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Crystal structure of 7,8-dihydropteroate synthase from Bacillus anthracis: mechanism and novel inhibitor design.

Babaoglu K, Qi J, Lee RE, White SW
Structure 12 1705-17 (2004)
Related entries: 1tws, 1twz, 1tx0, 1tx2

Cited: 49 times
EuropePMC logo PMID: 15341734

Abstract

Dihydropterate synthase (DHPS) is the target for the sulfonamide class of antibiotics, but increasing resistance has encouraged the development of new therapeutic agents against this enzyme. One approach is to identify molecules that occupy the pterin binding pocket which is distinct from the pABA binding pocket that binds sulfonamides. Toward this goal, we present five crystal structures of DHPS from Bacillus anthracis, a well-documented bioterrorism agent. Three DHPS structures are already known, but our B. anthracis structures provide new insights into the enzyme mechanism. We show how an arginine side chain mimics the pterin ring in binding within the pterin binding pocket. The structures of two substrate analog complexes and the first structure of a DHPS-product complex offer new insights into the catalytic mechanism and the architecture of the pABA binding pocket. Finally, as an initial step in the development of pterin-based inhibitors, we present the structure of DHPS complexed with 5-nitro-6-methylamino-isocytosine.

Articles - 1tww mentioned but not cited (3)

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Reviews citing this publication (8)

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Articles citing this publication (38)

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  32. Synthesis of pyrazolo-1,2,4-triazolo[4,3-a]quinoxalines as antimicrobial agents with potential inhibition of DHPS enzyme. Z El-Attar MA, Elbayaa RY, Shaaban OG, Habib NS, Abdel Wahab AE, Abdelwahab IA, M El-Hawash SA. Future Med Chem 10 2155-2175 (2018)
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  35. Crystal structure of Arabidopsis thaliana HPPK/DHPS, a bifunctional enzyme and target of the herbicide asulam. Vadlamani G, Sukhoverkov KV, Haywood J, Breese KJ, Fisher MF, Stubbs KA, Bond CS, Mylne JS. Plant Commun 3 100322 (2022)
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