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Urm1p-terminal-Gly-AMP + human MOCS2A-SSH
Urm1p-terminal-Gly-COSH + human MOCS2A-SH + AMP
the N-terminal domain of Uba4 catalyzes the activation of either MOCS2A (protein essential for the biosynthesis of the molybdenum cofactor in human) or Urm1 by formation of an acyl-adenylate bond. After adenylation, persulfurated Uba4 is able to form a thiocarboxylate group at the C-terminal glycine of either Urm1 or MOCS2A. The formation of a thioester intermediate between Uba4 and Urm1 or MOCS2A is not observed. The functional similarities between Uba4 and MOCS3 further demonstrate the evolutionary link between ATP-dependent protein conjugation and ATP-dependent cofactor sulfuration
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Urm1p-terminal-Gly-AMP + Uba4-SSH
Urm1p-terminal-Gly-COSH + Uba4-SH + AMP
additional information
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Urm1p-terminal-Gly-AMP + Uba4-SSH
Urm1p-terminal-Gly-COSH + Uba4-SH + AMP
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the enzyme activates Urm1 for urmylation and tRNA thiolation
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Urm1p-terminal-Gly-AMP + Uba4-SSH
Urm1p-terminal-Gly-COSH + Uba4-SH + AMP
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Urm1p-terminal-Gly-AMP + Uba4-SSH
Urm1p-terminal-Gly-COSH + Uba4-SH + AMP
the N-terminal domain of Uba4 catalyzes the activation of Urm1 by formation of an acyl-adenylate bond. After adenylation, persulfurated Uba4 is able to form a thiocarboxylate group at the C-terminal glycine of Urm1. The formation of a thioester intermediate between Uba4 and Urm1 is not observed. The functional similarities between Uba4 and MOCS3 (protein essential for the biosynthesis of the molybdenum cofactor in human) further demonstrate the evolutionary link between ATP-dependent protein conjugation and ATP-dependent cofactor sulfuration
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Urm1p-terminal-Gly-AMP + Uba4-SSH
Urm1p-terminal-Gly-COSH + Uba4-SH + AMP
the substrate Urm1 is an ubiquitin-related modifier involved in protein urmylation. UBA4 is required for cytoplasmic 2-thiouridine formation. Uba4p (a paralog of the ubiquitin-activating enzyme E1) is an enzyme in the ubiquitin-related pathway that activates the C-terminus of Urm1p to form the acyl-adenylated intermediate, then transfers the persulfide sulfur from its C-terminal rhodanese-like domain (RLD) to form thiocarboxylated Urm1p (Urm1p-COSH) by releasing AMP. Urm1p-COSH is a substrate of 2-thiouridine formation catalyzed by Ncs2p and Ncs6p. For protein urmylation, Urm1p-COSH is conjugated with Uba4p, then the putative E3 enzyme transfers Urm1p to target proteins such as Ahp1p
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Urm1p-terminal-Gly-AMP + Uba4-SSH
Urm1p-terminal-Gly-COSH + Uba4-SH + AMP
Uba4p first adenylates and then directly transfers sulfur onto Urm1p. Thiolation function of Urm1p is critical to regulate cellular responses to nutrient starvation and oxidative stress conditions, most likely by increasing translation fidelity
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Urm1p-terminal-Gly-AMP + Uba4-SSH
Urm1p-terminal-Gly-COSH + Uba4-SH + AMP
the C-terminal Gly of Urm1p is first activated by Uba4p to synthesize the acyl-adenylated intermediate, then thiocarboxylated by releasing AMP. The rhodanese-like domain (RLD) of UBA4 acts as a persulfide carrier
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Urm1p-terminal-Gly-AMP + Uba4-SSH
Urm1p-terminal-Gly-COSH + Uba4-SH + AMP
the N-terminal domain of Uba4 catalyzes the activation of Urm1 by formation of an acyl-adenylate bond. After adenylation, persulfurated Uba4 is able to form a thiocarboxylate group at the C-terminal glycine of Urm1
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Urm1p-terminal-Gly-AMP + Uba4-SSH
Urm1p-terminal-Gly-COSH + Uba4-SH + AMP
Uba4p first adenylates and then directly transfers sulfur onto Urm1p. Uba4p, consists of an amino N-terminal nucleotide-binding domain (NBD), followed by a MoeZ motif and a carboxy C-terminal rhodanese domain (RHD). Urm1p, adenylated by the nucleotide-binding domain (NBD) of Uba4p, is converted to a Urm1p-thiocarboxylate by Uba4p rhodanese domain (RHD). The sulfur is then passed onto U34 either directly or with the help of Ncs6p/Ncs2p
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additional information
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Uba4 might function as a sulfur carrier protein required for the s2 (second position) modification of cytosolic tRNAs
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additional information
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the C-terminal domain of Uba4 has rhodanese activity and is able to transfer the sulfur from thiosulfate to cyanide in vitro
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additional information
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the C-terminal domain of Uba4 has rhodanese activity and is able to transfer the sulfur from thiosulfate to cyanide in vitro
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additional information
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Uba4p has the potential to act as an acceptor of the persulfide sulfur from Nfs1p, but does not function as an activator for Nfs1p. It is proposed that the persulfide sulfur of Nfs1p is mainly transferred to the rhodanese-like domain 2 (RLD2) Cys259 of Tum1p, and the sulfur is then relayed to the RLD (Cys397) of Uba4p. In addition, direct sulfur transfer from Nfs1p to the RLD (Cys397) of Uba4p also takes place as a minor pathway
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Urm1p-terminal-Gly-AMP + Uba4-SSH
Urm1p-terminal-Gly-COSH + Uba4-SH + AMP
additional information
?
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Uba4 might function as a sulfur carrier protein required for the s2 (second position) modification of cytosolic tRNAs
-
-
?
Urm1p-terminal-Gly-AMP + Uba4-SSH
Urm1p-terminal-Gly-COSH + Uba4-SH + AMP
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the enzyme activates Urm1 for urmylation and tRNA thiolation
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?
Urm1p-terminal-Gly-AMP + Uba4-SSH
Urm1p-terminal-Gly-COSH + Uba4-SH + AMP
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?
Urm1p-terminal-Gly-AMP + Uba4-SSH
Urm1p-terminal-Gly-COSH + Uba4-SH + AMP
the N-terminal domain of Uba4 catalyzes the activation of Urm1 by formation of an acyl-adenylate bond. After adenylation, persulfurated Uba4 is able to form a thiocarboxylate group at the C-terminal glycine of Urm1. The formation of a thioester intermediate between Uba4 and Urm1 is not observed. The functional similarities between Uba4 and MOCS3 (protein essential for the biosynthesis of the molybdenum cofactor in human) further demonstrate the evolutionary link between ATP-dependent protein conjugation and ATP-dependent cofactor sulfuration
-
-
?
Urm1p-terminal-Gly-AMP + Uba4-SSH
Urm1p-terminal-Gly-COSH + Uba4-SH + AMP
the substrate Urm1 is an ubiquitin-related modifier involved in protein urmylation. UBA4 is required for cytoplasmic 2-thiouridine formation. Uba4p (a paralog of the ubiquitin-activating enzyme E1) is an enzyme in the ubiquitin-related pathway that activates the C-terminus of Urm1p to form the acyl-adenylated intermediate, then transfers the persulfide sulfur from its C-terminal rhodanese-like domain (RLD) to form thiocarboxylated Urm1p (Urm1p-COSH) by releasing AMP. Urm1p-COSH is a substrate of 2-thiouridine formation catalyzed by Ncs2p and Ncs6p. For protein urmylation, Urm1p-COSH is conjugated with Uba4p, then the putative E3 enzyme transfers Urm1p to target proteins such as Ahp1p
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?
Urm1p-terminal-Gly-AMP + Uba4-SSH
Urm1p-terminal-Gly-COSH + Uba4-SH + AMP
Uba4p first adenylates and then directly transfers sulfur onto Urm1p. Thiolation function of Urm1p is critical to regulate cellular responses to nutrient starvation and oxidative stress conditions, most likely by increasing translation fidelity
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-
?
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C225A
the Uba4-C225A variant has a slower rate of molybdopterin production in Escherichia coli in comparison to that of wild-type Uba4 likely due to the reduced stability of the protein
C225S
when a plasmid harboring UBA4 with a C225S mutation is introduced into the DELTAUBA4 strain, no thiouridine formation of tRNAGlu can be observed, demonstrating that Cys225 is the active-site cysteine residue of UBA4 required for 2-thiouridine formation
C397A
comparison of the efficiencies of Uba4 and the C397A and C225A/C397A variants in producing molybdopterin in the presence of thiosulfate reveals that residue Cys397 is essential for sulfuration of human MOCS2A. Thus, the resulting persulfide group on Cys397 of Uba4 is specifically transferred to MOCS2A during the reaction
C397S
approximately half the fraction of tRNAGlu in the DELTAUBA4 strain can be 2-thiolated by the introduction of a plasmid encoding the wild-type UBA4. When pUBA4 C397S is introduced, no 2-thiouridine formation of tRNAGlu occurrs. Cys397 in the rhodanese-like domain (RLD) of UBA4 is critical for 2-thiouridine formation
C225A/C397A
comparison of the efficiencies of Uba4 and the C397A and C225A/C397A variants in producing molybdopterin in the presence of thiosulfate reveals that residue Cys397 is essential for sulfuration of human MOCS2A. Thus, the resulting persulfide group on Cys397 of Uba4 is specifically transferred to MOCS2A during the reaction
C225A/C397A
slightly different amounts of molybdopterin produced by the Uba4 variant C225A/C397A in Escherichia coli are likely due to the reduced stability of the protein
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Schmitz, J.; Chowdhury, M.M.; Hnzelmann, P.; Nimtz, M.; Lee, E.Y.; Schindelin, H.; Leimkhler, S.
The sulfurtransferase activity of Uba4 presents a link between ubiquitin-like protein conjugation and activation of sulfur carrier proteins
Biochemistry
47
6479-6489
2008
Saccharomyces cerevisiae (P38820), Saccharomyces cerevisiae
brenda
Nakai, Y.; Nakai, M.; Hayashi, H.
Thio-modification of yeast cytosolic tRNA requires a ubiquitin-related system that resembles bacterial sulfur transfer systems.
J. Biol. Chem.
283
27469-27476
2008
Saccharomyces cerevisiae (P38820)
brenda
Leidel, S.; Pedrioli, P.G.; Bucher, T.; Brost, R.; Costanzo, M.; Schmidt, A.; Aebersold, R.; Boone, C.; Hofmann, K.; Peter, M.
Ubiquitin-related modifier Urm1 acts as a sulphur carrier in thiolation of eukaryotic transfer RNA
Nature
458
228-232
2009
Saccharomyces cerevisiae (P38820)
brenda
Noma, A.; Sakaguchi, Y.; Suzuki, T.
Mechanistic characterization of the sulfur-relay system for eukaryotic 2-thiouridine biogenesis at tRNA wobble positions
Nucleic Acids Res.
37
1335-1352
2009
Saccharomyces cerevisiae (P38820)
brenda
Juedes, A.; Ebert, F.; Baer, C.; Thuering, K.; Harrer, A.; Klassen, R.; Helm, M.; Stark, M.; Schaffrath, R.
Urmylation and tRNA thiolation functions of ubiquitin-like Uba4 Urm1 systems are conserved from yeast to man
FEBS Lett.
589
904-909
2015
Homo sapiens
brenda
Sharma, V.; Sharma, P.; Selvapandiyan, A.; Salotra, P.
Leishmania donovani-specific Ub-related modifier-1: An early endosome-associated ubiquitin-like conjugation in Leishmania donovani
Mol. Microbiol.
99
597-610
2016
Leishmania donovani
brenda