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Nature Structural & Molecular Biology Jun 2022Cohesin is a DNA translocase that is instrumental in the folding of the genome into chromatin loops, with functional consequences on DNA-related processes. Chromatin...
Cohesin is a DNA translocase that is instrumental in the folding of the genome into chromatin loops, with functional consequences on DNA-related processes. Chromatin loop length and organization likely depend on cohesin processivity, translocation rate and stability on DNA. Here, we investigate and provide a comprehensive overview of the roles of various cohesin regulators in tuning chromatin loop expansion in budding yeast Saccharomyces cerevisiae. We demonstrate that Scc2, which stimulates cohesin ATPase activity, is also essential for cohesin translocation, driving loop expansion in vivo. Smc3 acetylation during the S phase counteracts this activity through the stabilization of Pds5, which finely tunes the size and stability of loops in G2.
Topics: Acetylation; Cell Cycle Proteins; Chromatin; Chromosomal Proteins, Non-Histone; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Cohesins
PubMed: 35710835
DOI: 10.1038/s41594-022-00780-0 -
Nature Chemical Biology Jan 2022The vast array of cell types of multicellular organisms must individually fine-tune their internal metabolism. One important metabolic and stress regulatory mechanism is... (Review)
Review
The vast array of cell types of multicellular organisms must individually fine-tune their internal metabolism. One important metabolic and stress regulatory mechanism is the dynamic attachment/removal of glucose-derived sugar N-acetylglucosamine on proteins (O-GlcNAcylation). The number of proteins modified by O-GlcNAc is bewildering, with at least 7,000 sites in human cells. The outstanding challenge is determining how key O-GlcNAc sites regulate a target pathway amidst thousands of potential global sites. Innovative solutions are required to address this challenge in cell models and disease therapy. This Perspective shares critical suggestions for the O-GlcNAc field gleaned from the international O-GlcNAc community. Further, we summarize critical tools and tactics to enable newcomers to O-GlcNAc biology to drive innovation at the interface of metabolism and disease. The growing pace of O-GlcNAc research makes this a timely juncture to involve a wide array of scientists and new toolmakers to selectively approach the regulatory roles of O-GlcNAc in disease.
Topics: Acetylglucosamine; Disease; Glycosylation; Humans; Protein Processing, Post-Translational; Proteins
PubMed: 34934185
DOI: 10.1038/s41589-021-00903-6 -
Ageing Research Reviews Mar 2024Diseases of the central nervous system (CNS), including stroke, brain tumors, and neurodegenerative diseases, have a serious impact on human health worldwide, especially... (Review)
Review
Diseases of the central nervous system (CNS), including stroke, brain tumors, and neurodegenerative diseases, have a serious impact on human health worldwide, especially in elderly patients. The brain, which is one of the body's most metabolically dynamic organs, lacks fuel stores and therefore requires a continuous supply of energy substrates. Metabolic abnormalities are closely associated with the pathogenesis of CNS disorders. Post-translational modifications (PTMs) are essential regulatory mechanisms that affect the functions of almost all proteins. Succinylation, a broad-spectrum dynamic PTM, primarily occurs in mitochondria and plays a crucial regulatory role in various diseases. In addition to directly affecting various metabolic cycle pathways, succinylation serves as an efficient and rapid biological regulatory mechanism that establishes a connection between metabolism and proteins, thereby influencing cellular functions in CNS diseases. This review offers a comprehensive analysis of succinylation and its implications in the pathological mechanisms of CNS diseases. The objective is to outline novel strategies and targets for the prevention and treatment of CNS conditions.
Topics: Humans; Aged; Lysine; Proteins; Protein Processing, Post-Translational; Central Nervous System Diseases; Metabolic Networks and Pathways
PubMed: 38387517
DOI: 10.1016/j.arr.2024.102242 -
Comparative Biochemistry and... 2021Zooplankton organisms face a variable food supply in their habitat. Metabolic adjustments during periods of starvation were analysed from changes in metabolite level to...
Zooplankton organisms face a variable food supply in their habitat. Metabolic adjustments during periods of starvation were analysed from changes in metabolite level to gene expression in the microcrustacean Daphnia pulex during starvation. The animals exploited their carbohydrate stores first, but their lipid and protein reserves were also degraded, albeit more slowly. Glycogenolysis and probably gluconeogenesis led to hyperglycaemia after 16 h of starvation. The concentration of α-ketoglutarate and the rate of oxygen consumption also reached maxima during this period. Nuclear HIF-1α levels and α-ketoglutarate concentration showed inverse correlation. Effects of this 2-oxoacid on prolyl hydroxylase activity, HIF-1α stability and the role of this transcription factor in the changes of the expression level of several putatively HIF-1-mediated metabolic genes are discussed. Transcriptome profiling via RNA-Seq revealed a downregulation of genes for protein biosynthesis and an upregulation of genes for carbohydrate metabolism during starvation. Thus, the adjustments of energy metabolism in response to food deprivation were quantified from the level of metabolites, signal transduction and gene expression, and possible connections of the respective dynamics of observed changes were analysed.
Topics: Animals; Arthropod Proteins; Daphnia; Energy Metabolism; Gene Expression Regulation; Gluconeogenesis; Glycogenolysis; Starvation
PubMed: 33662567
DOI: 10.1016/j.cbpb.2021.110591 -
Biotechnology Advances Dec 2023The development of novel, sustainable, and robust food production technologies represents one of the major pillars to address the most significant challenges humanity is... (Review)
Review
The development of novel, sustainable, and robust food production technologies represents one of the major pillars to address the most significant challenges humanity is going to face on earth in the upcoming decades - climate change, population growth, and resource depletion. The implementation of microfoods, i.e., foods formulated with ingredients from microbial cultivation, into the food supply chain has a huge potential to contribute towards energy-efficient and nutritious food manufacturing and represents a means to sustainably feed a growing world population. This review recapitulates and assesses the current state in the establishment and usage of gas fermenting bacteria as an innovative feedstock for protein production. In particular, we focus on the most promising representatives of this taxon: the hydrogen-oxidizing bacteria (hydrogenotrophs) and the methane-oxidizing bacteria (methanotrophs). These unicellular microorganisms can aerobically metabolize gaseous hydrogen and methane, respectively, to provide the required energy for building up cell material. A protein yield over 70% in the dry matter cell mass can be reached with no need for arable land and organic substrates making it a promising alternative to plant- and animal-based protein sources. We illuminate the holistic approach to incorporate protein extracts obtained from the cultivation of gas fermenting bacteria into microfoods. Herein, the fundamental properties of the bacteria, cultivation methods, downstream processing, and potential food applications are discussed. Moreover, this review covers existing and future challenges as well as sustainability aspects associated with the production of microbial protein through gas fermentation.
Topics: Animals; Fermentation; Food; Bacteria; Hydrogen; Technology; Proteins
PubMed: 37647973
DOI: 10.1016/j.biotechadv.2023.108240 -
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 -
Biochimica Et Biophysica Acta. Proteins... Mar 2022Molecular dynamics simulation is the most popular computational technique for investigating the structural and dynamical behaviour of proteins, in search of the... (Review)
Review
Molecular dynamics simulation is the most popular computational technique for investigating the structural and dynamical behaviour of proteins, in search of the molecular basis of their function. Far from being a completely settled field of research, simulations are still evolving to best capture the essential features of the atomic interactions that govern a protein's inner motions. Modern force fields are becoming increasingly accurate in providing a physical description adequate to this purpose, and allow us to model complex biological systems under fairly realistic conditions. Furthermore, the use of accelerated sampling techniques is improving our access to the observation of progressively larger molecular structures, longer time scales, and more hidden functional events. In this review, the basic principles of molecular dynamics simulations and a number of key applications in the area of protein science are summarized, and some of the most important results are discussed. Examples include the study of the structure, dynamics and binding properties of 'difficult' targets, such as intrinsically disordered proteins and membrane receptors, and the investigation of challenging phenomena like hydration-driven processes and protein aggregation. The findings described provide an overall picture of the current state of this research field, and indicate new perspectives on the road ahead to the upcoming future of molecular simulations.
Topics: Biological Phenomena; Humans; Intrinsically Disordered Proteins; Membrane Proteins; Models, Molecular; Molecular Dynamics Simulation; Molecular Structure; Protein Aggregates; Protein Binding; Protein Conformation
PubMed: 35051666
DOI: 10.1016/j.bbapap.2022.140757 -
Journal of Cellular Biochemistry Apr 2022Acetylation of proteins seems a widespread process found in the three domains of life. Several studies have shown that besides histones, acetylation of lysine residues... (Review)
Review
Acetylation of proteins seems a widespread process found in the three domains of life. Several studies have shown that besides histones, acetylation of lysine residues also occurs in non-nuclear proteins. Hence, it has been suggested that this covalent modification is a mechanism that might regulate diverse metabolic pathways by modulating enzyme activity, stability, and/or subcellular localization or interaction with other proteins. However, protein acetylation levels seem to have low correlation with modification of enzyme activity and pathway fluxes. In addition, the results obtained with mutant enzymes that presumably mimic acetylation have frequently been over-interpreted. Moreover, there is a generalized lack of rigorous enzyme kinetic analysis in parallel to acetylation level determinations. The purpose of this review is to analyze the current findings on the impact of acetylation on metabolic enzymes and its repercussion on metabolic pathways function/regulation.
Topics: Acetylation; Histones; Kinetics; Metabolic Networks and Pathways; Protein Processing, Post-Translational
PubMed: 34931340
DOI: 10.1002/jcb.30197 -
Environmental Microbiology Feb 2021Methyl-coenzyme M reductase (MCR) has been originally identified to catalyse the final step of the methanogenesis pathway. About 20 years ago anaerobic... (Review)
Review
Methyl-coenzyme M reductase (MCR) has been originally identified to catalyse the final step of the methanogenesis pathway. About 20 years ago anaerobic methane-oxidizing archaea (ANME) were discovered that use MCR enzymes to activate methane. ANME thrive at the thermodynamic limit of life, are slow-growing, and in most cases form syntrophic consortia with sulfate-reducing bacteria. Recently, archaea that have the ability to anaerobically oxidize non-methane multi-carbon alkanes such as ethane and n-butane were described in both enrichment cultures and environmental samples. These anaerobic multi-carbon alkane-oxidizing archaea (ANKA) use enzymes homologous to MCR named alkyl-coenzyme M reductase (ACR). Here we review the recent progresses on the diversity, distribution and functioning of both ANME and ANKA by presenting a detailed MCR/ACR-based phylogeny, compare their metabolic pathways and discuss the gaps in our knowledge of physiology of these organisms. To improve our understanding of alkane oxidation in archaea, we identified three directions for future research: (i) expanding cultivation attempts to validate omics-based metabolic models of yet-uncultured organisms, (ii) performing biochemical and structural analyses of key enzymes to understand thermodynamic and steric constraints and (iii) investigating the evolution of anaerobic alkane metabolisms and their impact on biogeochemical cycles.
Topics: Alkanes; Anaerobiosis; Archaea; Archaeal Proteins; Oxidation-Reduction; Oxidoreductases; Phylogeny
PubMed: 32367670
DOI: 10.1111/1462-2920.15057 -
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