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Information on EC 4.1.99.22 - GTP 3',8-cyclase and Organism(s) Staphylococcus aureus and UniProt Accession P65388

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EC Tree
     4 Lyases
         4.1 Carbon-carbon lyases
             4.1.99 Other carbon-carbon lyases
                4.1.99.22 GTP 3',8-cyclase
IUBMB Comments
The enzyme catalyses an early step in the biosynthesis of the molybdenum cofactor (MoCo). In bacteria and plants the reaction is catalysed by MoaA and Cnx2, respectively. In mammals it is catalysed by the MOCS1A domain of the bifunctional MOCS1 protein, which also catalyses EC 4.6.1.17, cyclic pyranopterin monophosphate synthase. The enzyme belongs to the superfamily of radical S-adenosyl-L-methionine (radical SAM) enzymes, and contains two oxygen-sensitive FeS clusters.
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Staphylococcus aureus
UNIPROT: P65388
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Word Map
The taxonomic range for the selected organisms is: Staphylococcus aureus
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
Synonyms
mocs1a, mocs1b, molybdenum cofactor biosynthetic enzyme, moco-biosynthesis protein, gtp 3',8-cyclase, molybdenum-cofactor biosynthesis protein, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
cnx2
-
-
-
-
MOCS1A
-
-
-
-
PATHWAY SOURCE
PATHWAYS
-
-
SYSTEMATIC NAME
IUBMB Comments
GTP 3',8-cyclase [(8S)-3',8-cyclo-7,8-dihydroguanosine 5'-triphosphate-forming]
The enzyme catalyses an early step in the biosynthesis of the molybdenum cofactor (MoCo). In bacteria and plants the reaction is catalysed by MoaA and Cnx2, respectively. In mammals it is catalysed by the MOCS1A domain of the bifunctional MOCS1 protein, which also catalyses EC 4.6.1.17, cyclic pyranopterin monophosphate synthase. The enzyme belongs to the superfamily of radical S-adenosyl-L-methionine (radical SAM) enzymes, and contains two oxygen-sensitive FeS clusters.
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
GTP
cyclic pyranopterin phosphate + diphosphate
show the reaction diagram
GTP + S-adenosyl-L-methionine + reduced electron acceptor
(8S)-3',8-cyclo-7,8-dihydroguanosine 5'-triphosphate + 5'-deoxyadenosine + L-methionine + oxidized electron acceptor
show the reaction diagram
-
-
-
?
(8S)-3',8-cyclo-7,8-dihydroguanosine 5'-triphosphate
cyclic pyranopterin phosphate + diphosphate
show the reaction diagram
GMP[CH2]PP + S-adenosyl-L-methionine + reduced electron acceptor
(8S)-3',8-cyclo-7,8-dihydroguanosine-P[CH2]PP + 5'-deoxyadenosine + L-methionine + oxidized electron acceptor
show the reaction diagram
substrate has a methylene bridge in place of an oxygen between the alpha and bveta phosphate groups
product has a methylene bridge in place of an oxygen between the alpha and beta phosphate groups and product is an uncleavable substrate analogue of cyclic pyranopterin monophosphate synthase accessory protein MoaC
-
?
GTP
(8S)-3',8-cyclo-7,8-dihydroguanosine 5'-triphosphate
show the reaction diagram
GTP
cyclic pyranopterin phosphate + diphosphate
show the reaction diagram
GTP + S-adenosyl-L-methionine + reduced electron acceptor
(8S)-3',8-cyclo-7,8-dihydroguanosine 5'-triphosphate + 5'-deoxyadenosine + L-methionine + oxidized electron acceptor
show the reaction diagram
-
pyranopterin triphosphate is formed as a by-product, the amount is 0.4Ā–3% of (8S)-3',8-cyclo-7,8-dihydroguanosine 5'-triphosphate + 5'-deoxyadenosine formed
-
?
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
GTP
cyclic pyranopterin phosphate + diphosphate
show the reaction diagram
the enzyme catalyses an early step in the biosynthesis of the molybdenum cofactor
-
-
?
GTP + S-adenosyl-L-methionine + reduced electron acceptor
(8S)-3',8-cyclo-7,8-dihydroguanosine 5'-triphosphate + 5'-deoxyadenosine + L-methionine + oxidized electron acceptor
show the reaction diagram
-
-
-
?
(8S)-3',8-cyclo-7,8-dihydroguanosine 5'-triphosphate
cyclic pyranopterin phosphate + diphosphate
show the reaction diagram
-
reaction of MoaC
-
-
?
GTP
(8S)-3',8-cyclo-7,8-dihydroguanosine 5'-triphosphate
show the reaction diagram
-
reaction of MoaA with GTP, S-adenosyl-L-methionine, and sodium dithionite in the absence of MoaC
-
-
?
GTP
cyclic pyranopterin phosphate + diphosphate
show the reaction diagram
-
-
-
-
?
additional information
?
-
-
MoaA catalyzes a unique radical C-C bond formation reaction via a 5'-deoxyadenosyl radical intermediate and that, in contrast to previous proposals, MoaC plays a major role in the complex rearrangement to generate the pyranopterin ring
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
iron-sulfur centre
S-adenosyl-L-methionine
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
iron-sulfur centre
Fe2+
-
MoaA harbors two [4Fe-4S]2+,1+ clusters, the N-terminal is used for reductive cleavage of S-adenosyl-L-methionine, the C-terminal [4Fe-4S] cluster binds various purine nucleoside 5'-triphosphates including GTP
iron-sulfur centre
-
guanine N1 binds to [4Fe-4S] cluster II
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
MoaC protein
-
MoaC protein
-
the S-adenosyl-L-methionine-dependent enzyme MoaA, in concert with MoaC, catalyzes the first step of molybdenum cofactor biosynthesis, the conversion of 5'-GTP into precursor Z
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0031 - 0.0069
GTP
0.0051 - 0.036
S-adenosyl-L-methionine
0.00079
(8S)-3',8-cyclo-7,8-dihydroguanosine 5'-triphosphate
-
pH 7.6, 25Ā°C, MoaC
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.00008 - 0.0007
GTP
0.00007 - 0.00075
S-adenosyl-L-methionine
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7.6
-
assay at, MoaA and MoaC
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
25
-
assay at, MoaA and MoaC
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
physiological function
the GG motif is essential for the activity of MoaA to produce (8S)-3',8-cyclo-7,8-dihydroguanosine 5'-triphosphate from GTP, and synthetic peptides corresponding to the C-terminal region of wild-type MoaA rescue the GTP 3',8-cyclase activity of the GG-motif mutants. The C-terminal tail containing the GG motif interacts with the SAM-binding pocket of MoaA, and is essential for the binding of SAM and subsequent radical initiation
physiological function
the physiological function of MoaA is the conversion of GTP to (8S)-3',8-cyclo-7,8-dihydroguanosine 5'-triphosphate (GTP 3?,8-cyclase), and that of MoaC is to catalyze the rearrangement of (8S)-3',8-cyclo-7,8-dihydroguanosine 5'-triphosphate into cyclic pyranopterin
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
41000
monomer, in solution MoaA exists as a monomer (41000 Da) and dimer (82000 Da), gel filtration
42000
82000
homodimer, in solution MoaA exists as a monomer (41000 Da) and dimer (82000 Da), gel filtration
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
dimer
2 * 42000, in solution MoaA exists as a monomer (41000 Da) and dimer (82000 Da)
monomer
1 * 42000, in solution MoaA exists as a monomer (41000 Da) and dimer (82000 Da)
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
crystal structure of wild-type MoaA, MoaA-R17A/R266A/R268A and MoaA in complex with 5'-GTP2.35 A resolution
crystals are grown under anaerobic conditions, hanging drop vapor diffusion technique, crystals belong to space group P2(1)2(1)2(1) with cell dimensions of a = 48.1, b = 102.4, and c = 191.2 A and contain two molecules per asymmetric unit, structures of MoaA in the apo-state (2.8 A) and in complex with S-adenosyl-L-methionine (2.2 A)
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
D198A
mutation in GG motif, decrease in affinity for S-adenosine-L-methionine
G339A
mutation in GG motif, loss of activity
G340A
mutation in GG motif, loss of activity
N124A/N165A
mutation reduces binding of 5'-GTP
R17A
complete loss of activity
R17A/R266A/R268A
complete loss of activity
R192A
80% loss of activity
R266A
complete loss of activity
R268A
complete loss of activity
R71A
80% loss of activity
S126A
mutant enzyme with low activity
T73A
mutant enzyme with low activity
Y30A
mutant enzyme with low activity
C24S/C28S/C31S
-
the mutant does not contain the catalytic S-adenosyl-L-methionine-binding cluster I
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
purified under anaerobic conditions
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expressed as His-tagged proteins in Escherichia coli
expression in Escherichia coli
expression in Escherichia coli
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Lees, N.S.; Hänzelmann, P.; Hernandez, H.L.; Subramanian, S.; Schindelin, H.; Johnson, M.K.; Hoffman, B.M.
ENDOR spectroscopy shows that guanine N1 binds to [4Fe-4S] cluster II of the S-adenosylmethionine-dependent enzyme MoaA: mechanistic implications
J. Am. Chem. Soc.
131
9184-9185
2009
Staphylococcus aureus
Manually annotated by BRENDA team
Hänzelmann, P.; Schindelin, H.
Crystal structure of the S-adenosylmethionine-dependent enzyme MoaA and its implications for molybdenum cofactor deficiency in humans
Proc. Natl. Acad. Sci. USA
101
12870-12875
2004
Staphylococcus aureus (P65388)
Manually annotated by BRENDA team
Hänzelmann, P.; Schindelin, H.
Binding of 5'-GTP to the C-terminal FeS cluster of the radical S-adenosylmethionine enzyme MoaA provides insights into its mechanism
Proc. Natl. Acad. Sci. USA
103
6829-6834
2006
Staphylococcus aureus (P65388)
Manually annotated by BRENDA team
Hover, B.M.; Loksztejn, A.; Ribeiro, A.A.; Yokoyama, K.
Identification of a cyclic nucleotide as a cryptic intermediate in molybdenum cofactor biosynthesis
J. Am. Chem. Soc.
135
7019-7032
2013
Homo sapiens, Staphylococcus aureus
Manually annotated by BRENDA team
Hover, B.M.; Lilla, E.A.; Yokoyama, K.
Mechanistic investigation of cPMP synthase in molybdenum cofactor biosynthesis using an uncleavable substrate analogue
Biochemistry
54
7229-7236
2015
Staphylococcus aureus (P69848), Staphylococcus aureus NCTC 8325 (P69848)
Manually annotated by BRENDA team
Hover, B.M.; Yokoyama, K.
C-Terminal glycine-gated radical initiation by GTP 3',8-cyclase in the molybdenum cofactor biosynthesis
J. Am. Chem. Soc.
137
3352-3359
2015
Staphylococcus aureus (P65388), Staphylococcus aureus N315 (P65388)
Manually annotated by BRENDA team
Hover, B.M.; Tonthat, N.K.; Schumacher, M.A.; Yokoyama, K.
Mechanism of pyranopterin ring formation in molybdenum cofactor biosynthesis
Proc. Natl. Acad. Sci. USA
112
6347-6352
2015
Staphylococcus aureus (P69848), Staphylococcus aureus NCTC 8325 (P69848)
Manually annotated by BRENDA team