ArticleThe FEBS journal2014
Defining critical residues for substrate binding to 1-deoxy-D-xylulose 5-phosphate synthase--active site substitutions stabilize the predecarboxylation intermediate C2α-lactylthiamin diphosphate.
Article in The FEBS journal, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 42 citations in OpenAlex.
- Analysis of the DXS Pan-Gene Family Reveals Evolutionary Conservation and Regulatory Divergence Underpinning Terpenoid Metabolism in Lauraceae.Plants (Basel, Switzerland) · 2026Article
- Differential Hydroxypyruvate Processing byBiochemistry · 2026Article
- Aromatic Residues in Mobile Regions Distal to the Active Site Support the Closed Conformation ofBiochemistry · 2026Article
- X-ray Co-crystal Structure of a Novel Pseudomonas aeruginosa DXPS Inhibitor Reveals an Unusual Allosteric Binding Pocket.Research square · 2026Article
- Exploring the antimicrobial activity of pantothenamides against uropathogenicMicrobiology spectrum · 2025Article
- Trihydroxybenzaldoximes are Redox Cycling Inhibitors of ThDP-Dependent DXP Synthase.ACS chemical biology · 2025Article
- Trihydroxybenzaldoximes are redox cycling inhibitors of ThDP-dependent DXP synthase.bioRxiv : the preprint server for biology · 2025Article
- Bisubstrate Analog Inhibitors of DXP Synthase Show Species Specificity.Biochemistry · 2025Article
- Aldehyde-based Activation of C2α-lactylthiamin Diphosphate Decarboxylation on Bacterial 1-deoxy-d-xylulose 5-phosphate Synthase.Chembiochem : a European journal of chemical biology · 2024Article
- Cryo-EM structure of 1-deoxy-D-xylulose 5-phosphate synthase DXPS from Plasmodium falciparum reveals a distinct N-terminal domain.Nature communications · 2024Article
- Potent Inhibition ofACS infectious diseases · 2024Article
- Disruption of an Active Site Network Leads to Activation of C2α-Lactylthiamin Diphosphate on the Antibacterial Target 1-Deoxy-d-xylulose-5-phosphate Synthase.Biochemistry · 2024Article
- Improving tyrosol production efficiency through shortening the allosteric signal transmission distance of pyruvate decarboxylase.Applied microbiology and biotechnology · 2023Article
- The Multifaceted MEP Pathway: Towards New Therapeutic Perspectives.Molecules (Basel, Switzerland) · 2023Review
- Discovery of novel drug-like antitubercular hits targeting the MEP pathway enzyme DXPS by strategic application of ligand-based virtual screening.Chemical science · 2022Article
- Antibacterial Target DXP Synthase Catalyzes the Cleavage of d-Xylulose 5-Phosphate: a Study of Ketose Phosphate Binding and Ketol Transfer Reaction.Biochemistry · 2022Article
- First crystal structures of 1-deoxy-D-xylulose 5-phosphate synthase (DXPS) from Mycobacterium tuberculosis indicate a distinct mechanism of intermediate stabilization.Scientific reports · 2022Article
- Genome-based identification and comparative analysis of enzymes for carotenoid biosynthesis in microalgae.World journal of microbiology & biotechnology · 2021Article
- Revealing Donor Substrate-Dependent Mechanistic Control on DXPS, an Enzyme in Bacterial Central Metabolism.Biochemistry · 2021Article
- Negative regulation of plastidial isoprenoid pathway by herbivore-induced β-cyclocitral inProceedings of the National Academy of Sciences of the United States of America · 2021Article
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
1-Deoxy-D-xylulose 5-phosphate (DXP) synthase catalyzes the formation of DXP from pyruvate and D-glyceraldehyde 3-phosphate (GraP) in a thiamin diphosphate-dependent manner, and is the first step in the essential pathway to isoprenoids in human pathogens. Understanding the mechanism of this unique enzyme is critical for developing new anti-infective agents that selectively target isoprenoid biosynthesis. The present study used mutagenesis and a combination of protein fluorescence, CD and kinetics experiments to investigate the roles of Arg420, Arg478 and Tyr392 in substrate binding and catalysis. The results support a random sequential, preferred order mechanism, and predict that Arg420 and Arg478 are involved in binding of the acceptor substrate, GraP. D-Glyceraldehyde, an alternative acceptor substrate lacking the phosphoryl group predicted to interact with Arg420 and Arg478, also accelerates decarboxylation of the predecarboxylation intermediate C2α-lactylthiamin diphosphate (LThDP) on DXP synthase, indicating that this binding interaction is not absolutely required, and that the hydroxyaldehyde sufficiently triggers decarboxylation. Unexpectedly, Tyr392 contributes to GraP affinity, and is not required for LThDP formation or its GraP-promoted decarboxylation. Time-resolved CD spectroscopy and NMR experiments indicate that LThDP is significantly stabilized on R420A and Y392F variants as compared with wild-type DXP synthase in the absence of acceptor substrate, but these substitutions do not appear to affect the rate of GraP-promoted LThDP decarboxylation in the presence of high levels of GraP, and LThDP formation remains the rate-limiting step. These results suggest a role of these residues in promoting GraP binding, which in turn facilitates decarboxylation, and also highlight interesting differences between DXP synthase and other thiamin diphosphate-dependent enzymes.
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