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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 -
Nature Communications Dec 2022N-degron pathway plays an important role in the protein quality control and maintenance of cellular protein homeostasis. ZER1 and ZYG11B, the substrate receptors of the...
N-degron pathway plays an important role in the protein quality control and maintenance of cellular protein homeostasis. ZER1 and ZYG11B, the substrate receptors of the Cullin 2-RING E3 ubiquitin ligase (CRL2), recognize N-terminal (Nt) glycine degrons and participate in the Nt-myristoylation quality control through the Gly/N-degron pathway. Here we show that ZER1 and ZYG11B can also recognize small Nt-residues other than glycine. Specifically, ZER1 binds better to Nt-Ser, -Ala, -Thr and -Cys than to -Gly, while ZYG11B prefers Nt-Gly but also has the capacity to recognize Nt-Ser, -Ala and -Cys in vitro. We found that Nt-Ser, -Ala and -Cys undergo Nt-acetylation catalyzed by Nt-acetyltransferase (NAT), thereby shielding them from recognition by ZER1/ZYG11B in cells. Instead, ZER1/ZYG11B readily targets a selection of small Nt-residues lacking Nt-acetylation for degradation in NAT-deficient cells, implicating its role in the Nt-acetylation quality control. Furthermore, we present the crystal structures of ZER1 and ZYG11B bound to various small Nt-residues and uncover the molecular mechanism of non-acetylated substrate recognition by ZER1 and ZYG11B.
Topics: Ubiquitin-Protein Ligases; Protein Processing, Post-Translational; Acetylation; Myristic Acid; Glycine
PubMed: 36496439
DOI: 10.1038/s41467-022-35169-6 -
Nature Communications Sep 2023Pathogenic aggregation of the protein tau is a hallmark of Alzheimer's disease and several other tauopathies. Tauopathies are characterized by the deposition of specific...
Pathogenic aggregation of the protein tau is a hallmark of Alzheimer's disease and several other tauopathies. Tauopathies are characterized by the deposition of specific tau isoforms as disease-related tau filament structures. The molecular processes that determine isoform-specific deposition of tau are however enigmatic. Here we show that acetylation of tau discriminates its isoform-specific aggregation. We reveal that acetylation strongly attenuates aggregation of four-repeat tau protein, but promotes amyloid formation of three-repeat tau. We further identify acetylation of lysine 298 as a hot spot for isoform-specific tau aggregation. Solid-state NMR spectroscopy demonstrates that amyloid fibrils formed by unmodified and acetylated three-repeat tau differ in structure indicating that site-specific acetylation modulates tau structure. The results implicate acetylation as a critical regulator that guides the selective aggregation of three-repeat tau and the development of tau isoform-specific neurodegenerative diseases.
Topics: Humans; 14-3-3 Proteins; Acetylation; Alzheimer Disease; tau Proteins; Tauopathies
PubMed: 37739953
DOI: 10.1038/s41467-023-41672-1 -
Annual Review of Microbiology Sep 2019Acetylation is a posttranslational modification conserved in all domains of life that is carried out by -acetyltransferases. While acetylation can occur on -amino... (Review)
Review
Acetylation is a posttranslational modification conserved in all domains of life that is carried out by -acetyltransferases. While acetylation can occur on -amino groups, this review will focus on -acetylation of lysyl residues and how the posttranslational modification changes the cellular physiology of bacteria. Up until the late 1990s, acetylation was studied in eukaryotes in the context of chromatin maintenance and gene expression. At present, bacterial protein acetylation plays a prominent role in central and secondary metabolism, virulence, transcription, and translation. Given the diversity of niches in the microbial world, it is not surprising that the targets of bacterial protein acetyltransferases are very diverse, making their biochemical characterization challenging. The paradigm for acetylation in bacteria involves the acetylation of acetyl-CoA synthetase, whose activity must be tightly regulated to maintain energy charge homeostasis. While this paradigm has provided much mechanistic detail for acetylation and deacetylation, in this review we discuss advances in the field that are changing our understanding of the physiological role of protein acetylation in bacteria.
Topics: Acetylation; Acetyltransferases; Bacteria; Lysine; Protein Processing, Post-Translational
PubMed: 31091420
DOI: 10.1146/annurev-micro-020518-115526 -
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 -
Biomedicine & Pharmacotherapy =... Sep 2023Histone lysine crotonylation was first identified as a new type of post-translational modification in 2011. In recent years, prominent progress has been made in the... (Review)
Review
Histone lysine crotonylation was first identified as a new type of post-translational modification in 2011. In recent years, prominent progress has been made in the study of histone and nonhistone crotonylation in reproduction, development, and disease. Although the regulatory enzyme systems and targets of crotonylation partially overlap with those of acetylation, the peculiar CC bond structure of crotonylation suggests that crotonylation may have specific biological functions. In this review, we summarize the latest research progress regarding crotonylation, especially its regulatory factors and relationship with diseases, which suggest further research directions for crotonylation and provide new ideas for developing disease intervention and treatment regimens.
Topics: Histones; Lysine; Acetylation; Protein Processing, Post-Translational
PubMed: 37392654
DOI: 10.1016/j.biopha.2023.115108 -
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 -
Yakugaku Zasshi : Journal of the... 2020In total and formal syntheses of dictyodendrins A, B, C, D, E and F, the key step involved the direct construction of the pyrrolo[2,3-c]carbazole core by the... (Review)
Review
In total and formal syntheses of dictyodendrins A, B, C, D, E and F, the key step involved the direct construction of the pyrrolo[2,3-c]carbazole core by the gold-catalyzed annulation of a conjugated diyne with a pyrrole to form three bonds and two aromatic rings. The subsequent introduction of substituents at the C1 (Suzuki-Miyaura coupling), C2 (acylation), N3 (alkylation) and C5 positions (Ullmann coupling) provided divergent access to dictyodendrins. Some dictyodendrin analogues exhibited inhibitory activities toward CDK2/CycA2 and GSK3.
Topics: Acylation; Alkylation; Carbazoles; Catalysis; Cyclin-Dependent Kinase 2; Diynes; Organic Chemistry Phenomena; Pyrroles
PubMed: 33132266
DOI: 10.1248/yakushi.20-00162 -
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