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Signal Transduction and Targeted Therapy Dec 2022Metabolic reprogramming is involved in the pathogenesis of not only cancers but also neurodegenerative diseases, cardiovascular diseases, and infectious diseases. With... (Review)
Review
Metabolic reprogramming is involved in the pathogenesis of not only cancers but also neurodegenerative diseases, cardiovascular diseases, and infectious diseases. With the progress of metabonomics and proteomics, metabolites have been found to affect protein acylations through providing acyl groups or changing the activities of acyltransferases or deacylases. Reciprocally, protein acylation is involved in key cellular processes relevant to physiology and diseases, such as protein stability, protein subcellular localization, enzyme activity, transcriptional activity, protein-protein interactions and protein-DNA interactions. Herein, we summarize the functional diversity and mechanisms of eight kinds of nonhistone protein acylations in the physiological processes and progression of several diseases. We also highlight the recent progress in the development of inhibitors for acyltransferase, deacylase, and acylation reader proteins for their potential applications in drug discovery.
Topics: Acyltransferases; Acylation; Proteins; Protein Processing, Post-Translational
PubMed: 36577755
DOI: 10.1038/s41392-022-01245-y -
Nature Reviews. Molecular Cell Biology Feb 2017Eight types of short-chain Lys acylations have recently been identified on histones: propionylation, butyrylation, 2-hydroxyisobutyrylation, succinylation, malonylation,... (Review)
Review
Eight types of short-chain Lys acylations have recently been identified on histones: propionylation, butyrylation, 2-hydroxyisobutyrylation, succinylation, malonylation, glutarylation, crotonylation and β-hydroxybutyrylation. Emerging evidence suggests that these histone modifications affect gene expression and are structurally and functionally different from the widely studied histone Lys acetylation. In this Review, we discuss the regulation of non-acetyl histone acylation by enzymatic and metabolic mechanisms, the acylation 'reader' proteins that mediate the effects of different acylations and their physiological functions, which include signal-dependent gene activation, spermatogenesis, tissue injury and metabolic stress. We propose a model to explain our present understanding of how differential histone acylation is regulated by the metabolism of the different acyl-CoA forms, which in turn modulates the regulation of gene expression.
Topics: Acetyl Coenzyme A; Acyl Coenzyme A; Acylation; Animals; Fatty Acids, Volatile; Gene Expression Regulation; Histones; Humans; Lysine; Male; Protein Domains; Protein Processing, Post-Translational; Spermatogenesis; Stress, Physiological
PubMed: 27924077
DOI: 10.1038/nrm.2016.140 -
Journal of Experimental & Clinical... Apr 2022Metabolites are intermediate products of cellular metabolism catalysed by various enzymes. Metabolic remodelling, as a biochemical fingerprint of cancer cells, causes... (Review)
Review
Metabolites are intermediate products of cellular metabolism catalysed by various enzymes. Metabolic remodelling, as a biochemical fingerprint of cancer cells, causes abnormal metabolite accumulation. These metabolites mainly generate energy or serve as signal transduction mediators via noncovalent interactions. After the development of highly sensitive mass spectrometry technology, various metabolites were shown to covalently modify proteins via forms of lysine acylation, including lysine acetylation, crotonylation, lactylation, succinylation, propionylation, butyrylation, malonylation, glutarylation, 2-hydroxyisobutyrylation and β-hydroxybutyrylation. These modifications can regulate gene expression and intracellular signalling pathways, highlighting the extensive roles of metabolites. Lysine acetylation is not discussed in detail in this review since it has been broadly investigated. We focus on the nine aforementioned novel lysine acylations beyond acetylation, which can be classified into two categories: histone acylations and nonhistone acylations. We summarize the characteristics and common functions of these acylation types and, most importantly, provide a glimpse into their fine-tuned control of tumorigenesis and potential value in tumour diagnosis, monitoring and therapy.
Topics: Acetylation; Acylation; Carcinogenesis; Histones; Humans; Lysine; Protein Processing, Post-Translational
PubMed: 35428309
DOI: 10.1186/s13046-022-02338-w -
Chemistry (Weinheim An Der Bergstrasse,... Sep 2022Acylated nucleoside analogues play an important role in medicinal chemistry and are extremely useful precursors to various other nucleoside analogues. However,...
Acylated nucleoside analogues play an important role in medicinal chemistry and are extremely useful precursors to various other nucleoside analogues. However, chemoselective acylation of nucleosides usually requires several protection and deprotection steps due to the competing nucleophilicity of hydroxy and amino groups. In contrast, direct protecting-group-free chemoselective acylation of nucleosides is a preferred strategy due to lower cost and fewer overall synthetic steps. Herein, a simple and efficient chemoselective acylation of nucleosides and nucleotides under mild reaction conditions, giving either O- or N-acylated products respectively with excellent chemoselectivity is reported.
Topics: Acylation; Chemistry, Pharmaceutical; Nucleosides; Nucleotides
PubMed: 35730928
DOI: 10.1002/chem.202201661 -
Molecular & Cellular Proteomics : MCP Mar 2022Protein post-translational modifications play key roles in multiple cellular processes by allowing rapid reprogramming of individual protein functions. Acylation, one of... (Review)
Review
Protein post-translational modifications play key roles in multiple cellular processes by allowing rapid reprogramming of individual protein functions. Acylation, one of the most important post-translational modifications, is involved in different physiological activities including cell differentiation and energy metabolism. In recent years, the progression in technologies, especially the antibodies against acylation and the highly sensitive and effective mass spectrometry-based proteomics, as well as optimized functional studies, greatly deepen our understanding of protein acylation. In this review, we give a general overview of the 12 main protein acylations (formylation, acetylation, propionylation, butyrylation, malonylation, succinylation, glutarylation, palmitoylation, myristoylation, benzoylation, crotonylation, and 2-hydroxyisobutyrylation), including their substrates (histones and nonhistone proteins), regulatory enzymes (writers, readers, and erasers), biological functions (transcriptional regulation, metabolic regulation, subcellular targeting, protein-membrane interactions, protein stability, and folding), and related diseases (cancer, diabetes, heart disease, neurodegenerative disease, and viral infection), to present a complete picture of protein acylations and highlight their functional significance in future research.
Topics: Acetylation; Acylation; Histones; Humans; Lysine; Neurodegenerative Diseases; Protein Processing, Post-Translational
PubMed: 34999219
DOI: 10.1016/j.mcpro.2022.100193 -
Molecular Cell Nov 2018Growing appreciation of the diversity of post-translational modifications (PTMs) in the mitochondria necessitates reevaluation of the roles these modifications play in... (Review)
Review
Growing appreciation of the diversity of post-translational modifications (PTMs) in the mitochondria necessitates reevaluation of the roles these modifications play in both health and disease. Compared to the cytosol and nucleus, the mitochondrial proteome is highly acylated, and remodeling of the mitochondrial "acylome" is a key adaptive mechanism that regulates fundamental aspects of mitochondrial biology. It is clear that we need to understand the underlying chemistry that regulates mitochondrial acylation, as well as how chemical properties of the acyl chain impact biological functions. Here, we dissect the sources of PTMs in the mitochondria, review major mitochondrial pathways that control levels of PTMs, and highlight how sirtuin enzymes respond to the bioenergetic state of the cell via NAD availability to regulate mitochondrial biology. By providing a framework connecting the chemistry of these modifications, their biochemical consequences, and the pathways that regulate the levels of acyl PTMs, we will gain a deeper understanding of the physiological significance of mitochondrial acylation and its role in mitochondrial adaptation.
Topics: Acylation; Humans; Lysine; Mitochondria; Mitochondrial Proteins; Protein Processing, Post-Translational; Sirtuins
PubMed: 30444998
DOI: 10.1016/j.molcel.2018.10.023 -
Cell Chemical Biology Jul 2022A critical step in repurposing the cellular translation machinery for the synthesis of polymeric products is the acylation of transfer RNA (tRNA) with unnatural... (Review)
Review
A critical step in repurposing the cellular translation machinery for the synthesis of polymeric products is the acylation of transfer RNA (tRNA) with unnatural monomers. Toward this goal, flexizymes, ribozymes capable of aminoacylation, have emerged as a uniquely adept tool for charging tRNA with ever increasingly diverse substrates. In this review, we present a library of monomer substrates that have been tested for tRNA acylation with the flexizyme system. From this mile-high view, we provide insights for understanding the chemical factors that influence flexizyme-mediated tRNA acylation. We conclude that flexizymes are primitive esterification catalysts that display a modest binding affinity to the monomer's aromatic recognition element. Together, these robust, yet flexible, flexizyme systems provide researchers with unprecedented access for preparing unnatural acyl-tRNA and the opportunity to repurpose the translation machinery for the synthesis of novel biologically derived structures beyond native proteins and peptides.
Topics: Acylation; Catalysis; Peptides; RNA, Catalytic; RNA, Transfer; Transfer RNA Aminoacylation
PubMed: 35413283
DOI: 10.1016/j.chembiol.2022.03.012 -
Progress in Lipid Research Jul 2016Long, short and medium chain fatty acids are covalently attached to hundreds of proteins. Each fatty acid confers distinct biochemical properties, enabling fatty... (Review)
Review
Long, short and medium chain fatty acids are covalently attached to hundreds of proteins. Each fatty acid confers distinct biochemical properties, enabling fatty acylation to regulate intracellular trafficking, subcellular localization, protein-protein and protein-lipid interactions. Myristate and palmitate represent the most common fatty acid modifying groups. New insights into how fatty acylation reactions are catalyzed, and how fatty acylation regulates protein structure and function continue to emerge. Myristate is typically linked to an N-terminal glycine, but recent studies reveal that lysines can also be myristoylated. Enzymes that remove N-terminal myristoyl-glycine or myristate from lysines have now been identified. DHHC proteins catalyze S-palmitoylation, but the mechanisms that regulate substrate recognition by individual DHHC family members remain to be determined. New studies continue to reveal thioesterases that remove palmitate from S-acylated proteins. Another area of rapid expansion is fatty acylation of the secreted proteins hedgehog, Wnt and Ghrelin, by Hhat, Porcupine and GOAT, respectively. Understanding how these membrane bound O-acyl transferases recognize their protein and fatty acyl CoA substrates is an active area of investigation, and is punctuated by the finding that these enzymes are potential drug targets in human diseases.
Topics: Acylation; Acyltransferases; Animals; Fatty Acids; Ghrelin; Hedgehog Proteins; Humans; Proteins; Wnt Proteins
PubMed: 27233110
DOI: 10.1016/j.plipres.2016.05.002 -
International Journal of Molecular... Jan 2019Lipid modification is an important post-translational modification. S-acylation is unique among lipid modifications, as it is reversible and has thus attracted much... (Review)
Review
Lipid modification is an important post-translational modification. S-acylation is unique among lipid modifications, as it is reversible and has thus attracted much attention. We summarize some proteins that have been shown experimentally to be S-acylated in plants. Two of these S-acylated proteins have been matched to the S-acyl transferase. More importantly, the first protein thioesterase with de-S-acylation activity has been identified in plants. This review shows that S-acylation is important for a variety of different functions in plants and that there are many unexplored aspects of S-acylation in plants.
Topics: Acylation; Lipid Metabolism; Models, Biological; Monomeric GTP-Binding Proteins; Plant Proteins; Protein Processing, Post-Translational; Transcription Factors
PubMed: 30699892
DOI: 10.3390/ijms20030560 -
Genomics, Proteomics & Bioinformatics Dec 2016
Topics: Acylation; Histones; Humans; Reading
PubMed: 28007607
DOI: 10.1016/j.gpb.2016.12.001