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Information on EC 2.8.1.12 - molybdopterin synthase and Organism(s) Homo sapiens
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2.8.1.12 molybdopterin synthaseIUBMB Comments
Catalyses the synthesis of molybdopterin from cyclic pyranopterin monophosphate. Two sulfur atoms are transferred to cyclic pyranopterin monophosphate in order to form the characteristic ene-dithiol group found in the molybdenum cofactor. Molybdopterin synthase consists of two large subunits forming a central dimer and two small subunits (molybdopterin-synthase sulfur-carrier proteins) that are thiocarboxylated at the C-terminus by EC 2.8.1.11, molybdopterin synthase sulfurtransferase. The reaction occurs in prokaryotes and eukaryotes.
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The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
Reaction Schemes
Synonyms
mpt synthase, molybdopterin synthase, moae2, moad-moae, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
SYSTEMATIC NAME
IUBMB Comments
thiocarboxylated molybdopterin synthase:cyclic pyranopterin monophosphate sulfurtransferase
Catalyses the synthesis of molybdopterin from cyclic pyranopterin monophosphate. Two sulfur atoms are transferred to cyclic pyranopterin monophosphate in order to form the characteristic ene-dithiol group found in the molybdenum cofactor. Molybdopterin synthase consists of two large subunits forming a central dimer and two small subunits (molybdopterin-synthase sulfur-carrier proteins) that are thiocarboxylated at the C-terminus by EC 2.8.1.11, molybdopterin synthase sulfurtransferase. The reaction occurs in prokaryotes and eukaryotes.
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
cyclic pyranopterin phosphate + 2 [molybdopterin-synthase sulfur-carrier protein]-Gly-NH-CH2-C(O)SH + H2O
molybdopterin + 2 molybdopterin-synthase sulfur-carrier protein
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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
cyclic pyranopterin phosphate + 2 [molybdopterin-synthase sulfur-carrier protein]-Gly-NH-CH2-C(O)SH + H2O
molybdopterin + 2 molybdopterin-synthase sulfur-carrier protein
-
-
-
?
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
molybdenum cofactor (Moco) biosynthesis is an evolutionarily conserved pathway present in eubacteria, archaea and eukaryotes, including humans. The strong structural similarity between the small subunit of MPT synthase and ubiquitin provides evidence for the evolutionary antecedence of the Moco biosynthetic pathway to the ubiquitin dependent protein degradation pathway
malfunction
metabolism
molybdopterin synthase is involved in the conversion of precursor Z to molybdopterin in the molybdenum cofactor biosynthetic pathway
physiological function
additional information
malfunction
characterization of mutants identified in group B patients of molybdenum cofactor deficiency, molecular mechanism leading to human molybdenum cofactor deficiency, overview
malfunction
genetic deficiencies of enzymes involved in Moco biosynthesis in humans lead to a severe and usually fatal disease
physiological function
the molybdenum cofactor contains a tricyclic pyranopterin, termed molybdopterin (MPT), that bears the cis-dithiolene group responsible for molybdenum ligation. The dithiolene group of MPT is generated by MPT synthase
physiological function
the small and large subunits in humans, MOCO1-A and MOCO1-B, respectively, together form molybdopterin synthase which adds sulphur to precursor Z
additional information
in the activated form of the enzyme this C-terminus is present as a thiocarboxylate. In the structure of a covalent complex of MPT synthase, an isopeptide bond is present between the C-terminus of the small subunit and a Lys side chain in the large subunit. The highly conserved active site residues are Arg39, Lys119, Lys126 and Arg140 in the large subunit
additional information
-
in the activated form of the enzyme this C-terminus is present as a thiocarboxylate. In the structure of a covalent complex of MPT synthase, an isopeptide bond is present between the C-terminus of the small subunit and a Lys side chain in the large subunit. The highly conserved active site residues are Arg39, Lys119, Lys126 and Arg140 in the large subunit
additional information
the rate of conversion of precursor Z to MPT by the human enzyme is slower than that of the eubacterial homologue from Escherichia coli
additional information
-
the rate of conversion of precursor Z to MPT by the human enzyme is slower than that of the eubacterial homologue from Escherichia coli
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). MOC2B_HUMAN
188
0
20944
Swiss-Prot
other Location (Reliability: 2)
A0A024QZS1_HUMAN
188
0
20944
TrEMBL
other Location (Reliability: 2)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
heterotetramer
additional information
heterotetramer
2 * 9700, subunit MOCO1-A, + 2 * 20900, subunit MOCO1-B, SDS-PAGE
heterotetramer
2 * 9800, subunit MOCS2A, + 2 * 20800, subunit MCS2B, SDS-PAGE
heterotetramer
the crystal structure of MPT synthase reveals a heterotetrameric protein in which the C-terminus of each small subunit is inserted into a large subunit to form the active site
additional information
comparison of structures and sequences of MPT synthases from different species, overview. The side chains of the aromatic residues Phe D7, Phe D75, Tyr E55 and Trp E125 are forming the hydrophobic core of the heterodimer interface, the highly conserved active site residues are Arg39, Lys119, Lys126 and Arg140 in the large subunit
additional information
-
comparison of structures and sequences of MPT synthases from different species, overview. The side chains of the aromatic residues Phe D7, Phe D75, Tyr E55 and Trp E125 are forming the hydrophobic core of the heterodimer interface, the highly conserved active site residues are Arg39, Lys119, Lys126 and Arg140 in the large subunit
additional information
human MPT synthase contains the subunits MOCS2A and MOCS2B
additional information
-
human MPT synthase contains the subunits MOCS2A and MOCS2B
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
purified recombinant enzyme, vapor diffusion, protein in M NaCl, 0.1 M HEPES, pH 7.5, is mixed with mother liquor containing 20% v/v glycerol, X-ray diffraction structure determination and analysis at 1.45 A resolution
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
E168K
naturally occuring substitution in MOCS2B, the E168K mutation, identified in a severely affected patient, attenuates binding of precursor Z, the MPT synthase tetramer is readily formed in mixtures of MOCS2B-E168K with equimolar amounts of MOCS2A
V7F
naturally occuring substitution in MOCS2A, identified in a patient with an unusual mild form of the disease, the mutation weakens the interaction between MOCS2A and MOCS2B, the MOCS2A-V7F variant does not form a complex with MOCS2B in either its carboxylated or thiocarboxylated form, and the mutant MPT synthase shows 90% reduced activity compared to the wild-type enzyme
additional information
additional information
a deletion of Ala150 is introduced into MOCS2B, attempts to purify MOCS2B-A150DELTA fails because the protein forms inclusion bodies upon expression in the Escherichia coli cells. Construction of a MOCS2B variant lacking the first 43 amino acid residues, the DELTA1-43 variant of MOCS2B is unstable because the majority of the protein was rapidly degraded during or after purification
additional information
-
a deletion of Ala150 is introduced into MOCS2B, attempts to purify MOCS2B-A150DELTA fails because the protein forms inclusion bodies upon expression in the Escherichia coli cells. Construction of a MOCS2B variant lacking the first 43 amino acid residues, the DELTA1-43 variant of MOCS2B is unstable because the majority of the protein was rapidly degraded during or after purification
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant enzyme from Escherichia coli strain BL21(DE3) by ammonium sulfate fractionation, dialysis, and gel filtration
recombinant human subunits MOCS2A and MOCS2B from Escherichia coli strain BL21(DE3) by ammonium sulfate fractionation and gel filtration. The separately purified subunits readily assemble into a functional MPT synthase tetramer
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
DNA and amino acid sequence determination and analysis, cDNA clones ATCC 960768 from adult uterus and ATCC 331184 from fetal liver and spleen, the MOCO1 locus resides on human chromosome 5 encoding subunits MOCO1-A and MOCO1-B
MOCS2A and MOCS2B genotyping, recombinant expression of human subunits MOCS2A and MOCS2B in Escherichia coli strain BL21(DE3), functional complementation of Escherichia coli moaD and moaE mutants. In vitro translation and mutagenesis experiments of MOCS2A and MOCS2B
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Leimkuhler, S.; Freuer, A.; Araujo, J.A.; Rajagopalan, K.V.; Mendel, R.R.
Mechanistic studies of human molybdopterin synthase reaction and characterization of mutants identified in group B patients of molybdenum cofactor deficiency
J. Biol. Chem.
278
26127-26134
2003
Homo sapiens (O96007), Homo sapiens
Rudolph, M.J.; Wuebbens, M.M.; Rajagopalan, K.V.; Schindelin, H.
Crystal structure of molybdopterin synthase and its evolutionary relationship to ubiquitin activation
Nat. Struct. Biol.
8
42-46
2001
Homo sapiens (O96007), Homo sapiens
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