Covalent protein modification: the current landscape of residue-specific electrophiles

Shannon, David A.; Weerapana, Eranthie

doi:10.1016/j.cbpa.2014.10.021

Cited by 198 publications

(183 citation statements)

References 69 publications

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“…We hypothesised that 1 may act as a covalent inhibitor towards LgtC, due to the presence of the Michael acceptor system, which is a known cysteine-reactive electrophile in covalent inhibitors and probes [24]. As no reports on pyrazol-3-ones as covalent enzyme inhibitors have previously been published, we set out to experimentally test this hypothesis.…”

Section: Biochemical Evaluation Of Inhibitorsmentioning

confidence: 99%

Covalent inhibitors of LgtC: A blueprint for the discovery of non-substrate-like inhibitors for bacterial glycosyltransferases

Smith

Vivoli

et al. 2017

Bioorganic & Medicinal Chemistry

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. Covalent inhibitors of LgtC: a blueprint for the discovery of non-substrate-like inhibitors for bacterial glycosyltransferases. Bioorganic and Medicinal Chemistry, 25(12), 3182-3194. https://doi.org/10.1016/j.bmc.2017.04.006Citing this paper Please note that where the full-text provided on King's Research Portal is the Author Accepted Manuscript or Post-Print version this may differ from the final Published version. If citing, it is advised that you check and use the publisher's definitive version for pagination, volume/issue, and date of publication details. And where the final published version is provided on the Research Portal, if citing you are again advised to check the publisher's website for any subsequent corrections. General rightsCopyright and moral rights for the publications made accessible in the Research Portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognize and abide by the legal requirements associated with these rights.•Users may download and print one copy of any publication from the Research Portal for the purpose of private study or research.•You may not further distribute the material or use it for any profit-making activity or commercial gain •You may freely distribute the URL identifying the publication in the Research Portal Take down policyIf you believe that this document breaches copyright please contact librarypure@kcl.ac.uk providing details, and we will remove access to the work immediately and investigate your claim. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.-1 - data reveals that non-catalytic cysteines are a common motif in the active site of many bacterial glycosyltransferases. Our results can therefore serve as a blueprint for the rational design of non-substrate-like, covalent inhibitors against a broad range of other bacterial glycosyltransferases.-3 -

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Section: Biochemical Evaluation Of Inhibitorsmentioning

confidence: 99%

Covalent inhibitors of LgtC: A blueprint for the discovery of non-substrate-like inhibitors for bacterial glycosyltransferases

Smith

Vivoli

et al. 2017

Bioorganic & Medicinal Chemistry

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“…Introduced functionality is useful since it can allow attachment of probes for imaging, 1,2,7 provide mimics of desirable post-translational modifications, 1,2 or be used as a means to precisely adjust biological and physical properties of biomacromolecules. 3,4 Numerous strategies, including biological 8 and chemical synthesis, 1,2 have been developed to either react with or modify natural residues, or replace them entirely, using highly selective processes.…”

Section: Introductionmentioning

confidence: 99%

Functional Modification of Thioether Groups in Peptides, Polypeptides, and Proteins

Deming

2017

Bioconjugate Chem.

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Recent developments in the modification of methionine and other thioether containing residues in peptides, polypeptides and proteins are reviewed. Properties and potential applications of the resulting functionalized products are also discussed. While much of this work is focused on natural Met residues, modifications at other side-chain residues have also emerged as new thioether containing amino acids have been incorporated into peptidic materials. Functional modification of thioether containing amino acids has many advantages, and is complimentary methodology to the widely utilized methods for modification at cysteine residues.

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“…Among amino acid side-chains that may be adducted by reactive electrophiles, cysteines are particularly sensitive to modification due to their inherent nucleophilicity (Pace and Weerapana, 2013; Shannon and Weerapana, 2015; Weerapana et al, 2010). This nucleophilicity can be enhanced by local protein microenvironments which lower the inherent pKa of certain cysteines (Poole, 2015).…”

Section: Resultsmentioning

confidence: 99%

“…These environmental electrophiles have the potential to covalently react with nucleophilic amino acid hotspots within the proteome, leading to protein dysfunction and subsequent pathological effects (Rappaport et al, 2012). These “hyper-reactive” nucleophilic hotspots include cysteine, serine, and lysine residues that are often involved in important biological functions such as catalysis, regulation, post-translational modifications, redox balance, metal binding, and protein-protein interactions (Shannon and Weerapana, 2015). Though we are exposed to a large array of potentially reactive chemicals, we have little to no understanding regarding their interactions with hyper-reactive proteome hotspots and the resulting effects on protein function, downstream biochemistry, or ensuing pathophysiological consequences.…”

Section: Introductionmentioning

confidence: 99%

Mapping Proteome-Wide Targets of Environmental Chemicals Using Reactivity-Based Chemoproteomic Platforms

Medina-Cleghorn

Bateman

Ford

et al. 2015

Chemistry & Biology

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We are exposed to a growing number of chemicals in our environment, most of which have not been characterized in terms of their toxicological potential or mechanisms. Here, we employ a chemoproteomic platform to map the cysteine reactivity of environmental chemicals using reactivity-based probes to mine for hyper-reactive hotspots across the proteome. We show that environmental contaminants such as monomethylarsonous acid and widely used pesticides such as chlorothalonil and chloropicrin possess common reactivity with a distinct set of proteins. Many of these proteins are involved in key metabolic processes, suggesting that these targets may be particularly sensitive to environmental electrophiles. We show that the widely used fungicide chlorothalonil specifically inhibits several metabolic enzymes involved in fatty acid metabolism and energetics, leading to dysregulated lipid metabolism in mice. Our results underscore the utility of using reactivity-based chemoproteomic platforms to uncover novel mechanistic insights into the toxicity of environmental chemicals.

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Covalent protein modification: the current landscape of residue-specific electrophiles

Cited by 198 publications

References 69 publications

Covalent inhibitors of LgtC: A blueprint for the discovery of non-substrate-like inhibitors for bacterial glycosyltransferases

Covalent inhibitors of LgtC: A blueprint for the discovery of non-substrate-like inhibitors for bacterial glycosyltransferases

Functional Modification of Thioether Groups in Peptides, Polypeptides, and Proteins

Mapping Proteome-Wide Targets of Environmental Chemicals Using Reactivity-Based Chemoproteomic Platforms

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