Binding Isotope Effects for para-Aminobenzoic Acid with Dihydropteroate Synthase from Staphylococcus aureus and Plasmodium falciparum

Christopher F. Stratton, Hilda A. Namanja-Magliano, Scott A. Cameron, Vern L. Schramm

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Dihydropteroate synthase is a key enzyme in folate biosynthesis and is the target of the sulfonamide class of antimicrobials. Equilibrium binding isotope effects and density functional theory calculations indicate that the substrate binding sites for para-aminobenzoic acid on the dihydropteroate synthase enzymes from Staphylococcus aureus and Plasmodium falciparum present distinct chemical environments. Specifically, we show that para-aminobenzoic acid occupies a more sterically constrained vibrational environment when bound to dihydropteroate synthase from P. falciparum relative to that of S. aureus. Deletion of a nonhomologous, parasite-specific insert from the plasmodial dihydropteroate synthase abrogated the binding of para-aminobenzoic acid. The loop specific to P. falciparum is important for effective substrate binding and therefore plays a role in modulating the chemical environment at the substrate binding site.

Original languageEnglish (US)
Pages (from-to)2182-2186
Number of pages5
JournalACS Chemical Biology
Volume10
Issue number10
DOIs
StatePublished - Oct 16 2015

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Dihydropteroate Synthase
4-Aminobenzoic Acid
Plasmodium falciparum
Isotopes
Staphylococcus aureus
Substrates
Binding Sites
Biosynthesis
Sulfonamides
Enzymes
Folic Acid
Density functional theory
Parasites

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

Cite this

Binding Isotope Effects for para-Aminobenzoic Acid with Dihydropteroate Synthase from Staphylococcus aureus and Plasmodium falciparum. / Stratton, Christopher F.; Namanja-Magliano, Hilda A.; Cameron, Scott A.; Schramm, Vern L.

In: ACS Chemical Biology, Vol. 10, No. 10, 16.10.2015, p. 2182-2186.

Research output: Contribution to journalArticle

Stratton, Christopher F. ; Namanja-Magliano, Hilda A. ; Cameron, Scott A. ; Schramm, Vern L. / Binding Isotope Effects for para-Aminobenzoic Acid with Dihydropteroate Synthase from Staphylococcus aureus and Plasmodium falciparum. In: ACS Chemical Biology. 2015 ; Vol. 10, No. 10. pp. 2182-2186.
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