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Information on EC 4.3.2.10 - imidazole glycerol-phosphate synthase and Organism(s) Thermotoga maritima and UniProt Accession Q9X0C6

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EC Tree
     4 Lyases
         4.3 Carbon-nitrogen lyases
             4.3.2 Amidine-lyases
                4.3.2.10 imidazole glycerol-phosphate synthase
IUBMB Comments
The enzyme is involved in histidine biosynthesis, as well as purine nucleotide biosynthesis. The enzymes from archaea and bacteria are heterodimeric. A glutaminase component (cf. EC 3.5.1.2, glutaminase) produces an ammonia molecule that is transferred by a 25 A tunnel to a cyclase component, which adds it to the imidazole ring, leading to lysis of the molecule and cyclization of one of the products. The glutminase subunit is only active within the dimeric complex. In fungi and plants the two subunits are combined into a single polypeptide.
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UNIPROT: Q9X0C6 not found.
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The taxonomic range for the selected organisms is: Thermotoga maritima
The enzyme appears in selected viruses and cellular organisms
Synonyms
hishf, hisfh, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
HIS7
-
-
-
-
hisFH
-
-
-
-
IGP synthase
-
-
-
-
SYSTEMATIC NAME
IUBMB Comments
5-[(5-phospho-1-deoxy-D-ribulos-1-ylamino)methylideneamino]-1-(5-phospho-beta-D-ribosyl)imidazole-4-carboxamide D-erythro-1-(imidazol-4-yl)glycerol 3-phosphate-lyase (L-glutamine-hydrolysing; 5-amino-1-(5-phospho-beta-D-ribosyl)imidazole-4-carboxamide-forming)
The enzyme is involved in histidine biosynthesis, as well as purine nucleotide biosynthesis. The enzymes from archaea and bacteria are heterodimeric. A glutaminase component (cf. EC 3.5.1.2, glutaminase) produces an ammonia molecule that is transferred by a 25 A tunnel to a cyclase component, which adds it to the imidazole ring, leading to lysis of the molecule and cyclization of one of the products. The glutminase subunit is only active within the dimeric complex. In fungi and plants the two subunits are combined into a single polypeptide.
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
5-[(5-phospho-1-deoxy-D-ribulos-1-ylamino)methylideneamino]-1-(5-phospho-beta-D-ribosyl)imidazole-4-carboxamide + L-glutamine
5-amino-1-(5-phospho-beta-D-ribosyl)imidazole-4-carboxamide + D-erythro-1-(imidazol-4-yl)glycerol 3-phosphate + L-glutamate
show the reaction diagram
5-[(5-phospho-1-deoxy-D-ribulos-1-ylamino)methylideneamino]-1-(5-phospho-beta-D-ribosyl)imidazole-4-carboxamide + NH3
5-amino-1-(5-phospho-beta-D-ribosyl)imidazole-4-carboxamide + D-erythro-1-(imidazol-4-yl)glycerol 3-phosphate + H2O
show the reaction diagram
the HisH subunit catalyzes Gln hydrolysis, and the HisF subunit catalyzes the cyclization of the allosteric activator 5-[(5-phospho-1-deoxy-D-ribulos-1-ylamino)methylideneamino]-1-(5-phospho-beta-D-ribosyl)imidazole-4-carboxamide. Ammonia generated in the HisH reaction traverses the dimer interface, where it is used as a substrate in the HisF reaction
-
-
?
5-[(5-phospho-1-deoxy-D-ribulos-1-ylamino)methylideneamino]-1-(5-phospho-beta-D-ribosyl)imidazole-4-carboxamide + NH4+
5-amino-1-(5-phospho-beta-D-ribosyl)imidazole-4-carboxamide + D-erythro-1-(imidazol-4-yl)glycerol 3-phosphate + H2O
show the reaction diagram
ammonia-dependent ImGP synthase reaction of isolated HisF subunit
-
-
?
5-[(5-phospho-1-deoxy-D-ribulos-1-ylamino)methylideneamino]-1-(5-phospho-ß-D-ribosyl)imidazole-4-carboxamide + NH3
5-amino-1-(5-phospho--D-ribosyl)imidazole-4-carboxamide + D-erythro-1-(imidazol-4-yl)glycerol 3-phosphate + H2O
show the reaction diagram
IGPS heterodimeric enzyme comprised of two proteins, HisH and HisF, that catalyze the hydrolysis of glutamine to produce NH3 in the HisH active site and the cyclization of ammonia with 5-[(5-phospho-1-deoxy-D-ribulos-1-ylamino)methylideneamino]-1-(5-phospho-beta-D-ribosyl)imidazole-4-carboxamide in HisF to produce 5-amino-1-(5-phospho-beta-D-ribosyl)imidazole-4-carboxamide and D-erythro-1-(imidazol-4-yl)glycerol 3-phosphate. Binding of 5-[(5-phospho-1-deoxy-D-ribulos-1-ylamino)methylideneamino]-1-(5-phospho-beta-D-ribosyl)imidazole-4-carboxamide and D-erythro-1-(imidazol-4-yl)glycerol 3-phosphate stimulates glutaminase activity in the HisH enzyme over 5000 and 100-fold, respectively, despite the active sites being more than 25 A apart
-
-
?
L-glutamine + H2O
L-glutamate + NH3
show the reaction diagram
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
5-[(5-phospho-1-deoxy-D-ribulos-1-ylamino)methylideneamino]-1-(5-phospho-beta-D-ribosyl)imidazole-4-carboxamide + L-glutamine
5-amino-1-(5-phospho-beta-D-ribosyl)imidazole-4-carboxamide + D-erythro-1-(imidazol-4-yl)glycerol 3-phosphate + L-glutamate
show the reaction diagram
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
7-benzyl-8-[(1-[[(2-hydroxyethyl)amino]methyl]propyl)amino]-1,3-dimethyl-2,3,6,7-tetrahydro-1H-2,6-purinedione
glutaminase activity is substantially suppressed upon binding of the inhibitor to the HisH-HisF interface. The allosteric inhibitor is able to uncouple motions induced by the effector ligand with essential motions in the distant active site, favoring an inactive conformation of this V-type enzyme
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
N'-[(5'-phosphoribulosyl)formimino]-5-aminoimidazole-4-carboxamide-ribonucleotide
binding of the allosteric effector ligand stimulates millisecond timescale motions in the enzyme that enhance its catalytic function. The flexibility of the apo enzyme is nearly identical to that of its N'-[(5'-phosphoribulosyl)formimino]-5-aminoimidazole-4-carboxamide-ribonucleotide activated state at 70°C, whereas conformational motions are considerably different between the two forms of the enzyme at room temperature. Allosteric activation by N'-[(5'-phosphoribulosyl)formimino]-5-aminoimidazole-4-carboxamide-ribonucleotide decreases to 65fold at 70°C, compared to 4200fold at 30°C
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0015 - 0.0017
5-[(5-phospho-1-deoxy-D-ribulos-1-ylamino)methylideneamino]-1-(5-phospho-beta-D-ribosyl)imidazole-4-carboxamide
0.32 - 4.91
L-glutamine
2.2
NH4+
pH 8.5, 25°C, ammonia-dependent reaction of isolated HisF subunit, wild-type
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.8 - 2.2
5-[(5-phospho-1-deoxy-D-ribulos-1-ylamino)methylideneamino]-1-(5-phospho-beta-D-ribosyl)imidazole-4-carboxamide
0.00165 - 5.92
L-glutamine
2
NH4+
pH 8.5, 25°C, ammonia-dependent reaction of isolated HisF subunit, wild-type
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
600 - 1300
5-[(5-phospho-1-deoxy-D-ribulos-1-ylamino)methylideneamino]-1-(5-phospho-beta-D-ribosyl)imidazole-4-carboxamide
0.00042 - 4480
L-glutamine
900
NH4+
pH 8.5, 25°C, ammonia-dependent reaction of isolated HisF subunit, wild-type
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
TEMPERATURE RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
30 - 70
binding of the allosteric effector ligand 5-[(5-phospho-1-deoxy-D-ribulos-1-ylamino)methylideneamino]-1-(5-phospho-beta-D-ribosyl)imidazole-4-carboxamide stimulates millisecond timescale motions in IGPS that enhance its catalytic function. Allosteric activation decreases to 65-fold at 70°C, compared to 4200-fold at 30°C
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
malfunction
knockouts of IGPS subunit HisF can increase the susceptibility of bacteria to ß-lactam antibiotics and lessen their infectivity
metabolism
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
dimer
heterodimer
the structure of the enzyme provides a model how ammonia is channeled over a distance of about 25 A. The larger part of the putative ammonia tunnel is provided by the interior of the beta barrel of subunit HisF, which has a (betaalpha)8 fold
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
vapor diffusion method
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
C9A
mutant of subunit HisF. The catalytic efficiencies kcat/Km of both isolated and complexed tHisF_C9A are not significantly different from wild-type tHisF, ruling out any central catalytic role for the replaced residue
D130N
mutant of subunit HisF. The catalytic efficiency kcat/Km for 5-[(5-phospho-1-deoxy-D-ribulos-1-ylamino)methylideneamino]-1-(5-phospho-beta-D-ribosyl)imidazole-4-carboxamide is decreased by approximately 5 orders of magnitude
D176N
mutant of subunit HisF. Variant tHisF_D176N shows a 40-50 fold decrease in kcat, both in isolated form and in complex with tHisH
D183N
mutant of subunit HisF. The catalytic efficiencies kcat/Km of both isolated and complexed tHisF_D183N are not significantly different from wild-type tHisF, ruling out any central catalytic role for the replaced residue. Both kcat and Km are drastically impaired in the mutant enzyme
D51N
mutant of subunit HisF. The catalytic efficiencies kcat/Km of both isolated and complexed tHisF_D51N are not significantly different from wild-type tHisF, ruling out any central catalytic role for the replaced residue
D98A
HisF subunit mutant, mutation reduces glutaminase activity to 3% compared to activity of wild-type enzyme
K19A
HisF subunit mutant, mutation reduces glutaminase activity to 3% compared to activity of wild-type enzyme
K19S
mutant of subunit HisF. The ammonia-dependent reactions of isolated tHisF_K19S are similarly efficient as those of wild-type tHisF. In contrast, the efficiencies of the glutamine-dependent reactions of the tHisHtHisF_K19S complex are significantly impaired
N103A
mutant of subunit HisF. The catalytic efficiencies kcat/Km of both isolated and complexed tHisF_N103A are not significantly different from wild-type tHisF, ruling out any central catalytic role for the replaced residue
T78M
mutant enzyme with reduced catalytic activity
V12A
HisF subunit mutant, mutation reduces glutaminase activity to 70% compared to activity of wild-type enzyme
V48A
HisF subunit mutant, mutation reduces glutaminase activity to 3% compared to activity of wild-type enzyme
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expression in Escherichia coli BL21(DE3)
tHisH and tHisF from Thermotoga maritima are produced in Escherichia coli
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
agriculture
development of allosteric antibiotics, herbicides, and antifungal compounds because the enzyme is absent in mammals but provides an entry point to fundamental biosynthetic pathways in plants, fungi, and bacteria
drug development
the enzyme is a potential therapeutic target absent in mammals but present in bacteria, plants, and fungi. Many plant and human pathogens that infect the immunocompromised patient have an IGPS that is highly homologous to the Saccharomyces cerevisiae and Thermotoga maritima enzymes
pharmacology
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Rivalta, I.; Lisi, G.P.; Snoeberger, N.S.; Manley, G.; Loria, J.P.; Batista, V.S.
Allosteric communication disrupted by a small molecule binding to the imidazole glycerol phosphate synthase protein-protein interface
Biochemistry
55
6484-6494
2016
Thermotoga maritima (Q9X0C8 and Q9X0C6), Thermotoga maritima ATCC 43589 (Q9X0C8 and Q9X0C6)
Manually annotated by BRENDA team
Lisi, G.; Currier, A.; Loria, J.
Glutamine hydrolysis by imidazole glycerol phosphate synthase displays temperature dependent allosteric activation
Front. Mol. Biosci.
5
4
2018
Thermotoga maritima (Q9X0C6 AND Q9X0C8), Thermotoga maritima (Q9X0C8 and Q9X0C6), Thermotoga maritima ATCC 43589 (Q9X0C6 AND Q9X0C8), Thermotoga maritima ATCC 43589 (Q9X0C8 and Q9X0C6)
Manually annotated by BRENDA team
Beismann-Driemeyer, S.; Sterner, R.
Imidazole glycerol phosphate synthase from Thermotoga maritima. Quaternary structure, steady-state kinetics, and reaction mechanism of the bienzyme complex
J. Biol. Chem.
276
20387-20396
2001
Thermotoga maritima (Q9X0C6 AND Q9X0C8), Thermotoga maritima ATCC 43589 (Q9X0C6 AND Q9X0C8)
Manually annotated by BRENDA team
Lipchock, J.; Loria, J.P.
Millisecond dynamics in the allosteric enzyme imidazole glycerol phosphate synthase (IGPS) from Thermotoga maritima
J. Biomol. NMR
45
73-84
2009
Thermotoga maritima (Q9X0C6 AND Q9X0C8), Thermotoga maritima ATCC 43589 (Q9X0C6 AND Q9X0C8)
Manually annotated by BRENDA team
Lisi, G.P.; East, K.W.; Batista, V.S.; Loria, J.P.
Altering the allosteric pathway in IGPS suppresses millisecond motions and catalytic activity
Proc. Natl. Acad. Sci. USA
114
E3414-E3423
2017
Thermotoga maritima (Q9X0C8 and Q9X0C6)
Manually annotated by BRENDA team
Liebold, C.; List, F.; Kalbitzer, H.R.; Sterner, R.; Brunner, E.
The interaction of ammonia and xenon with the imidazole glycerol phosphate synthase from Thermotoga maritima as detected by NMR spectroscopy
Protein Sci.
19
1774-1782
2010
Thermotoga maritima (Q9X0C6 AND Q9X0C8), Thermotoga maritima ATCC 43589 (Q9X0C6 AND Q9X0C8)
Manually annotated by BRENDA team
Douangamath, A.; Walker, M.; Beismann-Driemeyer, S.; Vega-Fernandez, M.C.; Sterner, R.; Wilmanns, M.
Structural evidence for ammonia tunneling across the (beta alpha)(8) barrel of the imidazole glycerol phosphate synthase bienzyme complex
Structure
10
185-193
2002
Thermotoga maritima (Q9X0C6 AND Q9X0C8), Thermotoga maritima ATCC 43589 (Q9X0C6 AND Q9X0C8)
Manually annotated by BRENDA team