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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The taxonomic range for the selected organisms is: Thermotoga maritima The enzyme appears in selected viruses and cellular organisms
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.
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
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
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 100fold, respectively, despite the active sites being more than 25 A apart
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
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 100fold, respectively, despite the active sites being more than 25 A apart
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
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
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
pH 8.0, 37°C, wild-type enzyme, activated by 1 mM 5-[(5-phospho-1-deoxy-D-ribulos-1-ylamino)methylideneamino]-1-(5-phospho-beta-D-ribosyl)imidazole-4-carboxamide
pH 8.0, 37°C, wild-type enzyme, activated by 1 mM 5-[(5-phospho-1-deoxy-D-ribulos-1-ylamino)methylideneamino]-1-(5-phospho-beta-D-ribosyl)imidazole-4-carboxamide
pH 8.0, 37°C, wild-type enzyme, activated by 1 mM 5-[(5-phospho-1-deoxy-D-ribulos-1-ylamino)methylideneamino]-1-(5-phospho-beta-D-ribosyl)imidazole-4-carboxamide
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
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
imidazole glycerol phosphate synthase constitutes a bienzyme complex of the glutaminase subunit HisH and the synthase subunit HisF. Isolated tHisH shows no detectable glutaminase activity but is stimulated by complex formation with tHisF to which either the product imidazole glycerol phosphate or a substrate analogue are bound
the enzyme is a 1:1 complex of the glutaminase subunit HisH and the cyclase subunit HisF. Subunit HisF contains three distinct internal cavities, which can be identified by xenon-induced chemical shift changes of the neighboring amino acid residues. Two of these cavities are located at the active site at opposite ends of the substrate N'-[(5'-phosphoribulosyl)formimino]-5-aminoimidazole-4-carboxamide ribonucleotide binding groove. The third cavity is located in the interior of the central beta-barrel of HisF and overlaps with the putative ammonia transport channel
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
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
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
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
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
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
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
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
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
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
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)