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Information on EC 6.2.1.45 - E1 ubiquitin-activating enzyme and Organism(s) Mus musculus and UniProt Accession Q02053
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6.2.1.45 E1 ubiquitin-activating enzymeIUBMB Comments
Catalyses the ATP-dependent activation of ubiquitin through the formation of a thioester bond between the C-terminal glycine of ubiquitin and the sulfhydryl side group of a cysteine residue in the E1 protein. The two-step reaction consists of the ATP-dependent formation of an E1-ubiquitin adenylate intermediate in which the C-terminal glycine of ubiquitin is bound to AMP via an acyl-phosphate linkage, then followed by the conversion to an E1-ubiquitin thioester bond via the cysteine residue on E1 in the second step.
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Word Map
- 6.2.1.45
- proteasome
-
ubiquitin-proteasome
-
polyubiquitination
- ligases
- ubiquitin-protein
- finger
-
ubiquitin-dependent
-
sumoylation
- isg15
- cdc34
- rad6
-
isgylation
-
ubiquitin-mediated
-
deubiquitinating
-
anaphase-promoting
-
genorm
-
ubiquitin-related
- ubch7
-
normfinder
-
multiubiquitination
- sumo-1
-
nonpermissive
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proteasome-dependent
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cullins
- lactacystin
-
bestkeeper
-
ub-conjugating
- thiolester
- nedd8
-
postreplication
-
interferon-stimulated
- peroxins
-
ubiquitin-ligase
-
ring-h2
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lys63-linked
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mono-ubiquitination
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error-free
- sic1
- drug development
- ube2l3
-
translesion
- synthesis
-
cullin-ring
- medicine
The taxonomic range for the selected organisms is: Mus musculus
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Reaction Schemes
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[E1 ubiquitin-activating enzyme]-L-cysteine
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S-ubiquitinyl-[E1 ubiquitin-activating enzyme]-L-cysteine
Synonyms
ubiquitin-conjugating enzyme, ube1l, ubiquitin-activating enzyme, ubiquitin-activating enzyme e1, ubiquitin-activating enzyme (e1), ubiquitin activating enzyme, sumo e1, e1 ubiquitin-activating enzyme, ubiquitin e1, ubiquitin activating enzyme e1, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
ATP + ubiquitin + [E1 ubiquitin-activating enzyme]-L-cysteine = AMP + diphosphate + S-ubiquitinyl-[E1 ubiquitin-activating enzyme]-L-cysteine
E1 consumes ATP and converts ubiquitin to a transfer-competent, enzyme-bound thioester. The reaction begins with ubiquitin-adenylate formation and the release of diphosohate. The active site cysteine of the E1 then displaces the AMP leading to a ubiquitin-E1 thioester complex
ATP + ubiquitin + [E1 ubiquitin-activating enzyme]-L-cysteine = AMP + diphosphate + S-ubiquitinyl-[E1 ubiquitin-activating enzyme]-L-cysteine
in the ATP-dependent activation reaction, ubiquitin is covalently attached to a cysteine residue of the E1 component through a thiol ester bond
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PATHWAY SOURCE
PATHWAYS
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SYSTEMATIC NAME
IUBMB Comments
ubiquitin:[E1 ubiquitin-activating enzyme] ligase (AMP-forming)
Catalyses the ATP-dependent activation of ubiquitin through the formation of a thioester bond between the C-terminal glycine of ubiquitin and the sulfhydryl side group of a cysteine residue in the E1 protein. The two-step reaction consists of the ATP-dependent formation of an E1-ubiquitin adenylate intermediate in which the C-terminal glycine of ubiquitin is bound to AMP via an acyl-phosphate linkage, then followed by the conversion to an E1-ubiquitin thioester bond via the cysteine residue on E1 in the second step.
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
ATP + ubiquitin + [E1 ubiquitin-activating enzyme]-L-cysteine
AMP + diphosphate + S-ubiquitinyl-[E1 ubiquitin-activating enzyme]-L-cysteine
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-
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-
?
ATP + ubiquitin + [ubiquitin-activating protein E1]-L-cysteine
AMP + diphosphate + [ubiquitin-activating protein E1]-S-ubiquitinyl-L-cysteine
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-
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?
additional information
?
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E1 consumes ATP and converts ubiquitin to a transfer-competent, enzyme-bound thioester. The reaction begins with ubiquitin-adenylate formation and the release of diphosohate. The active site cysteine of the E1 then displaces the AMP leading to a ubiquitin-E1 thioester complex
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-
?
additional information
?
-
-
E1 consumes ATP and converts ubiquitin to a transfer-competent, enzyme-bound thioester. The reaction begins with ubiquitin-adenylate formation and the release of diphosohate. The active site cysteine of the E1 then displaces the AMP leading to a ubiquitin-E1 thioester complex
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-
?
additional information
?
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E1 activity is assesssed by the capacity of the enzyme to form a thiol ester conjugate with ubiquitin in an ATP-dependent process and to transfer this activated ubiquitin molecule to an conjugating enzyme
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-
?
additional information
?
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chimeric mutant Aos1-Uba2 SUMO-E1 enzyme shows SUMO-E1 activity. The E1 enzyme catalyzes the formation of a thioester-linked complex between SUMO and the E2 enzyme. This process is initiated by activation of the carboxyl terminus of SUMO by adenylation, followed by a thioesterification reaction in which SUMO is conjugated to a cysteine residue at the active site of Uba2 in the E1 enzyme. SUMO is then transferred to the active site cysteine of the E2 enzyme, Ubc9, via a trans-thioesterification reaction. A SUMO-charged E2 enzyme and substrate are finally bound with or without the assistance of a distinct class of SUMO E3-ligases, resulting in the activated SUMO bound to the substrate through an isopeptide linkage
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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
ATP + ubiquitin + [E1 ubiquitin-activating enzyme]-L-cysteine
AMP + diphosphate + S-ubiquitinyl-[E1 ubiquitin-activating enzyme]-L-cysteine
-
-
-
-
?
additional information
?
-
E1 consumes ATP and converts ubiquitin to a transfer-competent, enzyme-bound thioester. The reaction begins with ubiquitin-adenylate formation and the release of diphosohate. The active site cysteine of the E1 then displaces the AMP leading to a ubiquitin-E1 thioester complex
-
-
?
additional information
?
-
-
E1 consumes ATP and converts ubiquitin to a transfer-competent, enzyme-bound thioester. The reaction begins with ubiquitin-adenylate formation and the release of diphosohate. The active site cysteine of the E1 then displaces the AMP leading to a ubiquitin-E1 thioester complex
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-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
1-(3-chloro-4-fluorophenyl)-4-[(5-nitro-2-furyl)methylene]-3,5-pyrazolidinedione
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i.e. PYZD-4409. In a mouse model of leukemia, intraperitoneal administration of PYZD-4409 decreases tumor weight and volume compared with control without untoward toxicity
4[4-(5-nitro-furan-2-ylmethylene)-3,5-dioxo-pyrazolidin-1-yl]-benzoic acid ethyl ester
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i.e. PYR-41, potential of the inhibitor as therapeutic in cancer
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
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mouse embryo fibroblast cell, thermosensitive for ubiquitin-activating enzyme E1
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
physiological function
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in mouse embryo fibroblast cell A31N-ts20, which is thermosensitive for ubiquitin-activating enzyme E1, the enzymatic activity of the enzyme is heat-inactivatable in vitro; and a major mechanism responsible for E1 inactivation in vivo consists of accelerated destruction. In vivo, ubiquitination of the various protein substrates in A31N-ts20 cells requires different amounts of E1 enzyme
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). UBA1_MOUSE
1058
0
117809
Swiss-Prot
other Location (Reliability: 5)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
130000
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recombinant His6-tagged chimeric mutant Aos1-Uba2 SUMO-E1 enzyme mAU, gel filtration
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
NMR structural studies of the first catalytic cysteine half domain FCCH, interaction studies of FCCH and the other catalytic E1 domain SCCH, second catalytic cysteine half-domain. The E1 has several domains, an adenylation domain, composed of an active and inactive adenylation subdomains, and a catalytic cysteine domain, and smaller accessory domains: a four helix bundle and a ubiquitin fold domain. NMR cannot detect interactions between the FCCH and ubiquitin, or betweenween FCCH and SCCH if they are on separate poypeptide chains
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
A189T
A189T/W714C
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mutant protein is less stable than its wildtype counterpart, and restrictive temperature of 39°C accelerates its degradation
W714C
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the mutant enzyme is less stable than its wild-type counterpart, and restrictive temperature (39°C) accelerates its degradation
additional information
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construction of a mouse Aos1-Uba2 chimeric SUMO(small ubiquitin-related modifier)-E1 enzyme, mAU. The SUMO-E1 enzyme consists of two subunits, a heterodimer of activation of Smt3p 1 (Aos1) and ubiquitin activating enzyme 2 (Uba2), which resembles the N- and C-terminal halves of ubiquitin E1 (Uba1), the functional domains appear to be arranged in a fashion similar to Uba1. mAU has SUMO-E1 activity, indicating that mAU can be expressed in baculovirus-insect cells and represents a suitable source of SUMO-E1, enzymatic mechanism and structure of SUMO-E1, overview
A189T
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the mutant enzyme is less stable than its wild-type counterpart, and restrictive temperature (39°C) accelerates its degradation
A189T
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improved stability and activity compared to mutant A189T/W714C, but when incubated at 39°C, cells expressing the mutant show increased apoptotic rate ompared to wild-type. Mutant is able to monoubiquitinate histone H2A and to support growth of TS20 cells at 39°C. Compared to mutant A189T/W714C, mutation A189T significantly improves the ubiquitination-dependent disposal of HIF-1alpha
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
-70°C, the storage of the recombinant mouse E1 does not result in a detectable denaturation of the enzyme
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PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant His-tagged chimeric mutant Aos1-Uba2 SUMO-E1 enzyme mAU from insect cells by nickel affinity chromatography
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recombinant protein, HIS-Select nickel affinity chromatography, further steps, ion exchange chromatography, followed by gel filtration
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant expression of His6-tagged chimeric mutant Aos1-Uba2 SUMO-E1 enzyme mAU in Spodoptera frugiperda Sf9 insect cells via baculovirus transformation, mAU has SUMO-E1 activity. Recombinant expression of GST-tagged mAU in Escherichia coli
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
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in a mouse model of leukemia, intraperitoneal administration of inhibitor 1-(3-chloro-4-fluorophenyl)-4-[(5-nitro-2-furyl)methylene]-3,5-pyrazolidinedione, i.e. PYZD-4409, decreases tumor weight and volume compared with control without untoward toxicity
synthesis
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510 mg of histidine-tagged mouse ubiquitin-activating enzyme E1 can be easily obtained from a 1 l Escherichia coli culture. A low temperature during the protein induction step is critical to obtain an active enzyme
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Yang, Y.; Kitagaki, J.; Dai, R.M.; Tsai, Y.C.; Lorick, K.L.; Ludwig, R.L.; Pierre, S.A.; Jensen, J.P.; Davydov, I.V.; Oberoi, P.; Li, C.C.; Kenten, J.H.; Beutler, J.A.; Vousden, K.H.; Weissman, A.M.
Inhibitors of ubiquitin-activating enzyme (E1), a new class of potential cancer therapeutics
Cancer Res.
67
9472-9481
2007
Homo sapiens, Mus musculus
Pelzer, C.; Kassner, I.; Matentzoglu, K.; Singh, R.K.; Wollscheid, H.P.; Scheffner, M.; Schmidtke, G.; Groettrup, M.
UBE1L2, a novel E1 enzyme specific for ubiquitin
J. Biol. Chem.
282
23010-23014
2007
Homo sapiens, Homo sapiens (A0AVT1), Mus musculus
Xu, G.W.; Ali, M.; Wood, T.E.; Wong, D.; Maclean, N.; Wang, X.; Gronda, M.; Skrtic, M.; Li, X.; Hurren, R.; Mao, X.; Venkatesan, M.; Beheshti Zavareh, R.; Ketela, T.; Reed, J.C.; Rose, D.; Moffat, J.; Batey, R.A.; Dhe-Paganon, S.; Schimmer, A.D.
The ubiquitin-activating enzyme E1 as a therapeutic target for the treatment of leukemia and multiple myeloma
Blood
115
2251-2259
2010
Homo sapiens, Mus musculus
Lao, T.; Chen, S.; Sang, N.
Two mutations impair the stability and function of ubiquitin-activating enzyme (E1)
J. Cell. Physiol.
227
1451-1458
2012
Mus musculus
Jaremko, M.; Jaremko, L.; Nowakowski, M.; Wojciechowski, M.; Szczepanowski, R.H.; Panecka, R.; Zhukov, I.; Bochtler, M.; Ejchart, A.
NMR structural studies of the first catalytic half-domain of ubiquitin activating enzyme
J. Struct. Biol.
185
69-78
2014
Mus musculus (Q02053), Mus musculus
Carvalho, A.F.; Pinto, M.P.; Grou, C.P.; Vitorino, R.; Domingues, P.; Yamao, F.; Sa-Miranda, C.; Azevedo, J.E.
High-yield expression in Escherichia coli and purification ofmouse ubiquitin-activating enzyme E1
Mol. Biotechnol.
51
254-261
2012
Mus musculus
Salvat, C.; Acquaviva, C.; Scheffner, M.; Robbins, I.; Piechaczyk, M.; Jariel-Encontre, I.
Molecular characterization of the thermosensitive E1 ubiquitin-activating enzyme cell mutant A31N-ts20. Requirements upon different levels of E1 for the ubiquitination/degradation of the various protein substrates in vivo
Eur. J. Biochem.
267
3712-3722
2000
Mus musculus
Lao, T.; Chen, S.; Sang, N.
Two mutations impair the stability and function of ubiquitin-activating enzyme (E1)
J. Cell. Physiol.
227
1561-1568
2012
Mus musculus
EXTERNAL LINKS (specific for EC-Number 6.2.1.45)
Transporter Classification Database (TCDB): 3.A.25.2.1
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