bound at allosteric site AS2, pH 7.8, temperature not specified in the publication
0.0056
dCTP
-
dATP bound at allosteric site AS2, pH 7.8, temperature not specified in the publication
0.0225
dCTP
-
dTTP bound at allosteric site AS2, pH 7.8, temperature not specified in the publication
0.2
dCTP
pH 7.5, 37°C, presence of 0.02 mM GTP plus 0.02 mM dATP
0.29
dCTP
pH 7.5, 37°C, presence of 0.02 mM GTP plus 0.02 mM dATP
0.0021
dGTP
-
dCTP bound at allosteric site AS2, pH 7.8, temperature not specified in the publication
0.0037
dGTP
-
dGTP bound at allosteric site AS2, pH 7.8, temperature not specified in the publication
0.0065
dGTP
-
dATP bound at allosteric site AS2, pH 7.8, temperature not specified in the publication
0.0135
dGTP
-
dTTP bound at allosteric site AS2, pH 7.8, temperature not specified in the publication
0.002
dTTP
-
dCTP bound at allosteric site AS2, pH 7.8, temperature not specified in the publication
0.0035
dTTP
-
dGTP bound at allosteric site AS2, pH 7.8, temperature not specified in the publication
0.0077
dTTP
-
dATP bound at allosteric site AS2, pH 7.8, temperature not specified in the publication
0.0153
dTTP
-
dTTP bound at allosteric site AS2, pH 7.8, temperature not specified in the publication
0.28
dTTP
pH 7.5, 37°C, presence of 0.02 mM GTP plus 0.02 mM dATP
0.3
dTTP
pH 7.5, 37°C, presence of 0.02 mM GTP plus 0.02 mM dATP
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metabolism
SAMHD1 and R451A/L453A mutant proteins are degraded by virion-associated protein Vpx from HIV-2 but are not spontaneously ubiquitinated in the absence of Vpx. Their protein levels are enhanced only when both proteasomal and autophagy degradation pathways are inhibited
physiological function
-
allosteric dGTP binding induces conformational changes at the active site, allowing a more stable interaction with the substrate and explaining the dGTP-induced dNTPase activity. Mutations of dGTP binding residues in the allosteric site affect tetramer formation, dNTPase activity and HIV-1 restriction. dGTP-triggered tetramer formation is also important for SAMHD1-mediated retrotransposition of LINE-1 elements
physiological function
treatment of lung or skin fibroblasts with enzyme-specific siRNA results in the disappearence of enzyme protein accompanied by loss of the cell-cycle regulation of dNTP pool sizes and dNTP imbalance. Cells accumulate in G1 phase with oversized pools and stopp growing. Following removal of the siRNA, the pools are normalized and cell growth restarted, but only after enzyme SAMHD1 has reappeared. In quiescent cultures SAMHD1 down-regulation leads to a marked expansion of dNTP pools. In all cases the largest effect was on dGTP, the preferred substrate of SAMHD1
physiological function
in the mouse, SAMHD1 is expressed as isoforms ISF1 and ISF2 that differ at the carboxyl terminus due to alternative splicing of the last coding exon. Both isoforms are antiviral in nondividing cells. Phosphomimetic mutation at Thr-634 of ISF1 ablates its antiviral activity but has little effect on phosphohydrolase activity in vitro. dGTP causes ISF1 to tetramerize, activating its catalytic activity. Isoform ISF2 lacks the phosphorylation site, is significantly more active, tetramerizes, and is active without added dGTP. Mouse SAMHD1 does not degrade HIV-1 genomic viral RNA
physiological function
S-phase kinase CDK2-cyclin A phosphorylates SAMHD1 at residue Thr-592. Thr-592 phosphorylation occurs first at the G1/S border and is removed during mitotic exit. Thr-592 phosphorylation does not cause rapid protein degradation. SAMHD1 influences the size of the four dNTP pools independently of its phosphorylation
physiological function
SAMHD1 also acts as a nuclease, specifically degrading retroviral genomic RNA in monocyte-derived macrophage-like cells and in primary monocyte-derived macrophages. SAMHD1 selectively restricts retroviral replication, but does not affect the replication of other common non-retro RNA genome viruses
physiological function
-
the monomer and apo- or GTP-bound dimer of SAMHD1 are catalytically inactive. Binding of dNTP at allosteric site 2 (AS2), adjacent to the GTP-binding, allosteric site 1 (AS1), induces formation of tetramer, the catalytically active form. The apparent Km values of dNTPs at AS2 vary, in increasing order of dCTP, dGTP, dATP, dTTP. dCTP binding at AS2 significantly reduces the dCTP hydrolysis rate, which is restored to a rate comparable to that of other dNTPs upon dGTP, dATP or dTTP binding at AS2. Cyclin A2 binding at the C-terminus of SAMHD1 induces disassembly of the SAMHD1 tetramer,
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H114A
no residual activity
H129A
less than 5% residual activity
K14A
less than 5% residual activity
K330A
no residual activity
N36A
no residual activity
Q241A
about 10% residual activity
Q41A
less than 5% residual activity
R17A
no residual activity
R17Q
about 5% residual activity
R206A/R209A
no residual activity
R206Q
about 30% residual activity
R209S
about 70% residual activity
R326A
about 40% residual activity
Y199A
no residual activity
H114A
-
no residual activity
-
H129A
-
less than 5% residual activity
-
K14A
-
less than 5% residual activity
-
R17A
-
no residual activity
-
Y199A
-
no residual activity
-
C320A
mutant shows the formation of disulfide bonds similar to wild type
C341A
mutant shows no disulfide species
C350A
mutant shows no disulfide species
C522A
mutant shows no significant inhibition by oxidation
D137A
-
reduced ability to form tetramers, reduced dNTPase activity
D311A
mutation which removes one of the metal coordination residues in the active site and results in the loss of dNTPase activity
K405R
mutant cannot be acetylated, reduced activity compared to acetylated wild-type protein. K405R mutant expressing cancer cells show reduced G1/S transition and slower proliferation compared to wildtype
Q142E/R145K
-
reduced ability to form tetramers, reduced dNTPase activity
R333E
-
reduced ability to form tetramers, reduced dNTPase activity
R333E/R451E
-
reduced ability to form tetramers, reduced dNTPase activity
R451A/L453A
mutation in the RXL motif, disrupts SAMHD1 tetramer formation and abolishes its dNTPase activity in vitro and in cells. The mutant fails to restrict HIV-1 infection and has reduced binding to cyclin A2
R451E
-
reduced ability to form tetramers, reduced dNTPase activity
T592E
phosphomimetic mutation, reduces the stability of the SAMHD1 tetramer. about 3fold decrease in activity
T592V
neutral substitution, does not perturb the structure
Y146S/Y154S
dimerization-defective mutant, displays a severe dNTPase defect in vitro, but is indistinguishable from wild-type in its ability to deplete cellular dNTP pools and to restrict HIV replication
P635A
mutation retains antiviral activity of ISF1, and increased its catalytic activity to that of ISF2
T634A
mutation retains antiviral activity of ISF1
T634E
mutation in ISF1, mimics phosphorylated SAMHD1. Mutant is inactive
T592D
mutant affects kinetics of tetramer assembly and disassembly, but its effects on tetramerization equilibrium and dNTPase activity are insignificant
T592D
-
mutant as well as phospho-Thr592, show a significantly altered substrate specificity, with the rate of dCTP hydrolysis being selectively reduced regardless of which dNTP binds at allosteric site AS2
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Miazzi, C.; Ferraro, P.; Pontarin, G.; Rampazzo, C.; Reichard, P.; Bianchi, V.
Allosteric regulation of the human and mouse deoxyribonucleotide triphosphohydrolase sterile alpha-motif/histidine-aspartate domain-containing protein 1 (SAMHD1)
J. Biol. Chem.
289
18339-18346
2014
Mus musculus (Q60710), Mus musculus, Homo sapiens (Q9Y3Z3), Homo sapiens
brenda
Vorontsov, I.I.; Wu, Y.; DeLucia, M.; Minasov, G.; Mehrens, J.; Shuvalova, L.; Anderson, W.F.; Ahn, J.
Mechanisms of allosteric activation and inhibition of the deoxyribonucleoside triphosphate triphosphohydrolase from Enterococcus faecalis
J. Biol. Chem.
289
2815-2824
2014
Enterococcus faecalis (Q836G9), Enterococcus faecalis, Enterococcus faecalis ATCC 700802 (Q836G9)
brenda
Zhu, C.; Gao, W.; Zhao, K.; Qin, X.; Zhang, Y.; Peng, X.; Zhang, L.; Dong, Y.; Zhang, W.; Li, P.; Wei, W.; Gong, Y.; Yu, X.
Structural insight into dGTP-dependent activation of tetrameric SAMHD1 deoxynucleoside triphosphate triphosphohydrolase
Nat. Commun.
4
2722
2013
Homo sapiens
brenda
Franzolin, E.; Pontarin, G.; Rampazzo, C.; Miazzi, C.; Ferraro, P.; Palumbo, E.; Reichard, P.; Bianchi, V.
The deoxynucleotide triphosphohydrolase SAMHD1 is a major regulator of DNA precursor pools in mammalian cells
Proc. Natl. Acad. Sci. USA
110
14272-14277
2013
Homo sapiens (Q9Y3Z3), Homo sapiens
brenda
Zhu, C.F.; Wei, W.; Peng, X.; Dong, Y.H.; Gong, Y.; Yu, X.F.
The mechanism of substrate-controlled allosteric regulation of SAMHD1 activated by GTP
Acta Crystallogr. Sect. D
71
516-524
2015
Homo sapiens (Q9Y3Z3), Homo sapiens
brenda
Mauney, C.H.; Rogers, L.C.; Harris, R.S.; Daniel, L.W.; Devarie-Baez, N.O.; Wu, H.; Furdui, C.M.; Poole, L.B.; Perrino, F.W.; Hollis, T.
The SAMHD1 dNTP triphosphohydrolase is controlled by a redox switch
Antioxid. Redox Signal.
27
1317-1331
2017
Homo sapiens (Q9Y3Z3)
brenda
Jang, S.; Zhou, X.; Ahn, J.
Substrate specificity of SAMHD1 triphosphohydrolase activity is controlled by deoxyribonucleoside triphosphates and phosphorylation at Thr592
Biochemistry
55
5635-5646
2016
Homo sapiens
brenda
Mauney, C.H.; Perrino, F.W.; Hollis, T.
Identification of inhibitors of the dNTP triphosphohydrolase SAMHD1 using a novel and direct high-throughput assay
Biochemistry
57
6624-6636
2018
Homo sapiens (Q9Y3Z3)
brenda
Tramentozzi, E.; Ferraro, P.; Hossain, M.; Stillman, B.; Bianchi, V.; Pontarin, G.
The dNTP triphosphohydrolase activity of SAMHD1 persists during S-phase when the enzyme is phosphorylated at T592
Cell Cycle
17
1102-1114
2018
Homo sapiens (Q9Y3Z3)
brenda
Franzolin, E.; Salata, C.; Bianchi, V.; Rampazzo, C.
The deoxynucleoside triphosphate triphosphohydrolase activity of SAMHD1 protein contributes to the mitochondrial DNA depletion associated with genetic deficiency of deoxyguanosine kinase
J. Biol. Chem.
290
25986-25996
2015
Homo sapiens (Q9Y3Z3), Homo sapiens
brenda
Tang, C.; Ji, X.; Wu, L.; Xiong, Y.
Impaired dNTPase activity of SAMHD1 by phosphomimetic mutation of Thr-592
J. Biol. Chem.
290
26352-26359
2015
Homo sapiens (Q9Y3Z3)
brenda
Bloch, N.; Glaesker, S.; Sitaram, P.; Hofmann, H.; Shepard, C.N.; Schultz, M.L.; Kim, B.; Landau, N.R.
A highly active isoform of lentivirus restriction factor SAMHD1 in mouse
J. Biol. Chem.
292
1068-1080
2017
Mus musculus (Q60710), Mus musculus
brenda
Seamon, K.J.; Stivers, J.T.
A high-throughput enzyme-coupled assay for SAMHD1 dNTPase
J. Biomol. Screen.
20
801-809
2015
Homo sapiens (Q9Y3Z3)
brenda
Gelais, C.; Kim, S.; Maksimova, V.; Buzovetsky, O.; Knecht, K.; Shepard, C.; Kim, B.; Xiong, Y.; Wu, L.
A cyclin-binding motif in human SAMHD1 is required for its HIV-1 restriction, dNTPase activity, tetramer formation, and efficient phosphorylation
J. Virol.
92
e01787
2018
Homo sapiens (Q9Y3Z3), Homo sapiens
brenda
Lee, E.J.; Seo, J.H.; Park, J.H.; Vo, T.T.L.; An, S.; Bae, S.J.; Le, H.; Lee, H.S.; Wee, H.J.; Lee, D.; Chung, Y.H.; Kim, J.A.; Jang, M.K.; Ryu, S.H.; Yu, E.; Jang, S.H.; Park, Z.Y.; Kim, K.W.
SAMHD1 acetylation enhances its deoxynucleotide triphosphohydrolase activity and promotes cancer cell proliferation
Oncotarget
8
68517-68529
2017
Homo sapiens (Q9Y3Z3), Homo sapiens
brenda
Choi, J.; Ryoo, J.; Oh, C.; Hwang, S.; Ahn, K.
SAMHD1 specifically restricts retroviruses through its RNase activity
Retrovirology
12
46
2015
Homo sapiens (Q9Y3Z3), Homo sapiens
brenda
Bhattacharya, A.; Wang, Z.; White, T.; Buffone, C.; Nguyen, L.A.; Shepard, C.N.; Kim, B.; Demeler, B.; Diaz-Griffero, F.; Ivanov, D.N.
Effects of T592 phosphomimetic mutations on tetramer stability and dNTPase activity of SAMHD1 can not explain the retroviral restriction defect
Sci. Rep.
6
31353
2016
Homo sapiens (Q9Y3Z3)
brenda