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Structural-functional studies of Burkholderia cenocepacia D-glycero-β-D-manno-heptose 7-phosphate kinase (HldA) and characterization of inhibitors with antibiotic adjuvant and antivirulence properties.

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Lee TW, Verhey TB, Antiperovitch PA, Atamanyuk D, Desroy N, Oliveira C, Denis A, Gerusz V, Drocourt E, Loutet SA, Hamad MA, Stanetty C, Andres SN, Sugiman-Marangos S, Kosma P, Valvano MA, Moreau F, Junop MS
OpenAccess logo J Med Chem 56 1405-17 (2013)
Related entries: 4e8w, 4e8y, 4e8z

Cited: 4 times
EuropePMC logo PMID: 23256532

Abstract

As an essential constituent of the outer membrane of Gram-negative bacteria, lipopolysaccharide contributes significantly to virulence and antibiotic resistance. The lipopolysaccharide biosynthetic pathway therefore serves as a promising therapeutic target for antivirulence drugs and antibiotic adjuvants. Here we report the structural-functional studies of D-glycero-β-D-manno-heptose 7-phosphate kinase (HldA), an absolutely conserved enzyme in this pathway, from Burkholderia cenocepacia. HldA is structurally similar to members of the PfkB carbohydrate kinase family and appears to catalyze heptose phosphorylation via an in-line mechanism mediated mainly by a conserved aspartate, Asp270. Moreover, we report the structures of HldA in complex with two potent inhibitors in which both inhibitors adopt a folded conformation and occupy the nucleotide-binding sites. Together, these results provide important insight into the mechanism of HldA-catalyzed heptose phosphorylation and necessary information for further development of HldA inhibitors.

Articles citing this publication (4)

  1. Unraveling the B. pseudomallei Heptokinase WcbL: From Structure to Drug Discovery. Vivoli M, Isupov MN, Nicholas R, Hill A, Scott AE, Kosma P, Prior JL, Harmer NJ. Chem. Biol. 22 1622-1632 (2015)
  2. General assay for enzymes in the heptose biosynthesis pathways using electrospray ionization mass spectrometry. Park J, Lee D, Seo EK, Ryu JS, Shin DH. Appl. Microbiol. Biotechnol. 101 4521-4532 (2017)
  3. A conservative distribution of tridomain NDP-heptose synthetases in actinobacteria. Tang Y, Tang W, Wang M, Zhang Z, Chen Y. Sci China Life Sci 65 1014-1023 (2022)
  4. Crystal structure of D-glycero-Β-D-manno-heptose-1-phosphate adenylyltransferase from Burkholderia pseudomallei. Park J, Kim H, Kim S, Lee D, Kim MS, Shin DH. Proteins 86 124-131 (2018)


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