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Structure-based inhibitor discovery of Helicobacter pylori dehydroquinate synthase.

Liu JS, Cheng WC, Wang HJ, Chen YC, Wang WC
Biochem Biophys Res Commun 373 1-7 (2008)
Cited: 18 times
EuropePMC logo PMID: 18503755

Abstract

Dehydroquinate synthase (DHQS) is a nicotinamide adenine dinucleotide (NAD)-dependent enzyme that converts 3-deoxy-D-arabino-heptulosonate 7-phosphate (DAHP) into 3-dehydroquinate (DHQ). Since it catalyzes the second key step in the shikimate pathway, which is crucial for the aromatic amino acid metabolism in bacteria, fungi, and plants, but not in mammals, DHQS is a potential target for new antimicrobial agents, anti-parasitic agents and herbicides. The crystal structure of Helicobacter pylori DHQS (HpDHQS) complexed with NAD has been determined at 2.4-A resolution and was found to possess an N-terminal Rossmann-fold domain and a C-terminal alpha-helical domain. Structural comparison reveals that the binary complex adopts an open-state conformation and shares conserved residues in the binding pocket. Virtual docking of compounds into the active site of the HpDHQS structure using the GOLD docking program led to the identification of several inhibitors. The most active compound had an IC(50) value of 61 microM, which may serve as a lead for potent inhibitors.

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  1. The Blueprint of a Minimal Cell: MiniBacillus. Reuß DR, Commichau FM, Gundlach J, Zhu B, Stülke J. Microbiol Mol Biol Rev 80 955-987 (2016)

Articles - 3clh mentioned but not cited (5)

  1. Dissection study on the severe acute respiratory syndrome 3C-like protease reveals the critical role of the extra domain in dimerization of the enzyme: defining the extra domain as a new target for design of highly specific protease inhibitors. Shi J, Wei Z, Song J. J Biol Chem 279 24765-24773 (2004)
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  5. Expression, Purification, and Characterisation of Dehydroquinate Synthase from Pyrococcus furiosus. Negron L, Patchett ML, Parker EJ. Enzyme Res 2011 134893 (2011)


Reviews citing this publication (1)

  1. Exploring alternative treatments for Helicobacter pylori infection. Ayala G, Escobedo-Hinojosa WI, de la Cruz-Herrera CF, Romero I. World J Gastroenterol 20 1450-1469 (2014)

Articles citing this publication (11)

  1. Future perspective for potential Helicobacter pylori eradication therapies. Debraekeleer A, Remaut H. Future Microbiol 13 671-687 (2018)
  2. Cyanobacterial antimetabolite 7-deoxy-sedoheptulose blocks the shikimate pathway to inhibit the growth of prototrophic organisms. Brilisauer K, Rapp J, Rath P, Schöllhorn A, Bleul L, Weiß E, Stahl M, Grond S, Forchhammer K. Nat Commun 10 545 (2019)
  3. Structures of Helicobacter pylori shikimate kinase reveal a selective inhibitor-induced-fit mechanism. Cheng WC, Chen YF, Wang HJ, Hsu KC, Lin SC, Chen TJ, Yang JM, Wang WC. PLoS One 7 e33481 (2012)
  4. Δ1-pyrroline-5-carboxylate reductase as a new target for therapeutics: inhibition of the enzyme from Streptococcus pyogenes and effects in vivo. Forlani G, Petrollino D, Fusetti M, Romanini L, Nocek B, Joachimiak A, Berlicki L, Kafarski P. Amino Acids 42 2283-2291 (2012)
  5. Biochemical and structural characterisation of dehydroquinate synthase from the New Zealand kiwifruit Actinidia chinensis. Mittelstädt G, Negron L, Schofield LR, Marsh K, Parker EJ. Arch Biochem Biophys 537 185-191 (2013)
  6. IMB-T130 targets 3-dehydroquinate synthase and inhibits Mycobacterium tuberculosis. Zhu N, Wang X, Li D, Lin Y, You X, Jiang J, Xu Y, Jiang W, Si S. Sci Rep 8 17439 (2018)
  7. Analysis of Biosynthetic Gene Clusters, Secretory, and Antimicrobial Peptides Reveals Environmental Suitability of Exiguobacterium profundum PHM11. Srivastava AK, Srivastava R, Bharati AP, Singh AK, Sharma A, Das S, Tiwari PK, Srivastava AK, Chakdar H, Kashyap PL, Saxena AK. Front Microbiol 12 785458 (2021)
  8. Structure-guided design of Serratia marcescens short-chain dehydrogenase/reductase for stereoselective synthesis of (R)-phenylephrine. Liu JS, Kuan YC, Tsou Y, Lin TY, Hsu WH, Yang MT, Lin JY, Wang WC. Sci Rep 8 2316 (2018)
  9. Dehydroquinate Synthase Directly Binds to Streptomycin and Regulates Susceptibility of Mycobacterium bovis to Streptomycin in a Non-canonical Mode. Wei W, Qiao J, Jiang X, Cai L, Hu X, He J, Chen M, Yang M, Cui T. Front Microbiol 13 818881 (2022)
  10. Molecular analysis and essentiality of Aro1 shikimate biosynthesis multi-enzyme in Candida albicans. Stogios PJ, Liston SD, Semper C, Quade B, Michalska K, Evdokimova E, Ram S, Otwinowski Z, Borek D, Cowen LE, Savchenko A. Life Sci Alliance 5 e202101358 (2022)
  11. Systematic analysis and integrative discovery of active-site subpocket-specific dehydroquinate synthase inhibitors combating antibiotic-resistant Staphylococcus aureus infection. Liu Q, Li L, Xu F. J Bioinform Comput Biol 16 1850027 (2018)


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