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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 -
Molecular Aspects of Medicine Aug 2022Protein post-translational modifications (PTMs) profoundly influence protein functions and play crucial roles in essentially all cell biological processes. The diverse... (Review)
Review
Protein post-translational modifications (PTMs) profoundly influence protein functions and play crucial roles in essentially all cell biological processes. The diverse realm of PTMs and their crosstalk is linked to many critical signaling events involved in neoplastic transformation, carcinogenesis and metastasis. The pathological roles of various PTMs are implicated in all aspects of cancer hallmark functions, cancer metabolism and regulation of tumor microenvironment. Study of PTMs has become an important area in cancer research to understand cancer biology and discover novel biomarkers and therapeutic targets. With a limited scope, this review attempts to discuss some PTMs of high frequency with recognized importance in cancer biology, including phosphorylation, acetylation, glycosylation, palmitoylation and ubiquitination, as well as their implications in clinical applications. These protein modifications are among the most abundant PTMs and profoundly implicated in carcinogenesis.
Topics: Acetylation; Carcinogenesis; Humans; Neoplasms; Phosphorylation; Protein Processing, Post-Translational; Proteins; Tumor Microenvironment
PubMed: 35400524
DOI: 10.1016/j.mam.2022.101097 -
Cell Research May 2023Posttranslational modifications add tremendous complexity to proteomes; however, gaps remain in knowledge regarding the function and regulatory mechanism of newly...
Posttranslational modifications add tremendous complexity to proteomes; however, gaps remain in knowledge regarding the function and regulatory mechanism of newly discovered lysine acylation modifications. Here, we compared a panel of non-histone lysine acylation patterns in metastasis models and clinical samples, and focused on 2-hydroxyisobutyrylation (Khib) due to its significant upregulation in cancer metastases. By the integration of systemic Khib proteome profiling in 20 paired primary esophageal tumor and metastatic tumor tissues with CRISPR/Cas9 functional screening, we identified N-acetyltransferase 10 (NAT10) as a substrate for Khib modification. We further showed that Khib modification at lysine 823 in NAT10 functionally contribute to metastasis. Mechanistically, NAT10 Khib modification enhances its interaction with deubiquitinase USP39, resulting in increased NAT10 protein stability. NAT10 in turn promotes metastasis by increasing NOTCH3 mRNA stability in an N4-acetylcytidine-dependent manner. Furthermore, we discovered a lead compound #7586-3507 that inhibited NAT10 Khib modification and showed efficacy in tumor models in vivo at a low concentration. Together, our findings bridge newly identified lysine acylation modifications with RNA modifications, thus providing novel insights into epigenetic regulation in human cancer. We propose that pharmacological inhibition of NAT10 K823 Khib modification constitutes a potential anti-metastasis strategy.
Topics: Humans; Lysine; Epigenesis, Genetic; Acylation; Protein Processing, Post-Translational; Acetyltransferases; Neoplasms; N-Terminal Acetyltransferases; Ubiquitin-Specific Proteases
PubMed: 36882514
DOI: 10.1038/s41422-023-00793-4 -
Science Advances Jan 2022Lysine L-lactylation [K(L-la)] is a newly discovered histone mark stimulated under conditions of high glycolysis, such as the Warburg effect. K(L-la) is associated with...
Lysine L-lactylation [K(L-la)] is a newly discovered histone mark stimulated under conditions of high glycolysis, such as the Warburg effect. K(L-la) is associated with functions that are different from the widely studied histone acetylation. While K(L-la) can be introduced by the acetyltransferase p300, histone delactylases enzymes remained unknown. Here, we report the systematic evaluation of zinc- and nicotinamide adenine dinucleotide–dependent histone deacetylases (HDACs) for their ability to cleave ε--L-lactyllysine marks. Our screens identified HDAC1–3 and SIRT1–3 as delactylases in vitro. HDAC1–3 show robust activity toward not only K(L-la) but also K(D-la) and diverse short-chain acyl modifications. We further confirmed the de-L-lactylase activity of HDACs 1 and 3 in cells. Together, these data suggest that histone lactylation is installed and removed by regulatory enzymes as opposed to spontaneous chemical reactivity. Our results therefore represent an important step toward full characterization of this pathway’s regulatory elements.
Topics: Acetylation; Histone Deacetylases; Histones; Lysine
PubMed: 35044827
DOI: 10.1126/sciadv.abi6696 -
Molecular Cancer Jun 2023Divergent N-methyladenosine (mA) modifications are dynamic and reversible posttranscriptional RNA modifications that are mediated by mA regulators or mA RNA methylation... (Review)
Review
Divergent N-methyladenosine (mA) modifications are dynamic and reversible posttranscriptional RNA modifications that are mediated by mA regulators or mA RNA methylation regulators, i.e., methyltransferases ("writers"), demethylases ("erasers"), and mA-binding proteins ("readers"). Aberrant mA modifications are associated with cancer occurrence, development, progression, and prognosis. Numerous studies have established that aberrant mA regulators function as either tumor suppressors or oncogenes in multiple tumor types. However, the functions and mechanisms of mA regulators in cancer remain largely elusive and should be explored. Emerging studies suggest that mA regulators can be modulated by epigenetic modifications, namely, ubiquitination, SUMOylation, acetylation, methylation, phosphorylation, O-GlcNAcylation, ISGylation, and lactylation or via noncoding RNA action, in cancer. This review summarizes the current roles of mA regulators in cancer. The roles and mechanisms for epigenetic modification of mA regulators in cancer genesis are segregated. The review will improve the understanding of the epigenetic regulatory mechanisms of mA regulators.
Topics: Humans; Oncogenes; Neoplasms; Acetylation; Epigenesis, Genetic; RNA
PubMed: 37391814
DOI: 10.1186/s12943-023-01810-1 -
Molecular Aspects of Medicine Aug 2022Post-translational modifications (PTMs) have been proposed as a link between the oxidative stress-inflammation-ageing trinity, thereby affecting several hallmarks of... (Review)
Review
Post-translational modifications (PTMs) have been proposed as a link between the oxidative stress-inflammation-ageing trinity, thereby affecting several hallmarks of ageing. Phosphorylation, acetylation, and ubiquitination cover >90% of all the reported PTMs. Several of the main PTMs are involved in normal "healthy" ageing and in different age-related diseases, for instance neurodegenerative, metabolic, cardiovascular, and bone diseases, as well as cancer and chronic kidney disease. Ultimately, data from human rare progeroid syndromes, but also from long-living animal species, imply that PTMs are critical regulators of the ageing process. Mechanistically, PTMs target epigenetic and non-epigenetic pathways during ageing. In particular, epigenetic histone modification has critical implications for the ageing process and can modulate lifespan. Therefore, PTM-based therapeutics appear to be attractive pharmaceutical candidates to reduce the burden of ageing-related diseases. Several phosphorylation and acetylation inhibitors have already been FDA-approved for the treatment of other diseases and offer a unique potential to investigate both beneficial effects and possible side-effects. As an example, the most well-studied senolytic compounds dasatinib and quercetin, which have already been tested in Phase 1 pilot studies, also act as kinase inhibitors, targeting cellular senescence and increasing lifespan. Future studies need to carefully determine the best PTM-based candidates for the treatment of the "diseasome of ageing".
Topics: Acetylation; Aging; Animals; Histones; Humans; Oxidative Stress; Phosphorylation; Protein Processing, Post-Translational
PubMed: 35689974
DOI: 10.1016/j.mam.2022.101099 -
Nature Jul 2022Wnt signalling is essential for regulation of embryonic development and adult tissue homeostasis, and aberrant Wnt signalling is frequently associated with cancers. Wnt...
Wnt signalling is essential for regulation of embryonic development and adult tissue homeostasis, and aberrant Wnt signalling is frequently associated with cancers. Wnt signalling requires palmitoleoylation on a hairpin 2 motif by the endoplasmic reticulum-resident membrane-bound O-acyltransferase Porcupine (PORCN). This modification is indispensable for Wnt binding to its receptor Frizzled, which triggers signalling. Here we report four cryo-electron microscopy structures of human PORCN: the complex with the palmitoleoyl-coenzyme A (palmitoleoyl-CoA) substrate; the complex with the PORCN inhibitor LGK974, an anti-cancer drug currently in clinical trials; the complex with LGK974 and WNT3A hairpin 2 (WNT3Ap); and the complex with a synthetic palmitoleoylated WNT3Ap analogue. The structures reveal that hairpin 2 of WNT3A, which is well conserved in all Wnt ligands, inserts into PORCN from the lumenal side, and the palmitoleoyl-CoA accesses the enzyme from the cytosolic side. The catalytic histidine triggers the transfer of the unsaturated palmitoleoyl group to the target serine on the Wnt hairpin 2, facilitated by the proximity of the two substrates. The inhibitor-bound structure shows that LGK974 occupies the palmitoleoyl-CoA binding site to prevent the reaction. Thus, this work provides a mechanism for Wnt acylation and advances the development of PORCN inhibitors for cancer treatment.
Topics: Acylation; Acyltransferases; Antineoplastic Agents; Binding Sites; Coenzyme A; Cryoelectron Microscopy; Histidine; Humans; Membrane Proteins; Neoplasms; Palmitoyl Coenzyme A; Pyrazines; Pyridines; Serine; Substrate Specificity; Wnt Signaling Pathway; Wnt3A Protein
PubMed: 35831507
DOI: 10.1038/s41586-022-04952-2 -
Cellular and Molecular Life Sciences :... May 2021Crop productivity is directly dependent on the growth and development of plants and their adaptation during different environmental stresses. Histone acetylation is an... (Review)
Review
Crop productivity is directly dependent on the growth and development of plants and their adaptation during different environmental stresses. Histone acetylation is an epigenetic modification that regulates numerous genes essential for various biological processes, including development and stress responses. Here, we have mainly discussed the impact of histone acetylation dynamics on vegetative growth, flower development, fruit ripening, biotic and abiotic stress responses. Besides, we have also emphasized the information gaps which are obligatory to be examined for understanding the complete role of histone acetylation dynamics in plants. A comprehensive knowledge about the histone acetylation dynamics will ultimately help to improve stress resistance and reduce yield losses in different crops due to climate changes.
Topics: Acetylation; Histones; Humans; Plant Development; Plants; Stress, Physiological
PubMed: 33638653
DOI: 10.1007/s00018-021-03794-x -
Nature Communications Dec 2022Pluripotent stem cells hold great promise in regenerative medicine and developmental biology studies. Mitochondrial metabolites, including tricarboxylic acid (TCA) cycle...
Pluripotent stem cells hold great promise in regenerative medicine and developmental biology studies. Mitochondrial metabolites, including tricarboxylic acid (TCA) cycle intermediates, have been reported to play critical roles in pluripotency. Here we show that TCA cycle enzymes including Pdha1, Pcb, Aco2, Cs, Idh3a, Ogdh, Sdha and Mdh2 are translocated to the nucleus during somatic cell reprogramming, primed-to-naive transition and totipotency acquisition. The nuclear-localized TCA cycle enzymes Pdha1, Pcb, Aco2, Cs, Idh3a promote somatic cell reprogramming and primed-to-naive transition. In addition, nuclear-localized TCA cycle enzymes, particularly nuclear-targeted Pdha1, facilitate the 2-cell program in pluripotent stem cells. Mechanistically, nuclear Pdha1 increases the acetyl-CoA and metabolite pool in the nucleus, leading to chromatin remodeling at pluripotency genes by enhancing histone H3 acetylation. Our results reveal an important role of mitochondrial TCA cycle enzymes in the epigenetic regulation of pluripotency that constitutes a mitochondria-to-nucleus retrograde signaling mode in different states of pluripotent acquisition.
Topics: Acetylation; Histones; Epigenesis, Genetic; Cell Nucleus; Mitochondria
PubMed: 36460681
DOI: 10.1038/s41467-022-35199-0 -
Molecules (Basel, Switzerland) Jun 2021Phytochemicals belonging to the group of alkaloids are signature specialized metabolites endowed with countless biological activities. Plants are armored with these... (Review)
Review
Phytochemicals belonging to the group of alkaloids are signature specialized metabolites endowed with countless biological activities. Plants are armored with these naturally produced nitrogenous compounds to combat numerous challenging environmental stress conditions. Traditional and modern healthcare systems have harnessed the potential of these organic compounds for the treatment of many ailments. Various chemical entities (functional groups) attached to the central moiety are responsible for their diverse range of biological properties. The development of the characterization of these plant metabolites and the enzymes involved in their biosynthesis is of an utmost priority to deliver enhanced advantages in terms of biological properties and productivity. Further, the incorporation of whole/partial metabolic pathways in the heterologous system and/or the overexpression of biosynthetic steps in homologous systems have both become alternative and lucrative methods over chemical synthesis in recent times. Moreover, in-depth research on alkaloid biosynthetic pathways has revealed numerous chemical modifications that occur during alkaloidal conversions. These chemical reactions involve glycosylation, acylation, reduction, oxidation, and methylation steps, and they are usually responsible for conferring the biological activities possessed by alkaloids. In this review, we aim to discuss the alkaloidal group of plant specialized metabolites and their brief classification covering major categories. We also emphasize the diversity in the basic structures of plant alkaloids arising through enzymatically catalyzed structural modifications in certain plant species, as well as their emerging diverse biological activities. The role of alkaloids in plant defense and their mechanisms of action are also briefly discussed. Moreover, the commercial utilization of plant alkaloids in the marketplace displaying various applications has been enumerated.
Topics: Acylation; Alkaloids; Biosynthetic Pathways; Glycosylation; Methylation; Molecular Structure; Oxidation-Reduction; Phytochemicals; Plant Physiological Phenomena; Plants
PubMed: 34204857
DOI: 10.3390/molecules26113374