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Cell Death & Disease Jul 2021Lysine crotonylation has been discovered in histone and non-histone proteins and found to be involved in diverse diseases and biological processes, such as... (Review)
Review
Lysine crotonylation has been discovered in histone and non-histone proteins and found to be involved in diverse diseases and biological processes, such as neuropsychiatric disease, carcinogenesis, spermatogenesis, tissue injury, and inflammation. The unique carbon-carbon π-bond structure indicates that lysine crotonylation may use distinct regulatory mechanisms from the widely studied other types of lysine acylation. In this review, we discussed the regulation of lysine crotonylation by enzymatic and non-enzymatic mechanisms, the recognition of substrate proteins, the physiological functions of lysine crotonylation and its cross-talk with other types of modification. The tools and methods for prediction and detection of lysine crotonylation were also described.
Topics: Acylation; Animals; Humans; Lysine; Lysine Acetyltransferases; Protein Conformation; Protein Processing, Post-Translational; Proteins; Structure-Activity Relationship; Substrate Specificity
PubMed: 34262024
DOI: 10.1038/s41419-021-03987-z -
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 -
Molecules (Basel, Switzerland) Feb 2021Head group-acylated chloroplast lipids were discovered in the 1960s, but interest was renewed about 15 years ago with the discovery of Arabidopsides E and G, acylated... (Review)
Review
Head group-acylated chloroplast lipids were discovered in the 1960s, but interest was renewed about 15 years ago with the discovery of Arabidopsides E and G, acylated monogalactosyldiacylglycerols with oxidized fatty acyl chains originally identified in . Since then, plant biologists have applied the power of mass spectrometry to identify additional oxidized and non-oxidized chloroplast lipids and quantify their levels in response to biotic and abiotic stresses. The enzyme responsible for the head-group acylation of chloroplast lipids was identified as a cytosolic protein closely associated with the chloroplast outer membrane and christened acylated galactolipid-associated phospholipase 1 (AGAP1). Despite many advances, critical questions remain about the biological functions of AGAP1 and its head group-acylated products.
Topics: Acylation; Arabidopsis; Arabidopsis Proteins; Chloroplasts; Galactolipids; Membrane Lipids; Plant Leaves; Stress, Physiological
PubMed: 33652855
DOI: 10.3390/molecules26051273 -
Biochemical Society Transactions Apr 2020S-acylation is a common yet poorly understood fatty acid-based post-translational modification of proteins in all eukaryotes, including plants. While exact roles for... (Review)
Review
S-acylation is a common yet poorly understood fatty acid-based post-translational modification of proteins in all eukaryotes, including plants. While exact roles for S-acylation in protein function are largely unknown the reversibility of S-acylation indicates that it is likely able to play a regulatory role. As more studies reveal the roles of S-acylation within the cell it is becoming apparent that how S-acylation affects proteins is conceptually different from other reversible modifications such as phosphorylation or ubiquitination; a new mind-set is therefore required to fully integrate these data into our knowledge of plant biology. This review aims to highlight recent advances made in the function and enzymology of S-acylation in plants, highlights current and emerging technologies for its study and suggests future avenues for investigation.
Topics: Acylation; Arabidopsis; Cell Membrane; Fatty Acids; Lipoylation; Plant Physiological Phenomena; Plant Proteins; Plant Roots; Plants; Protein Conformation; Protein Processing, Post-Translational; Pyrus; Zea mays
PubMed: 32239188
DOI: 10.1042/BST20190703 -
The Journal of Cell Biology Nov 2023With a limited number of genes, cells achieve remarkable diversity. This is to a large extent achieved by chemical posttranslational modifications of proteins. Amongst...
With a limited number of genes, cells achieve remarkable diversity. This is to a large extent achieved by chemical posttranslational modifications of proteins. Amongst these are the lipid modifications that have the unique ability to confer hydrophobicity. The last decade has revealed that lipid modifications of proteins are extremely frequent and affect a great variety of cellular pathways and physiological processes. This is particularly true for S-acylation, the only reversible lipid modification. The enzymes involved in S-acylation and deacylation are only starting to be understood, and the list of proteins that undergo this modification is ever-increasing. We will describe the state of knowledge on the enzymes that regulate S-acylation, from their structure to their regulation, how S-acylation influences target proteins, and finally will offer a perspective on how alterations in the balance between S-acylation and deacylation may contribute to disease.
Topics: Acylation; Lipid Metabolism; Protein Processing, Post-Translational; Lipids
PubMed: 37756661
DOI: 10.1083/jcb.202307103 -
Clinical Science (London, England :... Mar 2020Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality worldwide. Metabolic dysfunction is a fundamental core mechanism underlying CVDs.... (Review)
Review
Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality worldwide. Metabolic dysfunction is a fundamental core mechanism underlying CVDs. Previous studies generally focused on the roles of long-chain fatty acids (LCFAs) in CVDs. However, a growing body of study has implied that short-chain fatty acids (SCFAs: namely propionate, malonate, butyrate, 2-hydroxyisobutyrate (2-HIBA), β-hydroxybutyrate, crotonate, succinate, and glutarate) and their cognate acylations (propionylation, malonylation, butyrylation, 2-hydroxyisobutyrylation, β-hydroxybutyrylation, crotonylation, succinylation, and glutarylation) participate in CVDs. Here, we attempt to provide an overview landscape of the metabolic pattern of SCFAs in CVDs. Especially, we would focus on the SCFAs and newly identified acylations and their roles in CVDs, including atherosclerosis, hypertension, and heart failure.
Topics: Acetylation; Animals; Cardiovascular Diseases; Fatty Acids, Volatile; Humans
PubMed: 32219347
DOI: 10.1042/CS20200128 -
The FEBS Journal Dec 2021Protein palmitoylation (S-acylation) has emerged as an important player in a range of cellular processes, and as a result, the palmitoyl-acyltransferase (PAT) enzymes... (Review)
Review
Protein palmitoylation (S-acylation) has emerged as an important player in a range of cellular processes, and as a result, the palmitoyl-acyltransferase (PAT) enzymes which mediate this modification have entered into the spotlight. Palmitoyltransferase ZDHHC5 (ZDHHC5) is among the more unique members of the PAT family as it is mainly localised to the plasma membrane and contains an extended cytoplasmic domain with several regulatory features. ZDHHC5 plays a vital role in a wide range of processes in different cell types. In this review, we offer a summary of the functions of ZDHHC5 in synaptic plasticity, cardiac function, cell adhesion and fatty acid uptake, among other processes. We also explore recent work has revealed several mechanisms to control the activity, localisation and function of ZDHHC5.
Topics: Acylation; Acyltransferases; Animals; Brain; Cell Membrane; Humans; Membrane Proteins; Neuronal Plasticity; Palmitic Acid; Protein Processing, Post-Translational
PubMed: 33415776
DOI: 10.1111/febs.15709 -
The Biochemical Journal Aug 2023Post-translational modifications (PTMs) provide a rapid response to stimuli, finely tuning metabolism and gene expression and maintain homeostasis. Advances in mass... (Review)
Review
Post-translational modifications (PTMs) provide a rapid response to stimuli, finely tuning metabolism and gene expression and maintain homeostasis. Advances in mass spectrometry over the past two decades have significantly expanded the list of known PTMs in biology and as instrumentation continues to improve, this list will surely grow. While many PTMs have been studied in detail (e.g. phosphorylation, acetylation), the vast majority lack defined mechanisms for their regulation and impact on cell fate. In this review, we will highlight the field of PTM research as it currently stands, discussing the mechanisms that dictate site specificity, analytical methods for their detection and study, and the chemical tools that can be leveraged to define PTM regulation. In addition, we will highlight the approaches needed to discover and validate novel PTMs. Lastly, this review will provide a starting point for those interested in PTM biology, providing a comprehensive list of PTMs and what is known regarding their regulation and metabolic origins.
Topics: Humans; Protein Processing, Post-Translational; Phosphorylation; Acetylation; Cell Differentiation; Homeostasis
PubMed: 37610048
DOI: 10.1042/BCJ20220251 -
The Journal of Biological Chemistry Oct 2020The human zDHHC -acyltransferase family comprises 23 enzymes that mediate the -acylation of a multitude of cellular proteins, including channels, receptors,... (Review)
Review
The human zDHHC -acyltransferase family comprises 23 enzymes that mediate the -acylation of a multitude of cellular proteins, including channels, receptors, transporters, signaling molecules, scaffolds, and chaperones. This reversible post-transitional modification (PTM) involves the attachment of a fatty acyl chain, usually derived from palmitoyl-CoA, to specific cysteine residues on target proteins, which affects their stability, localization, and function. These outcomes are essential to control many processes, including synaptic transmission and plasticity, cell growth and differentiation, and infectivity of viruses and other pathogens. Given the physiological importance of -acylation, it is unsurprising that perturbations in this process, including mutations in genes, have been linked to different neurological pathologies and cancers, and there is growing interest in zDHHC enzymes as novel drug targets. Although zDHHC enzymes control a diverse array of cellular processes and are associated with major disorders, our understanding of these enzymes is surprisingly incomplete, particularly with regard to the regulatory mechanisms controlling these enzymes. However, there is growing evidence highlighting the role of different PTMs in this process. In this review, we discuss how PTMs, including phosphorylation, -acylation, and ubiquitination, affect the stability, localization, and function of zDHHC enzymes and speculate on possible effects of PTMs that have emerged from larger screening studies. Developing a better understanding of the regulatory effects of PTMs on zDHHC enzymes will provide new insight into the intracellular dynamics of -acylation and may also highlight novel approaches to modulate -acylation for clinical gain.
Topics: Acylation; Acyltransferases; Animals; Humans; Lipoylation; Methylation; Phosphorylation; Protein Processing, Post-Translational; Substrate Specificity; Ubiquitination
PubMed: 32817054
DOI: 10.1074/jbc.REV120.014717 -
Nucleic Acids Research Aug 2021Recent studies demonstrate that histones are subjected to a series of short-chain fatty acid modifications that is known as histone acylations. However, the enzymes...
Recent studies demonstrate that histones are subjected to a series of short-chain fatty acid modifications that is known as histone acylations. However, the enzymes responsible for histone acylations in vivo are not well characterized. Here, we report that HBO1 is a versatile histone acyltransferase that catalyzes not only histone acetylation but also propionylation, butyrylation and crotonylation both in vivo and in vitro and does so in a JADE or BRPF family scaffold protein-dependent manner. We show that the minimal HBO1/BRPF2 complex can accommodate acetyl-CoA, propionyl-CoA, butyryl-CoA and crotonyl-CoA. Comparison of CBP and HBO1 reveals that they catalyze histone acylations at overlapping as well as distinct sites, with HBO1 being the key enzyme for H3K14 acylations. Genome-wide chromatin immunoprecipitation assay demonstrates that HBO1 is highly enriched at and contributes to bulk histone acylations on the transcriptional start sites of active transcribed genes. HBO1 promoter intensity highly correlates with the level of promoter histone acylation, but has no significant correlation with level of transcription. We also show that HBO1 is associated with a subset of DNA replication origins. Collectively our study establishes HBO1 as a versatile histone acyltransferase that links histone acylations to promoter acylations and selection of DNA replication origins.
Topics: Acetyl Coenzyme A; Acyl Coenzyme A; Acylation; Chromatin; DNA Replication; Histone Acetyltransferases; Histones; Homeodomain Proteins; Humans; Promoter Regions, Genetic; Protein Processing, Post-Translational; Replication Origin; Tumor Suppressor Proteins
PubMed: 34259319
DOI: 10.1093/nar/gkab607