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Protein S-fatty acylation or S-palmitoylation is a reversible and regulated lipid post-translational modification (PTM) in eukaryotes. Loss-of-function mutagenesis studies have suggested important roles for protein S-fatty acylation in many fundamental biological pathways in development, neurobiology, and immunity that are also associated with human diseases. However, the hydrophobicity and reversibility of this PTM have made site-specific gain-of-function studies more challenging to investigate. In this review, we summarize recent chemical biology approaches and methods that have enabled site-specific gain-of-function studies of protein S-fatty acylation and the investigation of the mechanisms and significance of this PTM in eukaryotic biology., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Understanding the molecular mechanisms of endogenous and environmental metabolites is crucial for basic biology and drug discovery. With the genome, proteome, and metabolome of many organisms being readily available, researchers now have the opportunity to dissect how key metabolites regulate complex cellular pathways in vivo. Nonetheless, characterizing the specific and functional protein targets of key metabolites associated with specific cellular phenotypes remains a major challenge. Innovations in chemical biology are now poised to address this fundamental limitation in physiology and disease. In this review, we highlight recent advances in chemoproteomics for targeted and proteome-wide analysis of metabolite-protein interactions that have enabled the discovery of unpredicted metabolite-protein interactions and facilitated the development of new small molecule therapeutics., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Protein fatty-acylation in eukaryotes has been associated with many fundamental biological processes. However, the diversity, abundance and regulatory mechanisms of protein fatty-acylation in vivo remain to be explored. Herein, we review the proteomic analysis of fatty-acylated proteins, with a focus on N-myristoylation and S-palmitoylation. We then highlight major challenges and emerging methods for direct site identification, quantitation, and lipid structure characterization to understand the functions and regulatory mechanisms of fatty-acylated proteins in physiology and disease., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Bacterial pathogens secrete protein toxins and effectors that hijack metabolites to covalently modify host proteins and interfere with their function during infection. Adenosine metabolites, such as nicotinamide adenine dinucleotide (NAD) and adenosine triphosphate (ATP), have in particular been coopted by these secreted virulence factors to reprogram host pathways. While some host targets for secreted virulence factors have been identified, other toxin and effector substrates have been elusive, which require new methods for their characterization. In this review, we focus on chemical reporters based on NAD and ATP that should facilitate the discovery and characterization of adenosine diphosphate (ADP)-ribosylation and adenylylation/AMPylation in bacterial pathogenesis and cell biology.

Protein function is largely dependent on coordinated and dynamic interactions of the protein with biomolecules including other proteins, nucleic acids and lipids. Although powerful methods for global profiling of protein-protein and protein-nucleic acid interactions are available, proteome-wide mapping of protein-lipid interactions is still challenging and rarely performed. The emergence of bifunctional lipid probes with photoactivatable and clickable groups offers new chemical tools for globally profiling protein-lipid interactions under cellular contexts. In this review, we summarize recent advances in the development of bifunctional lipid probes for studying protein-lipid interactions. We also highlight how in vivo photocrosslinking reactions contribute to the characterization of lipid-binding proteins and lipidation-mediated protein-protein interactions., (Copyright © 2014. Published by Elsevier Ltd.)

The activation of innate and adaptive immune signaling pathways and effector functions often occur at cellular membranes and are regulated by complex mechanisms. Here we review the growing number of proteins which are known to be regulated by S-palmitoylation in immune cells emerging from recent advances in chemical proteomics. These chemical proteomic studies have highlighted the roles of this dynamic lipid modification in regulating the specificity and strength of immune responses in different lymphocyte populations., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Lipidation of proteins is an important mechanism to regulate protein trafficking and activity in cell and tissues. The targeting of proteins to membranes by lipidation plays key roles in many physiological processes and when not regulated properly can lead to cancer and neurological disorders. Dissecting the precise roles of protein lipidation in physiology and disease is a major challenge. Recent advances in chemical biology have now enabled the semisynthesis of lipidated proteins for fundamental biochemical and cellular studies. In addition, new chemical reporters of protein lipidation have improved the detection and enabled the proteomic analysis of lipidated proteins. The expanding efforts in chemical biology are therefore providing new tools to dissect the mechanisms and functions of protein lipidation as well as develop therapeutics targeted at protein lipidation pathways in disease.