Dataset Information

Intramolecular cooperativity in the reaction of diacyl phosphates with serine beta-lactamases.

ABSTRACT: Asymmetric diaroyl phosphates (ArCOOPO(2)(-)OCOAr', where Ar = Ph, Ar' = 4-biphenyl, 2-benzothiophenyl and 2-benzofuranyl) have been prepared, evaluated as serine (classes A, C, and D) beta-lactamase inhibitors, and compared with respect to the latter with their symmetric parents, where Ar = Ar'. The asymmetric compounds, in general, were found to react with the beta-lactamases in two modes, corresponding to different orientations with respect to the active site, whereby either of the two aroyl groups may acylate the enzyme to form two different inert acyl-enzymes, E-COAr and E-COAr' . In all cases, the asymmetric compounds, in one orientation, react more rapidly with the enzymes tested than one symmetrical parent but not both. From comparisons of activation free energy differences, it was found that the changes in free energy on changing from one aryl group to another, in either the acyl group or the leaving group, were not additive, i.e., that the effect of changing one aroyl group to another depended on the leaving group and vice versa. Thus, intramolecular cooperativity between the aroyl groups must exist, arising either from direct interaction between them or from protein-mediated interaction or from a combination of both. Such cooperativity brings fresh opportunities and challenges to the search for novel beta-lactamase inhibitors.

SUBMITTER: Majumdar S

PROVIDER: S-EPMC2885897 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

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Intramolecular cooperativity in the reaction of diacyl phosphates with serine beta-lactamases.

Majumdar Sudipta S Pratt R F RF

Biochemistry 20090901 35

Asymmetric diaroyl phosphates (ArCOOPO(2)(-)OCOAr', where Ar = Ph, Ar' = 4-biphenyl, 2-benzothiophenyl and 2-benzofuranyl) have been prepared, evaluated as serine (classes A, C, and D) beta-lactamase inhibitors, and compared with respect to the latter with their symmetric parents, where Ar = Ar'. The asymmetric compounds, in general, were found to react with the beta-lactamases in two modes, corresponding to different orientations with respect to the active site, whereby either of the two aroyl ...[more]

PMID: 19678666

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Project description:Beta-lactamases represent the main bacterial mechanism of resistance to beta-lactam antibiotics and are a significant challenge to modern medicine. We have developed an automated classification and analysis protocol that exploits structure- and sequence-based approaches and which allows us to propose a grouping of serine beta-lactamases that more consistently captures and rationalizes the existing three classification schemes: Classes, (A, C and D, which vary in their implementation of the mechanism of action); Types (that largely reflect evolutionary distance measured by sequence similarity); and Variant groups (which largely correspond with the Bush-Jacoby clinical groups). Our analysis platform exploits a suite of in-house and public tools to identify Functional Determinants (FDs), i.e. residue sites, responsible for conferring different phenotypes between different classes, different types and different variants. We focused on Class A beta-lactamases, the most highly populated and clinically relevant class, to identify FDs implicated in the distinct phenotypes associated with different Class A Types and Variants. We show that our FunFHMMer method can separate the known beta-lactamase classes and identify those positions likely to be responsible for the different implementations of the mechanism of action in these enzymes. Two novel algorithms, ASSP and SSPA, allow detection of FD sites likely to contribute to the broadening of the substrate profiles. Using our approaches, we recognise 151 Class A types in UniProt. Finally, we used our beta-lactamase FunFams and ASSP profiles to detect 4 novel Class A types in microbiome samples. Our platforms have been validated by literature studies, in silico analysis and some targeted experimental verification. Although developed for the serine beta-lactamases they could be used to classify and analyse any diverse protein superfamily where sub-families have diverged over both long and short evolutionary timescales.

Dataset Information

Intramolecular cooperativity in the reaction of diacyl phosphates with serine beta-lactamases.

Publications

Intramolecular cooperativity in the reaction of diacyl phosphates with serine beta-lactamases.

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