Chemical Biology Tools for Protein Lysine Acylation

Abstract

Lysine acylation plays pivotal roles in cell physiology, including DNA transcription and repair, signal transduction, immune defense, metabolism, and many other key cellular processes. Molecular mechanisms of dysregulated lysine acylation are closely involved in the pathophysiological progress of many human diseases, most notably cancers. In recent years, chemical biology tools have become instrumental in studying the function of post‐translational modifications (PTMs), identifying new “writers”, “erasers” and “readers”, and in targeted therapies. Here, we describe key developments in chemical biology approaches that have advanced the study of lysine acylation and its regulatory proteins (2016–2021). We further discuss the discovery of ligands (inhibitors and PROTACs) that are capable of targeting regulators of lysine acylation. Next, we discuss some current challenges of these chemical biology probes and suggest how chemists and biologists can utilize chemical probes with more discriminating capacity. Finally, we suggest some critical considerations in future studies of PTMs from our perspective.

Multiplex Identification of Post‐Translational Modifications at Point‐of‐Care by Deep Learning‐Assisted Hydrogel Sensors

“…[1,2] PTMs multiply the functional diversity of the proteome through enzymemediated covalent addition, cleavage or degradation of proteins, to orchestrate a variety of cellular functions including cell growth, differentiation and apoptosis. [3][4][5][6][7] Aberrant PTMs are markers of cellular stress or malfunction, and are implicated in numerous human diseases, especially in cancer. [5][6][7] For example, the core-fucosylation of alpha-fetoprotein (AFP-L3) has been widely used as a diagnostic and prognostic marker for liver cancer patients.…”

“…It is well‐known that the human proteome is far more complex than its genome, primarily caused by post‐translational modifications (PTMs) of proteins [1, 2] . PTMs multiply the functional diversity of the proteome through enzyme‐mediated covalent addition, cleavage or degradation of proteins, to orchestrate a variety of cellular functions including cell growth, differentiation and apoptosis [3–7] . Aberrant PTMs are markers of cellular stress or malfunction, and are implicated in numerous human diseases, especially in cancer [5–7] .…”

Therapeutic Potential and Activity Modulation of the Protein Lysine Deacylase Sirtuin 5

“…Recently, known enzymes that catalyze a diverse subset of reactions have been revealed to also exhibit lysine acyltransferase activity. 44 , 45 These include carnitine palmitoyl transferase 1A (CPT1A) and HATs p300/CBP and general control nondepressible 5 (GCN5), which were shown to demonstrate succinyltransferase activity. 46 − 48 GCN5 also exhibits lysine glutaryltransferase activity.…”

“…SIRT5 has been shown to selectively cleave negatively charged acyl lysine modifications, such as glutarate, succinate, and malonate, both in vitro and in vivo , although it also has weak deacetylase activity (Figure ), with a catalytic efficiency roughly 1000-fold lower than those of the deacylation reactions. , While lysine acetylation is catalyzed by many enzymes belonging to the HAT family, the identification of acyltransferases that catalyze the transfer of nonacetyl groups has remained elusive for many years. Recently, known enzymes that catalyze a diverse subset of reactions have been revealed to also exhibit lysine acyltransferase activity. , These include carnitine palmitoyl transferase 1A (CPT1A) and HATs p300/CBP and general control nondepressible 5 (GCN5), which were shown to demonstrate succinyltransferase activity. − GCN5 also exhibits lysine glutaryltransferase activity . In the case of long-chain fatty acids, the N -terminal glycine myristoyltransferases (NMTs) 1 and 2 were recently shown to also catalyze lysine myristoylation .…”

Histidine-specific bioconjugationviavisible-light-promoted thioacetal activation

“…Post-translational modications (PTMs) of proteins enable a marked increase in protein functional diversity 1 for manipulation of protein structure and function. 2 Various chemical tools have been developed to assess modied sites of proteins, exploring a large quantity of important information about protein interactions and/or enzymatic mechanisms in drug development, molecular biology and medicine. [3][4][5][6] However, most labeling strategies are limited to the functionalization of nucleophilic residues, namely cysteine, lysine and tyrosine.…”