Issue 6, 2021

Insights into auto-S-fatty acylation: targets, druggability, and inhibitors

Abstract

Posttranslational S-fatty acylation (or S-palmitoylation) modulates protein localization and functions, and has been implicated in neurological, metabolic, and infectious diseases, and cancers. Auto-S-fatty acylation involves reactive cysteine residues in the proteins which directly react with fatty acyl-CoA through thioester transfer reactions, and is the first step in some palmitoyl acyltransferase (PAT)-mediated catalysis reactions. In addition, many structural proteins, transcription factors and adaptor proteins might possess such “enzyme-like” activities and undergo auto-S-fatty acylation upon fatty acyl-CoA binding. Auto-S-fatty acylated proteins represent a new class of potential drug targets, which often harbor lipid-binding hydrophobic pockets and reactive cysteine residues, providing potential binding sites for covalent and non-covalent modulators. Therefore, targeting auto-S-fatty acylation could be a promising avenue to pharmacologically intervene in important cellular signaling pathways. Here, we summarize the recent progress in understanding the regulation and functions of auto-S-fatty acylation in cell signaling and diseases. We highlight the druggability of auto-S-fatty acylated proteins, including PATs and other proteins, with potential in silico and rationalized drug design approaches. We also highlight structural analysis and examples of currently known small molecules targeting auto-S-fatty acylation, to gain insights into targeting this class of proteins, and to expand the “druggable” proteome.

Graphical abstract: Insights into auto-S-fatty acylation: targets, druggability, and inhibitors

Transparent peer review

To support increased transparency, we offer authors the option to publish the peer review history alongside their article.

View this article’s peer review history

Article information

Article type
Review Article
Submitted
19 Mai 2021
Accepted
22 Aug 2021
First published
25 Aug 2021
This article is Open Access
Creative Commons BY-NC license

RSC Chem. Biol., 2021,2, 1567-1579

Insights into auto-S-fatty acylation: targets, druggability, and inhibitors

L. Hu, Z. Tao and X. Wu, RSC Chem. Biol., 2021, 2, 1567 DOI: 10.1039/D1CB00115A

This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. You can use material from this article in other publications, without requesting further permission from the RSC, provided that the correct acknowledgement is given and it is not used for commercial purposes.

To request permission to reproduce material from this article in a commercial publication, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party commercial publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements