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Information on EC 2.7.7.80 - molybdopterin-synthase adenylyltransferase
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2.7.7.80 molybdopterin-synthase adenylyltransferaseIUBMB Comments
Adenylates the C-terminus of the small subunit of the molybdopterin synthase. This activation is required to form the thiocarboxylated C-terminus of the active molybdopterin synthase small subunit. The reaction occurs in prokaryotes and eukaryotes. In the human, the reaction is catalysed by the N-terminal domain of the protein MOCS3, which also includes a molybdopterin-synthase sulfurtransferase (EC 2.8.1.11) C-terminal domain.
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Word Map
- 2.7.7.80
- sulfur
-
mocs2a
- trna
- moco
-
thiocarboxylate
- sulfite
-
thiolation
-
rhodanese-like
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sulfurtransferase
- l-cysteine
- thiosulfate
-
desulfurase
- nfs1
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sulfur-containing
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encephalopathy
- rhodanese
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encephalomalacia
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exome
- persulfide
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seizures
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ubiquitin-like
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thioester
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molybdoenzymes
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intractable
- xanthine
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uric
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two-domain
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gephyrin
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microcephaly
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urmylation
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autosomal-recessive
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molybdenum-dependent
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria, Archaea
Reaction Schemes
Synonyms
mocs3, 
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
ATP + [molybdopterin-synthase sulfur-carrier protein]-Gly-Gly = diphosphate + [molybdopterin-synthase sulfur-carrier protein]-Gly-Gly-AMP
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SYSTEMATIC NAME
IUBMB Comments
ATP:molybdopterin-synthase adenylyltransferase
Adenylates the C-terminus of the small subunit of the molybdopterin synthase. This activation is required to form the thiocarboxylated C-terminus of the active molybdopterin synthase small subunit. The reaction occurs in prokaryotes and eukaryotes. In the human, the reaction is catalysed by the N-terminal domain of the protein MOCS3, which also includes a molybdopterin-synthase sulfurtransferase (EC 2.8.1.11) C-terminal domain.
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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 + [molybdopterin-synthase sulfur-carrier protein]-Gly-Gly
diphosphate + [molybdopterin-synthase sulfur-carrier protein]-Gly-Gly-AMP
ATP + [molybdopterin-synthase sulfur-carrier protein]-Gly-Gly
diphosphate + [molybdopterin-synthase sulfur-carrier protein]-Gly-Gly-AMP
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-
-
?
ATP + [molybdopterin-synthase sulfur-carrier protein]-Gly-Gly
diphosphate + [molybdopterin-synthase sulfur-carrier protein]-Gly-Gly-AMP
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the Mg2+ may remain associated with the diphosphate-leaving group
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?
ATP + [molybdopterin-synthase sulfur-carrier protein]-Gly-Gly
diphosphate + [molybdopterin-synthase sulfur-carrier protein]-Gly-Gly-AMP
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-
-
?
ATP + [molybdopterin-synthase sulfur-carrier protein]-Gly-Gly
diphosphate + [molybdopterin-synthase sulfur-carrier protein]-Gly-Gly-AMP
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-
-
-
?
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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 + [molybdopterin-synthase sulfur-carrier protein]-Gly-Gly
diphosphate + [molybdopterin-synthase sulfur-carrier protein]-Gly-Gly-AMP
ATP + [molybdopterin-synthase sulfur-carrier protein]-Gly-Gly
diphosphate + [molybdopterin-synthase sulfur-carrier protein]-Gly-Gly-AMP
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-
-
?
ATP + [molybdopterin-synthase sulfur-carrier protein]-Gly-Gly
diphosphate + [molybdopterin-synthase sulfur-carrier protein]-Gly-Gly-AMP
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-
-
?
ATP + [molybdopterin-synthase sulfur-carrier protein]-Gly-Gly
diphosphate + [molybdopterin-synthase sulfur-carrier protein]-Gly-Gly-AMP
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-
-
-
?
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Mg2+
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DISEASE
TITLE OF PUBLICATION
LINK TO PUBMED
Encephalomalacia
Case Report: Compound Heterozygous Variants in MOCS3 Identified in a Chinese Infant With Molybdenum Cofactor Deficiency.
Neurologic Manifestations
Case Report: Compound Heterozygous Variants in MOCS3 Identified in a Chinese Infant With Molybdenum Cofactor Deficiency.
Perinatal Death
Case Report: Compound Heterozygous Variants in MOCS3 Identified in a Chinese Infant With Molybdenum Cofactor Deficiency.
Pulmonary Disease, Chronic Obstructive
Exome-wide analysis of rare coding variation identifies novel associations with COPD and airflow limitation in MOCS3, IFIT3 and SERPINA12.
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
MoeB beongs to the MoeB/E1 enzyme superfamily, conserved active site structure, overview. The molybdenum cofactor (Moco) biosynthesis, involving Escherichia coli proteins MoeB and MoaD, is an evolutionarily conserved pathway
malfunction
metabolism
Escherichia coli proteins MoeB and MoaD are involved in molybdenum cofactor (Moco) biosynthesis
physiological function
additional information
malfunction
The Escherichia coli moeB mutant strains contain an inactive, desulfo form of MPT synthase. Substitutions of every cysteine residue in MoeB does not affect activity, except for the mutations in the cysteine residues located in putative Zn-binding motifs, which cause loss of metal binding correlated with loss of activity
malfunction
in homozygous MOCS3-knockout HEK293T cells, sulfite oxidase activity is almost completely abolished, on the basis of the absence of Moco in these cells. In addition, mcm5s2U thio-modified tRNAs are not detectable. Impact of a MOCS3 knockout on the cellular localization of NFS1, MOCS3-independent localization of NFS1 (a L-cysteine desulfurase NFS1 acting as a sulfur donor for MOCS3 in the cytosol) at the tips of the centrosome
physiological function
MOCS3 catalyzes both the adenylation and the subsequent generation of a thiocarboxylate group at the C-terminus of the smaller subunit of molybdopterin synthase during molybdenum cofactor biosynthesis in humans. Similar to ubiquitin activating enzymes, the N-terminus of MOCS3 is expected to activate the C-terminal glycine of MOCS2A to form an acyl adenylate. Subsequently, the C-terminal rhodanese-like domain of MOCS3 acts as a direct sulfur donor for the formation of a thiocarboxylate group on MOCS2A. The MOCS2A thiocarboxylate sulfur is used for the generation of the dithiolene moiety of molybdopterin which coordinates the molybdenum atom in the molybdenum cofactor
physiological function
MoeB is involved in molybdenum cofactor (Moco) biosynthesis, it activates the C-terminus of MoaD to form an acyl-adenylate. The MoeB-MoaD interface is the C-terminal extension of the MoaD C-terminus into a pocket on the MoeB surface, MoeB-MoaD-ATP ternary complex structure, overview. A preference for small amino acids (Gly, Ala, Ser) at the centre of beta5 of MoeB, facilitating the insertion of the Gly-Gly motif of MoaD into the active site of MoeB, Arg 14 is inserted into the active site across the dimer interface and has a critical role during ATP hydrolysis
physiological function
MoeB is involved in the activation of molybdopterin synthase for the biosynthesis of the molybdenum cofactor. MoeB-dependent formation of a C-terminal thiocarboxylate on the MoaD subunit of molybdopterin synthase might resemble the ubiquitin-activating step in the ubiquitin-targeted degradation of proteins in eukaryotes, but without formation of a thioester intermediate between MoeB and MoaD, overview. But formation of a complex of MoeB and MoaD adenylate, that is stable to gel filtration, occurs
physiological function
the MOCS3 protein is believed to catalyze both the adenylation and the subsequent generation of a thiocarboxylate group at the C terminus of the smaller subunit of molybdopterin (MPT) synthase, the N-terminal MOCS3 MoeB-like domain, i.e. MOCS3-MoeBD, is similar to the Escherichia coli MoeB protein
physiological function
human MOCS3 is a dual-function protein that plays an important role in Moco biosynthesis and in the mcm5s2U thio modifications of nucleosides in cytosolic tRNAs for Lys, Gln, and Glu. Cellular roles of MOCS3, overview. MOCS3 is involved in mcm5s2U34 tRNA modifications in the cytosol by forming a thiocarboxylate group on URM1, which is further used as sulfur-providing protein for the tRNA nucleoside modification. The overall cytosolic levels of the mcm5s2U modification seem to be very low
additional information
the human MOCS3 protein contains an N-terminal domain similar to the Escherichia coli MoeB protein. This N-terminal MoeB-like domain is active in catalyzing the adenylyltransferase activity, and C239 of the N-terminal MoeB-like domain of MOCS3 is most likely involved in the sulfur transfer mechanism of the persulfide sulfur to MOCS2A
additional information
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the human MOCS3 protein contains an N-terminal domain similar to the Escherichia coli MoeB protein. This N-terminal MoeB-like domain is active in catalyzing the adenylyltransferase activity, and C239 of the N-terminal MoeB-like domain of MOCS3 is most likely involved in the sulfur transfer mechanism of the persulfide sulfur to MOCS2A
Show AA Sequence and Transmembrane Helices (3137 entries)
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PDB
SCOP
CATH
UNIPROT
ORGANISM
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MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
MoeB-MoaD complex formation, the interface is the C-terminal extension of the MoaD C-terminus into a pocket on the MoeB surface, apo- and ligand-bound structures, overview
additional information
two CXXC motifs near the C-terminus of MoeB. The MoeB-MoaD adenylate complex is a tetramer with a mass of 71.8 kDa
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CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
MoeB-MoaD complex in its apo, ATP-bound, and MoaD-adenylate forms, equal volumes of 23 mg/ml MoeB and 10 mg/ml MoaD at 4°C for 1 h, followed by hanging drop vapour diffusion against a reservoir containing 1.7 M Li2SO4, and 100 mM HEPES, pH 7.5, for the ternary complex, crystals of the apo complex are soaked for 24 h in a solution consisting of 1.7 M Li2SO4, 100 mM HEPES, pH 7.5, and 20 mM ATP, X-ray diffraction structure determination and analysis at 1.7-3.5 A resolutions, modeling
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
C142A
site-directed mutagenesis, the mutant shows activity like the wild-type enzyme
C142A/C187A
site-directed mutagenesis, the mutant shows activity like the wild-type enzyme
C172A
site-directed mutagenesis, the mutant's Zn2+ content is below the limit of detection, the activity is reduced compared to the wild-type enzyme
C175A
site-directed mutagenesis, the mutant's Zn2+ content is below the limit of detection, the activity is reduced compared to the wild-type enzyme
C187A
site-directed mutagenesis, the mutant shows activity like the wild-type enzyme
C231A
site-directed mutagenesis, the mutant shows activity like the wild-type enzyme
C244A
site-directed mutagenesis, the mutant's Zn2+ content is below the limit of detection, the activity is reduced compared to the wild-type enzyme
C247A
site-directed mutagenesis, the mutant's Zn2+ content is below the limit of detection, the activity is reduced compared to the wild-type enzyme
C44A
site-directed mutagenesis, the mutant shows activity like the wild-type enzyme
D130E
site-directed mutagenesis, the mutant shows highly reduced activity compared to the wild-type enzyme
R14A
site-directed mutagenesis, the mutant shows similar activity compared to the wild-type enzyme
R14K
site-directed mutagenesis, the mutant shows similar activity compared to the wild-type enzyme
R14K/R73A
site-directed mutagenesis, the mutant shows highly reduced activity compared to the wild-type enzyme
R73A
site-directed mutagenesis, the mutant shows slighty reduced activity compared to the wild-type enzyme
R73K
site-directed mutagenesis, the mutant shows highly reduced activity compared to the wild-type enzyme
C239A
the MOCS3 N-terminal domain mutant shows 81% reduced MoeB-like activity compared to wild-type MOCS3, the cysteine 293 residue in the MOCS3-MoeB domain is involved in the sulfur transfer reaction of MOCS3, EC 2.8.1.11
additional information
additional information
the human MOCS3-MoeB domain can be functionally substituted by Escherichia coli MoeB protein
additional information
-
the human MOCS3-MoeB domain can be functionally substituted by Escherichia coli MoeB protein
additional information
construction of a homozygous MOCS3 knockout in HEK293T cells using the CRISPR/Cas9 system. The sulfite oxidase activity in the heterozygous (+/-) MOCS3 cell line is not affected, still containing one functional allele for MOCS3. The low levels of MOCS3 present in the (+/-) cells are sufficient to maintain the levels of sulfite oxidase activity. The sulfite oxidase activity of the homozygous (-/-) MOCS3 knockout can be rescued by reintroducing the MOCS3 protein, which results in an 80% increase in activity. Separate introduction of the N-terminal MOCS3 MoeB-like domain or only the C-terminal MOCS3 rhodanese-like domain does not result in a detectable increase in sulfite oxidase activity. In the heterozygous MOCS3 knockout cell line, a small amount of the mcm5U precursor is detected, while it is undetectable in wild-type HEK293T cells. This low level of accumulation of the mcm5U precursor might be based on the low levels of MOCS3 in the (+/-) cells that are sufficient to maintain almost the levels of the modified mcm5s2U as wild-type levels. No significant effect of the absence of MOCS3 on isocitrate dehydrogenase (ICDH) activity, while aconitase activities are reduced. MOCS3 does not seem to impact the cytosolic localization of NFS1
additional information
-
construction of a homozygous MOCS3 knockout in HEK293T cells using the CRISPR/Cas9 system. The sulfite oxidase activity in the heterozygous (+/-) MOCS3 cell line is not affected, still containing one functional allele for MOCS3. The low levels of MOCS3 present in the (+/-) cells are sufficient to maintain the levels of sulfite oxidase activity. The sulfite oxidase activity of the homozygous (-/-) MOCS3 knockout can be rescued by reintroducing the MOCS3 protein, which results in an 80% increase in activity. Separate introduction of the N-terminal MOCS3 MoeB-like domain or only the C-terminal MOCS3 rhodanese-like domain does not result in a detectable increase in sulfite oxidase activity. In the heterozygous MOCS3 knockout cell line, a small amount of the mcm5U precursor is detected, while it is undetectable in wild-type HEK293T cells. This low level of accumulation of the mcm5U precursor might be based on the low levels of MOCS3 in the (+/-) cells that are sufficient to maintain almost the levels of the modified mcm5s2U as wild-type levels. No significant effect of the absence of MOCS3 on isocitrate dehydrogenase (ICDH) activity, while aconitase activities are reduced. MOCS3 does not seem to impact the cytosolic localization of NFS1
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PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant wild-type and mutant MoeBs from Escherichia coli strain BL21(DE3) by ammonium sulfate fractionation, anion exchange chromatography, and gel filtration
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expression of the MOCS3 MoeB-like domain MOCS3-MoeBD in a Esccherichia coli MoeB-deficient strain moeB- (DE3)
gene moeB, DNA and amino acid sequence determinations, expression of wild-type MoeB in Escherichia coli strain BL21(DE3) and of MoeB mutants in Escerichia coli strain moeB- (DE3) cells from pMW15eB
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REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Matthies, A.; Nimtz, M.; Leimkhler, S.
Molybdenum cofactor biosynthesis in humans: Identification of a persulfide group in the rhodanese-like domain of MOCS3 by mass spectrometry
Biochemistry
44
7912-7920
2005
Homo sapiens (O95396), Homo sapiens
brenda
Leimkuehler, S.; Wuebbens, M.; Rajagopalan, K.
Characterization of Escherichia coli MoeB and its involvement in the activation of molybdopterin synthase for the biosynthesis of the molybdenum cofactor
J. Biol. Chem.
276
34695-34701
2001
Escherichia coli (P12282)
brenda
Lake, M.; Wuebbens, M.; Rajagopalan, K.; Schindelin, H.
Mechanism of ubiquitin activation revealed by the structure of a bacterial MoeB-MoaD complex
Nature
414
325-329
2001
Escherichia coli (P12282)
brenda
Matthies, A.; Rajagopalan, K.; Mendel, R.; Leimkhler, S.
Evidence for the physiological role of a rhodanese-like protein for the biosynthesis of the molybdenum cofactor in humans
Proc. Natl. Acad. Sci. USA
101
5946-5951
2004
Homo sapiens (O95396), Homo sapiens
brenda
Neukranz, Y.; Kotter, A.; Beilschmidt, L.; Marelja, Z.; Helm, M.; Graef, R.; Leimkuehler, S.
Analysis of the cellular roles of MOCS3 identifies a MOCS3-independent localization of NFS1 at the tips of the centrosome
Biochemistry
58
1786-1798
2019
Homo sapiens (O95396), Homo sapiens
brenda
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Release 2023.1 (January 2023)
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