The Evolutionary Origins of Detoxifying Enzymes

Hagit, Bar-Rogovsky; Hugenmatter, Adrian; Tawfik, Dan S.

doi:10.1074/jbc.m112.427922

Cited by 117 publications

(51 citation statements)

References 80 publications

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“…Notably, the limited dynamic range of the pH indicator based assay used could limit the observation of lower K M values. The observed K M value for GcL is in contrast to values observed for other MLL lactonases, such as AiiA and AiiB ( K M ≈1600–5600 μ m ), and other classes of lactonases (e.g., PLLs and PONs; K M ≈50–500 μ m ). Yet, these low K M values are similar to those observed for AidC and AaL .…”

Section: Resultsmentioning

confidence: 99%

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The Structural Determinants Accounting for the Broad Substrate Specificity of the Quorum Quenching Lactonase GcL

et al. 2019

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Quorum quenching lactonases are enzymes capable of hydrolyzing lactones, including N‐acyl homoserine lactones (AHLs). AHLs are molecules known as signals in bacterial communication dubbed quorum sensing. Bacterial signal disruption by lactonases was previously reported to inhibit behavior regulated by quorum sensing, such as the expression of virulence factors and the formation of biofilms. Herein, we report the enzymatic and structural characterization of a novel lactonase representative from the metallo‐β‐lactamase superfamily, dubbed GcL. GcL is a broad spectrum and highly proficient lactonase, with kcat/KM values in the range of 104 to 106 m−1 s−1. Analysis of free GcL structures and in complex with AHL substrates of different acyl chain length, namely, C4‐AHL and 3‐oxo‐C12‐AHL, allowed their respective binding modes to be elucidated. Structures reveal three subsites in the binding crevice: 1) the small subsite where chemistry is performed on the lactone ring; 2) a hydrophobic ring that accommodates the amide group of AHLs and small acyl chains; and 3) the outer, hydrophilic subsite that extends to the protein surface. Unexpectedly, the absence of structural accommodation for long substrate acyl chains seems to relate to the broad substrate specificity of the enzyme.

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Section: Resultsmentioning

confidence: 99%

“…A second family of lactonases are the paraoxonases (PONs), primarily isolated from mammals, exhibit a six‐bladed β‐propeller fold . PONs were shown to hydrolyze δ‐lactones, γ‐lactones, and AHLs …”

Section: Introductionmentioning

confidence: 99%

The Structural Determinants Accounting for the Broad Substrate Specificity of the Quorum Quenching Lactonase GcL

et al. 2019

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“…It is further stated that PONs have evolved from lactonases only after the introduction of the parathion, an organophosphate pesticide [38][39][40]. The evolutionary significance of lactonases has been found to be established in mammals, where they subsequently acquired the detoxifying functions to act as a tool of innate immunity [41]. The present classes of mammalian PONs: (1) PON1 (2) PON2 (3) PON3 have been shown to have originated from bacterial lactonases via horizontal gene transfer from an endosymbiotic bacteria.…”

Section: Discussionmentioning

confidence: 99%

Multiplicity of Quorum Quenching Enzymes: A Potential Mechanism to Limit Quorum Sensing Bacterial Population

Koul

Kalia

2016

Indian J Microbiol

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Bacteria express certain of their characteristics especially, pathogenicity factors at high cell densities. The process is termed as quorum sensing (QS). QS operates via signal molecules such as acylhomoserine lactones (AHLs). Other bacteria inhibit QS through the inactivation of AHL signals by producing enzymes like AHL-lactonases and -acylases. Comparative genomic analysis has revealed the multiplicity of genes for AHL lactonases (up to 12 copies per genome) among spp. and that of AHL-acylases (up to 5 copies per genome) among spp. This genetic evolution can be envisaged to enable host to withstand the attacks from bacterial population, which regulates its functioning through QS.

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“…Nature has typically resolved the challenge of detoxifying a broad range of related compounds by evolving paralogs, namely several enzyme variants that have diverged from one common ancestral enzyme. Although each is specific for a certain substrate, paralogous enzymes tend to overlap in activity, thus jointly tackling a broad spectrum of toxic compounds [4][5][6]. Here, we have adopted this strategy for nerve agent detoxification, by combining three enzyme variants that were evolved from the same parental enzyme.…”

Section: Introductionmentioning

confidence: 99%

“…Wild-type Bd-PTE hydrolyzes G-agents, including the ones with branched O-alkyl groups, sarin (GB) and soman (GD), with kcat/KM values ranging from 0.5 to 5x10 6 M -1 min -1 [11]. However, its activity towards VX and Russian VX (RVX) is 10 to 100fold lower [12,13].…”

Section: Introductionmentioning

confidence: 99%

A mixture of three engineered phosphotriesterases enables rapid detoxification of the entire spectrum of known threat nerve agents

Despotović

Aharon

Dubovetskyi

et al. 2019

Preprint

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Nerve agents are organophosphates that potently inhibit acetylcholinesterase and their enzymatic detoxification has been a long-standing goal. Nerve agents vary widely in size, charge, hydrophobicity, and the cleavable ester bond. A single enzyme is therefore unlikely to efficiently hydrolyze all agents. Here, we describe a mixture of three previously developed variants of the bacterial phosphotriesterase (Bd-PTE) that are highly stable and nearly sequence identical. This mixture enables effective detoxification of a broad spectrum of known threat agents -GA (tabun), GB (sarin), GD (soman), GF (cyclosarin), VX, and Russian-VX. The potential for dimer dissociation and exchange that could inactivate Bd-PTE has minimal impact, and the three enzyme variants are as active in a mixture as they are individually. To our knowledge, this engineered enzyme 'cocktail' comprises the first solution for enzymatic detoxification of the entire range of threat nerve agents.

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The Evolutionary Origins of Detoxifying Enzymes

Cited by 117 publications

References 80 publications

The Structural Determinants Accounting for the Broad Substrate Specificity of the Quorum Quenching Lactonase GcL

The Structural Determinants Accounting for the Broad Substrate Specificity of the Quorum Quenching Lactonase GcL

Multiplicity of Quorum Quenching Enzymes: A Potential Mechanism to Limit Quorum Sensing Bacterial Population

A mixture of three engineered phosphotriesterases enables rapid detoxification of the entire spectrum of known threat nerve agents

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