Regulatory effects of protein S-acylation on insulin secretion and insulin action

Chamberlain, Luke H.; Shipston, Michael J.; Gould, Gwyn W.

doi:10.1098/rsob.210017

Cited by 11 publications

(10 citation statements)

References 139 publications

(305 reference statements)

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“…36,37 Apart from histones, many other cellular proteins have been shown to be subject to post-translational N-, [38][39][40] O-, 41,42 and S-acetylation. 43 In particular, misregulation of KATs leads to a variety of diseases such as cancer 44 or neurological disorders. 45 Identification of new protein substrates has been facilitated by the incorporation of bioorthogonal handles and labelling through the use of chemical biology tools.…”

Section: Non-native Acylation Of Histone H4 Peptidementioning

confidence: 99%

Thioester Mediated Biocatalytic Amide Bond Synthesis with In Situ Thiol Recycling

Schnepel

Rodríguez‐Pérez

et al. 2022

Preprint

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The conversion of carboxylic acids to thioesters is a key step in the biosynthesis of natural products, resulting in activation of the acyl groups for subsequent reactions, e.g. acylation of nucleophiles including carbon-carbon bond formation. For example, thioesters of Coenzyme A (CoA-SH; e.g. acetyl-S-CoA) are intermediates in many metabolic pathways, and are increasingly recognised as important cofactors for epigenetic post-translational modifications, such as N-, O- and S-acylations of proteins. However, the limited availability of a broad range of structurally diverse thioesters has limited their wider exploitation in biochemistry, cell biology and biotechnology. Furthermore, the high cost of CoA-SH impairs its use in stoichiometric quantities. To address these challenges we show that the adenylation (A-) domain of the carboxylic acid reductase (CAR) from Segniliparus rugosus (CARsr-A) can function as a broad spectrum acyl-S-CoA synthetase, to generate acyl-S-CoA intermediates from a wide range of carboxylic acids. In addition, CARsr-A was able to generate thioesters from structurally simpler thiols such as pantetheine. The resulting thioesters were then used as substrates for acyltransferases to synthesise a wide range of amides, including the more difficult to prepare, but pharmaceutically relevant aryl amides. Importantly, CoA-SH is recycled during the reaction and can be used in sub-stoichiometric quantities. This approach has also been applied to acylate a histone peptide H4-20 with a range of carboxylic acids, including non-natural chemical labels, by employing a lysine acetyltransferase (HATp300). Overall, this combination of a broad spectrum biocatalyst for thioester synthesis, together with in-situ CoA-SH recycling, provides a generic platform for thioester-dependent cell-free synthesis, with potential applications beyond amide bond formation.

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Section: Non-native Acylation Of Histone H4 Peptidementioning

confidence: 99%

Thioester Mediated Biocatalytic Amide Bond Synthesis with In Situ Thiol Recycling

Schnepel

Rodríguez‐Pérez

et al. 2022

Preprint

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“…The article also highlights several potential venues for therapeutic targeting of protein palmitoylation in autoimmune diseases such as Crohn's and inflammatory bowel disease. Chamberlain et al [17] focus on the roles that S-palmitoylation plays for proteins involved in insulin secretion and signalling. K+ and Ca++ channels are multi-subunit transmembrane proteins that regulate fusion of insulin-containing secretory granules with the plasma membrane.…”

Section: Regulation Of Signalling Pathways By Palmitoylated Proteinsmentioning

confidence: 99%

“…Chamberlain et al [17] focus on the roles that S-palmitoylation plays for proteins involved in insulin secretion and signalling. K+ and Ca++ channels are multi-subunit transmembrane proteins that regulate fusion of insulin-containing secretory granules with the plasma membrane.…”

Section: Scope and Overview Of The Special Issuementioning

confidence: 99%

Open Biology: overview for special issue on dynamics of protein fatty acylation

Resh

2021

Open Biol.

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Fatty acylation is a widespread form of protein modification that occurs on specific intracellular and secreted proteins. Beyond increasing hydrophobicity and the affinity of the modified protein for lipid bilayers, covalent attachment of a fatty acid exerts effects on protein localization, inter- and intramolecular interactions and signal transduction. As such, research into protein fatty acylation has been embraced by an extensive community of biologists. This special issue highlights advances at the forefront of the field, by focusing on two families of enzymes that catalyse post-translational protein fatty acylation, zDHHC palmitoyl acyltransferases and membrane-bound O-acyl transferases, and signalling pathways regulated by their fatty acylated protein substrates. The collected contributions catalogue the tremendous progress that has been made in enzyme and substrate identification. In addition, articles in this special issue provide insights into the pivotal functions of fatty acylated proteins in immune cell, insulin and EGF receptor-mediated signalling pathways. As selective inhibitors of protein fatty acyltransferases are generated, the future holds great promise for therapeutic targeting of fatty acyltransferases that play key roles in human disease.

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“…For example, phosphorylation is required for signaling cascades mediating insulin secretion (Campbell and Newgard, 2021). SUMOylation and palmitoylation have been reported to regulate insulin secretion at multiple stages (Davey et al, 2019;Chamberlain et al, 2021). Acetylation, ubiquitination and O-GlcNAcylation are involved in insulin gene transcription (Mounier and Posner, 2006;Ozcan et al, 2010;Sampley and Ozcan, 2012).…”

Section: Introductionmentioning

confidence: 99%

Regulation of insulin secretion by the post-translational modifications

Yang

Wei

Zhao

et al. 2023

Front. Cell Dev. Biol.

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Post-translational modification (PTM) has a significant impact on cellular signaling and function regulation. In pancreatic β cells, PTMs are involved in insulin secretion, cell development, and viability. The dysregulation of PTM in β cells is clinically associated with the development of diabetes mellitus. Here, we summarized current findings on major PTMs occurring in β cells and their roles in insulin secretion. Our work provides comprehensive insight into understanding the mechanisms of insulin secretion and potential therapeutic targets for diabetes from the perspective of protein PTMs.

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Regulatory effects of protein S-acylation on insulin secretion and insulin action

Cited by 11 publications

References 139 publications

Thioester Mediated Biocatalytic Amide Bond Synthesis with In Situ Thiol Recycling

Thioester Mediated Biocatalytic Amide Bond Synthesis with In Situ Thiol Recycling

Open Biology: overview for special issue on dynamics of protein fatty acylation

Regulation of insulin secretion by the post-translational modifications

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