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Laboratory Investigation; a Journal of... Jan 2015Autophagy is a lysosome-mediated intracellular protein degradation process that involves about 38 autophagy-related genes as well as key signaling pathways that sense... (Review)
Review
Autophagy is a lysosome-mediated intracellular protein degradation process that involves about 38 autophagy-related genes as well as key signaling pathways that sense cellular metabolic and redox status, and has an important role in quality control of macromolecules and organelles. As with other major cellular pathways, autophagy proteins are subjected to regulatory post-translational modification. Phosphorylation is so far the most intensively studied post-translational modification in the autophagy process, followed by ubiquitination and acetylation. An interesting and new area is also now emerging, which appears to complement these more traditional mechanisms, and includes O-GlcNAcylation and redox regulation at thiol residues. Identification of the full spectrum of post-translational modifications of autophagy proteins, and determination of their impact on autophagy will be crucial for a better understanding of autophagy regulation, its deficits in diseases, and how to exploit this process for disease therapies.
Topics: Animals; Autophagy; Humans; Mitophagy; Phosphorylation; Protein Processing, Post-Translational; Proteins; Sulfhydryl Compounds; Ubiquitination
PubMed: 25365205
DOI: 10.1038/labinvest.2014.131 -
Current Opinion in Chemical Biology Dec 2021Protein S-fatty acylation or S-palmitoylation is a reversible and regulated lipid post-translational modification (PTM) in eukaryotes. Loss-of-function mutagenesis... (Review)
Review
Protein S-fatty acylation or S-palmitoylation is a reversible and regulated lipid post-translational modification (PTM) in eukaryotes. Loss-of-function mutagenesis studies have suggested important roles for protein S-fatty acylation in many fundamental biological pathways in development, neurobiology, and immunity that are also associated with human diseases. However, the hydrophobicity and reversibility of this PTM have made site-specific gain-of-function studies more challenging to investigate. In this review, we summarize recent chemical biology approaches and methods that have enabled site-specific gain-of-function studies of protein S-fatty acylation and the investigation of the mechanisms and significance of this PTM in eukaryotic biology.
Topics: Acylation; Humans; Lipoylation; Protein Processing, Post-Translational; Protein S
PubMed: 34333222
DOI: 10.1016/j.cbpa.2021.06.004 -
Critical Reviews in Biochemistry and... Apr 2017Protein translation is one of the most energetically demanding processes for a cell to undertake. Changes in the nutrient environment may result in conditions that... (Review)
Review
Protein translation is one of the most energetically demanding processes for a cell to undertake. Changes in the nutrient environment may result in conditions that cannot support the rates of translation required for cell proliferation. As such, a cell must monitor its metabolic state to determine which mRNAs to translate into protein. How the various RNA species that participate in translation might relay information about metabolic state to regulate this process is not well understood. In this review, we discuss emerging examples of the influence of metabolism on aspects of RNA biology. We discuss how metabolic state impacts the localization and fate of different RNA species, as well as how nutrient cues can impact post-transcriptional modifications of RNA to regulate their functions in the control of translation.
Topics: Animals; Gene Expression Regulation; Humans; Metabolic Networks and Pathways; Nutritional Physiological Phenomena; Protein Biosynthesis; Proteins; RNA; RNA Processing, Post-Transcriptional; RNA, Messenger
PubMed: 28152618
DOI: 10.1080/10409238.2017.1283294 -
Virus Research Apr 2015Helicases are versatile NTP-dependent motor proteins of monophyletic origin that are found in all kingdoms of life. Their functions range from nucleic acid duplex... (Review)
Review
Helicases are versatile NTP-dependent motor proteins of monophyletic origin that are found in all kingdoms of life. Their functions range from nucleic acid duplex unwinding to protein displacement and double-strand translocation. This explains their participation in virtually every metabolic process that involves nucleic acids, including DNA replication, recombination and repair, transcription, translation, as well as RNA processing. Helicases are encoded by all plant and animal viruses with a positive-sense RNA genome that is larger than 7 kb, indicating a link to genome size evolution in this virus class. Viral helicases belong to three out of the six currently recognized superfamilies, SF1, SF2, and SF3. Despite being omnipresent, highly conserved and essential, only a few viral helicases, mostly from SF2, have been studied extensively. In general, their specific roles in the viral replication cycle remain poorly understood at present. The SF1 helicase protein of viruses classified in the order Nidovirales is encoded in replicase open reading frame 1b (ORF1b), which is translated to give rise to a large polyprotein following a ribosomal frameshift from the upstream ORF1a. Proteolytic processing of the replicase polyprotein yields a dozen or so mature proteins, one of which includes a helicase. Its hallmark is the presence of an N-terminal multi-nuclear zinc-binding domain, the nidoviral genetic marker and one of the most conserved domains across members of the order. This review summarizes biochemical, structural, and genetic data, including drug development studies, obtained using helicases originating from several mammalian nidoviruses, along with the results of the genomics characterization of a much larger number of (putative) helicases of vertebrate and invertebrate nidoviruses. In the context of our knowledge of related helicases of cellular and viral origin, it discusses the implications of these results for the protein's emerging critical function(s) in nidovirus evolution, genome replication and expression, virion biogenesis, and possibly also post-transcriptional processing of viral RNAs. Using our accumulated knowledge and highlighting gaps in our data, concepts and approaches, it concludes with a perspective on future research aimed at elucidating the role of helicases in the nidovirus replication cycle.
Topics: Animals; Frameshifting, Ribosomal; Humans; Nidovirales; Protein Biosynthesis; Protein Conformation; Protein Processing, Post-Translational; RNA Helicases; Transcription, Genetic; Viral Proteins
PubMed: 25497126
DOI: 10.1016/j.virusres.2014.12.001 -
Current Genetics Jun 2019During cell division, the timing of mitosis and cytokinesis must be ordered to ensure that each daughter cell receives a complete, undamaged copy of the genome. In... (Review)
Review
During cell division, the timing of mitosis and cytokinesis must be ordered to ensure that each daughter cell receives a complete, undamaged copy of the genome. In fission yeast, the septation initiation network (SIN) is responsible for this coordination, and a mitotic checkpoint dependent on the E3 ubiquitin ligase Dma1 and the protein kinase CK1 controls SIN signaling to delay cytokinesis when there are errors in mitosis. The participation of kinases and ubiquitin ligases in cell cycle checkpoints that maintain genome integrity is conserved from yeast to human, making fission yeast an excellent model system in which to study checkpoint mechanisms. In this review, we highlight recent advances and remaining questions related to checkpoint regulation, which requires the synchronized modulation of protein ubiquitination, phosphorylation, and subcellular localization.
Topics: Cell Cycle Checkpoints; Cell Cycle Proteins; Cytokinesis; Mitosis; Phosphorylation; Schizosaccharomyces; Schizosaccharomyces pombe Proteins; Spatio-Temporal Analysis; Ubiquitination
PubMed: 30600396
DOI: 10.1007/s00294-018-0921-x -
Microbiology Spectrum Mar 2018Survival of bacteria in ever-changing habitats with fluctuating nutrient supplies requires rapid adaptation of their metabolic capabilities. To this end, carbohydrate... (Review)
Review
Survival of bacteria in ever-changing habitats with fluctuating nutrient supplies requires rapid adaptation of their metabolic capabilities. To this end, carbohydrate metabolism is governed by complex regulatory networks including posttranscriptional mechanisms that involve small regulatory RNAs (sRNAs) and RNA-binding proteins. sRNAs limit the response to substrate availability and set the threshold or time required for induction and repression of carbohydrate utilization systems. Carbon catabolite repression (CCR) also involves sRNAs. In , sRNA Spot 42 cooperates with the transcriptional regulator cyclic AMP (cAMP)-receptor protein (CRP) to repress secondary carbohydrate utilization genes when a preferred sugar is consumed. In pseudomonads, CCR operates entirely at the posttranscriptional level, involving RNA-binding protein Hfq and decoy sRNA CrcZ. Moreover, sRNAs coordinate fluxes through central carbohydrate metabolic pathways with carbohydrate availability. In Gram-negative bacteria, the interplay between RNA-binding protein CsrA and its cognate sRNAs regulates glycolysis and gluconeogenesis in response to signals derived from metabolism. Spot 42 and cAMP-CRP jointly downregulate tricarboxylic acid cycle activity when glycolytic carbon sources are ample. In addition, bacteria use sRNAs to reprogram carbohydrate metabolism in response to anaerobiosis and iron limitation. Finally, sRNAs also provide homeostasis of essential anabolic pathways, as exemplified by the hexosamine pathway providing cell envelope precursors. In this review, we discuss the manifold roles of bacterial sRNAs in regulation of carbon source uptake and utilization, substrate prioritization, and metabolism.
Topics: Bacteria; Carbohydrate Metabolism; Catabolite Repression; Citric Acid Cycle; Cyclic AMP Receptor Protein; Down-Regulation; Enterobacteriaceae; Gene Expression Regulation, Bacterial; Gluconeogenesis; Glycolysis; Hexosamines; Homeostasis; Host Factor 1 Protein; Metabolic Networks and Pathways; RNA, Bacterial; RNA, Small Untranslated; RNA-Binding Proteins; Repressor Proteins; Signal Transduction; Sugars; Trans-Activators
PubMed: 29573258
DOI: 10.1128/microbiolspec.RWR-0013-2017 -
Current Opinion in Cell Biology Apr 2020Recent years have seen a great expansion in our knowledge of the roles that metabolites play in cellular signaling. Structural data have provided crucial insights into... (Review)
Review
Recent years have seen a great expansion in our knowledge of the roles that metabolites play in cellular signaling. Structural data have provided crucial insights into mechanisms through which amino acids are sensed. New nutrient-coupled protein and RNA modifications have been identified and characterized. A growing list of functions has been ascribed to metabolic regulation of modifications such as acetylation, methylation, and glycosylation. A current challenge lies in developing an integrated understanding of the roles that metabolic signaling mechanisms play in physiology and disease, which will inform the design of strategies to target such mechanisms. In this brief article, we review recent advances in metabolic signaling through post-translational modification during cancer progression, to provide a framework for understanding signaling roles of metabolites in the context of cancer biology and illuminate areas for future investigation.
Topics: Acetylation; Animals; Disease Progression; Glycosylation; Humans; Metabolome; Methylation; Neoplasm Proteins; Neoplasms; Protein Processing, Post-Translational; Signal Transduction
PubMed: 32097832
DOI: 10.1016/j.ceb.2020.01.013 -
Nature Communications Apr 2018Methanol represents an attractive substrate for biotechnological applications. Utilization of reduced one-carbon compounds for growth is currently limited to...
Methanol represents an attractive substrate for biotechnological applications. Utilization of reduced one-carbon compounds for growth is currently limited to methylotrophic organisms, and engineering synthetic methylotrophy remains a major challenge. Here we apply an in silico-guided multiple knockout approach to engineer a methanol-essential Escherichia coli strain, which contains the ribulose monophosphate cycle for methanol assimilation. Methanol conversion to biomass was stoichiometrically coupled to the metabolization of gluconate and the designed strain was subjected to laboratory evolution experiments. Evolved strains incorporate up to 24% methanol into core metabolites under a co-consumption regime and utilize methanol at rates comparable to natural methylotrophs. Genome sequencing reveals mutations in genes coding for glutathione-dependent formaldehyde oxidation (frmA), NAD(H) homeostasis/biosynthesis (nadR), phosphopentomutase (deoB), and gluconate metabolism (gntR). This study demonstrates a successful metabolic re-routing linked to a heterologous pathway to achieve methanol-dependent growth and represents a crucial step in generating a fully synthetic methylotrophic organism.
Topics: Bacterial Proteins; Computer Simulation; Escherichia coli; Gene Knockout Techniques; Genome, Bacterial; Gluconates; Metabolic Engineering; Metabolic Networks and Pathways; Methanol
PubMed: 29666370
DOI: 10.1038/s41467-018-03937-y -
Archives of Toxicology May 2021The review presents metabolic properties of Ivermectin (IVM) as substrate and inhibitor of human P450 (P450, CYP) enzymes and drug transporters. IVM is metabolized, both... (Review)
Review
The review presents metabolic properties of Ivermectin (IVM) as substrate and inhibitor of human P450 (P450, CYP) enzymes and drug transporters. IVM is metabolized, both in vivo and in vitro, by C-hydroxylation and O-demethylation reactions catalyzed by P450 3A4 as the major enzyme, with a contribution of P450 3A5 and 2C9. In samples from both in vitro and in vivo metabolism, a number of metabolites were detected and as major identified metabolites were 3″-O-demethylated, C4-methyl hydroxylated, C25 isobutyl-/isopropyl-hydroxylated, and products of oxidation reactions. Ivermectin inhibited P450 2C9, 2C19, 2D6, and CYP3A4 with IC values ranging from 5.3 μM to no inhibition suggesting that it is no or weak inhibitor of the enzymes. It is suggested that P-gp (MDR1) transporter participate in IVM efflux at low drug concentration with a slow transport rate. At the higher, micromolar concentration range, which saturates MDR1 (P-gp), MRP1, and to a lesser extent, MRP2 and MRP3 participate in IVM transport across physiological barriers. IVM exerts a potent inhibition of P-gp (ABCB1), MRP1 (ABCC1), MRP2 (ABCC2), and BCRP1 (ABCG2), and medium to weak inhibition of OATP1B1 (SLC21A6) and OATP1B3 (SLCOB3) transport activity. The metabolic and transport properties of IVM indicate that when IVM is co-administered with other drugs/chemicals that are potent inhibitors/inducers P4503A4 enzyme and of MDR1 (P-gp), BCRP or MRP transporters, or when polymorphisms of the drug transporters and P450 3A4 exist, drug-drug or drug-toxic chemical interactions might result in suboptimal response to the therapy or to toxic effects.
Topics: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily G, Member 2; Biological Transport; Cells, Cultured; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Drug Interactions; Humans; Hydroxylation; Insecticides; Ivermectin; Membrane Transport Proteins; Microsomes, Liver; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins; Neoplasm Proteins; Pharmaceutical Preparations
PubMed: 33719007
DOI: 10.1007/s00204-021-03025-z -
Neuroscience Bulletin Oct 2018The brain has very high energy requirements and consumes 20% of the oxygen and 25% of the glucose in the human body. Therefore, the molecular mechanism underlying how... (Review)
Review
The brain has very high energy requirements and consumes 20% of the oxygen and 25% of the glucose in the human body. Therefore, the molecular mechanism underlying how the brain metabolizes substances to support neural activity is a fundamental issue for neuroscience studies. A well-known model in the brain, the astrocyte-neuron lactate shuttle, postulates that glucose uptake and glycolytic activity are enhanced in astrocytes upon neuronal activation and that astrocytes transport lactate into neurons to fulfill their energy requirements. Current evidence for this hypothesis has yet to reach a clear consensus, and new concepts beyond the shuttle hypothesis are emerging. The discrepancy is largely attributed to the lack of a critical method for real-time monitoring of metabolic dynamics at cellular resolution. Recent advances in fluorescent protein-based sensors allow the generation of a sensitive, specific, real-time readout of subcellular metabolites and fill the current technological gap. Here, we summarize the development of genetically encoded metabolite sensors and their applications in assessing cell metabolism in living cells and in vivo, and we believe that these tools will help to address the issue of elucidating neural energy metabolism.
Topics: Animals; Biosensing Techniques; Brain; Cytological Techniques; Energy Metabolism; Humans; Luminescent Proteins; Time Factors
PubMed: 29679217
DOI: 10.1007/s12264-018-0229-3