M. tuberculosis indole‐3‐glycerol phosphate synthase: a potential new tuberculosis drug target

ChemBioChem ◽  
2021 ◽  
Author(s):  
Nikolas Esposito ◽  
David Konas ◽  
Nina Goodey
Keyword(s):  
Drug Target ◽  
Glycerol Phosphate ◽  
Phosphate Synthase

scholarly journals A novel inhibitor of indole-3-glycerol phosphate synthase with activity against multidrug-resistant Mycobacterium tuberculosis

FEBS Journal ◽  
2008 ◽  
Vol 276 (1) ◽  
pp. 144-154 ◽  
Author(s):  
Hongbo Shen ◽  
Feifei Wang ◽  
Ying Zhang ◽  
Qiang Huang ◽  
Shengfeng Xu ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Multidrug Resistant ◽  
Glycerol Phosphate ◽  
Phosphate Synthase

Relationship of Catalysis and Active Site Loop Dynamics in the (βα)8-Barrel Enzyme Indole-3-glycerol Phosphate Synthase

Biochemistry ◽  
2018 ◽  
Vol 57 (23) ◽  
pp. 3265-3277 ◽  
Author(s):  
Sandra Schlee ◽  
Thomas Klein ◽  
Magdalena Schumacher ◽  
Julian Nazet ◽  
Rainer Merkl ◽  
...  
Keyword(s):  
Active Site ◽  
Glycerol Phosphate ◽  
Loop Dynamics ◽  
Relationship Of ◽  
Phosphate Synthase

scholarly journals Crystal Structure of Imidazole Glycerol Phosphate Synthase

Structure ◽  
2001 ◽  
Vol 9 (10) ◽  
pp. 987-997 ◽  
Author(s):  
Barnali N Chaudhuri ◽  
Stephanie C Lange ◽  
Rebecca S Myers ◽  
Sridar V Chittur ◽  
V.Jo Davisson ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Glycerol Phosphate ◽  
Imidazole Glycerol Phosphate ◽  
Phosphate Synthase

scholarly journals 2.0 å structure of indole-3-glycerol phosphate synthase from the hyperthermophile Sulfolobus solfataricus: possible determinants of protein stability

Structure ◽  
1995 ◽  
Vol 3 (12) ◽  
pp. 1295-1306 ◽  
Author(s):  
Michael Hennig ◽  
Beatrice Darimont ◽  
Reinhard Sterner ◽  
Kasper Kirschner ◽  
Johan N Jansonius
Keyword(s):  
Protein Stability ◽  
Sulfolobus Solfataricus ◽  
Glycerol Phosphate ◽  
Phosphate Synthase

scholarly journals Structure and kinetics of indole-3-glycerol phosphate synthase from Pseudomonas aeruginosa: Decarboxylation is not essential for indole formation

2020 ◽  
Vol 295 (47) ◽  
pp. 15948-15956
Author(s):  
Annika Söderholm ◽  
Matilda S. Newton ◽  
Wayne M. Patrick ◽  
Maria Selmer
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Phenyl Group ◽  
Nucleophilic Attack ◽  
Active Site Residues ◽  
Glycerol Phosphate ◽  
E Coli ◽  
Substrate Analog ◽  
The 1960S ◽  
Kinetics Of ◽  
Phosphate Synthase

In tryptophan biosynthesis, the reaction catalyzed by the enzyme indole-3-glycerol phosphate synthase (IGPS) starts with a condensation step in which the substrate's carboxylated phenyl group makes a nucleophilic attack to form the pyrrole ring of the indole, followed by a decarboxylation that restores the aromaticity of the phenyl. IGPS from Pseudomonas aeruginosa has the highest turnover number of all characterized IGPS enzymes, providing an excellent model system to test the necessity of the decarboxylation step. Since the 1960s, this step has been considered to be mechanistically essential based on studies of the IGPS–phosphoribosylanthranilate isomerase fusion protein from Escherichia coli. Here, we present the crystal structure of P. aeruginosa IGPS in complex with reduced CdRP, a nonreactive substrate analog, and using a sensitive discontinuous assay, we demonstrate weak promiscuous activity on the decarboxylated substrate 1-(phenylamino)-1-deoxyribulose-5-phosphate, with an ∼1000× lower rate of IGP formation than from the native substrate. We also show that E. coli IGPS, at an even lower rate, can produce IGP from decarboxylated substrate. Our structure of P. aeruginosa IGPS has eight molecules in the asymmetric unit, of which seven contain ligand and one displays a previously unobserved conformation closer to the reactive state. One of the few nonconserved active-site residues, Phe201 in P. aeruginosa IGPS, is by mutagenesis demonstrated to be important for the higher turnover of this enzyme on both substrates. Our results demonstrate that despite IGPS's classification as a carboxy-lyase (i.e. decarboxylase), decarboxylation is not a completely essential step in its catalysis.

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