Crystal Structures of Staphylococcus aureus Ketol‐Acid Reductoisomerase in Complex with Two Transition State Analogues that Have Biocidal Activity

Abstract:

Ketol‐acid reductoisomerase (KARI) is an NAD(P)H and Mg2+‐dependent enzyme of the branched‐chain amino acid (BCAA) biosynthesis pathway. Here, the first crystal structures of Staphylococcus aureus (Sa) KARI in complex with two transition state analogues, cyclopropane‐1,1‐dicarboxylate (CPD) and N‐isopropyloxalyl hydroxamate (IpOHA) are reported. These compounds bind competitively and in multi‐dentate manner to KARI with Ki values of 2.73 μm and 7.9 nm, respectively; however, IpOHA binds slowly to the enzyme. Interestingly, intact IpOHA is present in only ≈25 % of binding sites, whereas its deoxygenated form is present in the remaining sites. This deoxy form of IpOHA binds rapidly to Sa KARI, but with much weaker affinity (Ki=21 μm). Thus, our data pinpoint the origin of the slow binding mechanism of IpOHA. Furthermore, we propose that CPD mimics the early stage of the catalytic …

Año de publicación:

2017

Keywords:

Fuente:

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