Crystal Structures of Staphylococcus aureus Ketol-Acid Reductoisomerase in Complex with Two Transition State Analogues that Have Biocidal Activity.
Chemistry
; 23(72): 18289-18295, 2017 Dec 22.
Article
em En
| MEDLINE
| ID: mdl-28975665
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 2.73â
µm and 7.9â
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 =21â
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 reaction (preceding the reduction step), whereas IpOHA mimics the late stage (after the reduction took place). These structural insights will guide strategies to design potent and rapidly binding derivatives of these compounds for the development of novel biocides.
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01-internacional
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MEDLINE
Assunto principal:
Staphylococcus aureus
/
Proteínas de Bactérias
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Ciclopropanos
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Ácidos Dicarboxílicos
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Cetol-Ácido Redutoisomerase
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Ácidos Hidroxâmicos
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article