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Trends in Biochemical Sciences

Jesse R Poganik, Marcus J C Long, Yimon Aye
Understanding the targets and signaling roles of reactive electrophilic species (RES) at a specific cellular space and time has long been hampered by the reliance of the field on the bulk administration of excess RES from outside of cells and/or animals. Uncontrolled bolus methods provide limited understanding of target engagement for these individual nonenzymatic RES-modification events. REX technologies [targetable reactive electrophiles and oxidants (T-REX) and its genome-wide variant (G-REX)] were developed as a gateway to address these limitations...
February 11, 2019: Trends in Biochemical Sciences
Allan Green, Ronald E Bishop
In extreme conditions ketosis can progress to ketoacidosis, a dangerous and potentially life-threatening condition. Ketoacidosis is most common in new or poorly treated type 1 diabetes. The acidosis is usually attributed to the 'acidic' nature of the ketone bodies (acetoacetate, 3-hydroxybutyrate, and acetone). However, acetoacetate and 3-hydroxybutyrate are produced not as acids but as their conjugate bases, and acetone is neither an acid nor a base. This raises the question of why severe ketosis is accompanied by acidosis...
February 7, 2019: Trends in Biochemical Sciences
Amelie Stein, Douglas M Fowler, Rasmus Hartmann-Petersen, Kresten Lindorff-Larsen
The rapid decrease in DNA sequencing cost is revolutionizing medicine and science. In medicine, genome sequencing has revealed millions of missense variants that change protein sequences, yet we only understand the molecular and phenotypic consequences of a small fraction. Within protein science, high-throughput deep mutational scanning experiments enable us to probe thousands of variants in a single, multiplexed experiment. We review efforts that bring together these topics via experimental and computational approaches to determine the consequences of missense variants in proteins...
January 31, 2019: Trends in Biochemical Sciences
Victoria H Cowling
The mRNA cap is a structure that protects mRNA from degradation and recruits processing and translation factors. A new mRNA capping enzyme has been identified, PCIF1/CAPAM, which methylates adenosine when it is the first transcribed nucleotide. This discovery is crucial for understanding the function of cap adenosine methylation.
January 21, 2019: Trends in Biochemical Sciences
Kui Wang, Jingwen Jiang, Yunlong Lei, Shengtao Zhou, Yuquan Wei, Canhua Huang
Metabolic alterations and elevated levels of reactive oxygen species (ROS) are two characteristics of cancer. The metabolic patterns of cancer cells are elaborately reprogrammed to fulfill the high biomass demands of rapid propagation. ROS, the byproducts of metabolic processes, are accumulated in cancer cells partially due to metabolic abnormalities or oncogenic mutations. To prevent oxidative damage, cancer cells can orchestrate metabolic adaptation to maintain reduction-oxidation (redox) balance by producing reducing equivalents...
January 21, 2019: Trends in Biochemical Sciences
Mohamed A Eldeeb, Richard P Fahlman, Mansoore Esmaili, Edward A Fon
Unlike prokaryotes, N-terminal formylation has been confined to a handful of mitochondrial proteins in eukaryotes. A recent study unveils a new role for eukaryotic cytoplasmic N-terminal formylation linking diverse cellular stresses to N-terminal-dependent protein degradation. These findings suggest broad cellular implications in higher eukaryotes for N-terminal methionine formylation.
January 17, 2019: Trends in Biochemical Sciences
Armen Trchounian, Karen Trchounian
During fermentation FO F1 hydrolyzes ATP, coupling proton transport to proton-motive force (pmf) generation. Despite that, pmf generated by ATP hydrolysis does not satisfy the energy budget of a fermenting cell. However, pmf can also be generated by extrusion of weak organic acids such as lactate and by hydrogen cycling catalyzed by hydrogenases (Hyds). Here we highlight recent advances in our understanding of how the transport of weak organic acids and enzymes contributes to pmf generation during fermentation...
January 14, 2019: Trends in Biochemical Sciences
Philippe Icard, Ludovic Fournel, Zherui Wu, Marco Alifano, Hubert Lincet
Cell cycle progression and division is regulated by checkpoint controls and sequential activation of cyclin-dependent kinases (CDKs). Understanding of how these events occur in synchrony with metabolic changes could have important therapeutic implications. For biosynthesis, cancer cells enhance glucose and glutamine consumption. Inactivation of pyruvate kinase M2 (PKM2) promotes transcription in G1 phase. Glutamine metabolism supports DNA replication in S phase and lipid synthesis in G2 phase. A boost in glycolysis and oxidative metabolism can temporarily furnish more ATP when necessary (G1/S transition, segregation of chromosomes)...
January 14, 2019: Trends in Biochemical Sciences
Graeme C Clark, Nicholas R Casewell, Christopher T Elliott, Alan L Harvey, Andrew G Jamieson, Peter N Strong, Andrew D Turner
Toxins are substances produced from biological sources (e.g., animal, plants, microorganisms) that have deleterious effects on a living organism. Despite the obvious health concerns of being exposed to toxins, they are having substantial positive impacts in a number of industrial sectors. Several toxin-derived products are approved for clinical, veterinary, or agrochemical uses. This review sets out the case for toxins as 'friends' that are providing the basis of novel medicines, insecticides, and even nucleic acid sequencing technologies...
January 13, 2019: Trends in Biochemical Sciences
Mostafa Kamal Masud, Muhammad Umer, Md Shahriar A Hossain, Yusuke Yamauchi, Nam-Trung Nguyen, Muhammad J A Shiddiky
With revolutionary advances in next-generation sequencing, the human transcriptome has been comprehensively interrogated. These discoveries have highlighted the emerging functional and regulatory roles of a large fraction of RNAs suggesting the potential they might hold as stable and minimally invasive disease biomarkers. Although a plethora of molecular-biology- and biosensor-based RNA-detection strategies have been developed, clinical application of most of these is yet to be realized. Multifunctional nanomaterials coupled with sensitive and robust electrochemical readouts may prove useful in these applications...
January 10, 2019: Trends in Biochemical Sciences
Mandy Ducy, Laura Sesma-Sanz, Laure Guitton-Sert, Anahita Lashgari, Yuandi Gao, Nadine Brahiti, Amélie Rodrigue, Guillaume Margaillan, Marie-Christine Caron, Jacques Côté, Jacques Simard, Jean-Yves Masson
Partner and Localizer of BRCA2 (PALB2) has emerged as an important and versatile player in genome integrity maintenance. Biallelic mutations in PALB2 cause Fanconi anemia (FA) subtype FA-N, whereas monoallelic mutations predispose to breast, and pancreatic familial cancers. Herein, we review recent developments in our understanding of the mechanisms of regulation of the tumor suppressor PALB2 and its functional domains. Regulation of PALB2 functions in DNA damage response and repair occurs on multiple levels, including homodimerization, phosphorylation, and ubiquitylation...
January 10, 2019: Trends in Biochemical Sciences
H C Stephen Chan, Yi Li, Thamani Dahoun, Horst Vogel, Shuguang Yuan
Many central biological events rely on protein-ligand interactions. The identification and characterization of protein-binding sites for ligands are crucial for the understanding of functions of both endogenous ligands and synthetic drug molecules. G protein-coupled receptors (GPCRs) typically detect extracellular signal molecules on the cell surface and transfer these chemical signals across the membrane, inducing downstream cellular responses via G proteins or β-arrestin. GPCRs mediate many central physiological processes, making them important targets for modern drug discovery...
January 3, 2019: Trends in Biochemical Sciences
Sylvia Varland, Joël Vandekerckhove, Adrian Drazic
Actin is one of the most abundant proteins in eukaryotic cells and the main component of the microfilament system. It plays essential roles in numerous cellular activities, including muscle contraction, maintenance of cell integrity, and motility, as well as transcriptional regulation. Besides interacting with various actin-binding proteins (ABPs), proper actin function is regulated by post-translational modifications (PTMs), such as acetylation, arginylation, oxidation, and others. Here, we explain how actin PTMs can contribute to filament formation and stability, and may have additional actin regulatory functions, which potentially contribute to disease development...
January 2, 2019: Trends in Biochemical Sciences
Gergő Gógl, Alexandr P Kornev, Attila Reményi, Susan S Taylor
Since publication of the crystal structure of protein kinase (PK)A three decades ago, a structural portrait of the conserved kinase core has been drawn. The next challenge is to elucidate structures of full-length kinases and to address the intrinsically disordered regions (IDRs) that typically flank the core as well as the small linear motifs (SLiMs) that are embedded within the IDRs. It is increasingly apparent that unstructured regions integrate the kinase catalytic chassis into multienzyme-based regulatory networks...
January 2, 2019: Trends in Biochemical Sciences
Sebastian Hiller
Several recent atomic-resolution studies have resolved how chaperones interact with their client proteins. In some cases, molecular chaperones recognize and bind their clients in conformational ensembles that are locally highly dynamic and interconvert, while in other cases clients bind in unique conformations. The presence of a locally dynamic client ensemble state has important consequences, both for the interpretation of experimental data and for the functionality of chaperones, as local dynamics facilitate rapid client release, folding on and from the chaperone surface, and client recognition without shape complementarity...
January 2, 2019: Trends in Biochemical Sciences
Somenath Roy Chowdhury, Hemanta K Majumder
All organisms, including unicellular pathogens, compulsorily possess DNA topoisomerases for successful nucleic acid metabolism. But particular subtypes of topoisomerases exist, in all prokaryotes and in some unicellular eukaryotes, that are absent in higher eukaryotes. Moreover, topoisomerases from pathogenic members of a niche possess some unique molecular architecture and functionalities completely distinct from their nonpathogenic colleagues. This review will highlight the unique attributes associated with the structures and functions of topoisomerases from the unicellular pathogens, with special reference to bacteria and protozoan parasites...
January 1, 2019: Trends in Biochemical Sciences
Matthew L Starr, Rutilio A Fratti
In eukaryotes, organelles and vesicles modulate their contents and identities through highly regulated membrane fusion events. Membrane trafficking and fusion are carried out through a series of stages that lead to the formation of SNARE complexes between cellular compartment membranes to trigger fusion. Although the protein catalysts of membrane fusion are well characterized, their response to their surrounding microenvironment, provided by the lipid composition of the membrane, remains to be fully understood...
December 23, 2018: Trends in Biochemical Sciences
Kedar Puvar, Zhao-Qing Luo, Chittaranjan Das
Members of the SidE effector family from Legionella pneumophila represent a new paradigm in the ubiquitin world. These enzymes catalyze ubiquitination of target proteins via a mechanism different from that of conventional E1-E2-E3 biochemistry and play important roles in L. pneumophila virulence. They combine mono-ADP-ribosylation and phosphodiesterase activities to attach ubiquitin onto substrates, in great contrast to the orthodox pathway. A series of recent structural and mechanistic studies have clarified the action of these enzymes...
December 21, 2018: Trends in Biochemical Sciences
Punam Dalai, Nita Sahai
Protocells, the first life-like entities, likely contained three molecular components: a membrane, an information-carrying molecule, and catalytic molecules. Minerals have a wide range of properties that might have contributed to the synthesis and self-assembly of these molecular components. Minerals could have mediated the formation and concentration of prebiotic organic monomers, catalyzed their polymerization into biomolecules, and catalyzed protometabolic pathways, leading to protocell self-assembly. This review considers the following major aspects of protocell membrane-mineral interactions: (i) the effect of dissolved cations on the stability of mixed fatty acid and phospholipid vesicles; (ii) the rate of lipid self-assembly to vesicles; and (iii) the role of photocatalytic minerals in harvesting light energy to drive electron transfer reactions across membranes in the development of protometabolism...
December 21, 2018: Trends in Biochemical Sciences
Lydia Atangcho, Tejas Navaratna, Greg M Thurber
Stabilized peptide therapeutics have the potential to hit currently undruggable targets, dramatically expanding the druggable genome. However, major obstacles to their development include poor intracellular delivery, rapid degradation, low target affinity, and membrane toxicity. With the emergence of multiple stabilization techniques and screening technologies, the high efficacy of various bioactive peptides has been demonstrated in vitro, albeit with limited success in vivo. We discuss here the chemical and pharmacokinetic barriers to achieving in vivo efficacy, analyze the characteristics of FDA-approved peptide drugs, and propose a developmental tool that considers the molecular properties of stabilized peptides in a comprehensive and quantitative manner to achieve the necessary rates for in vivo delivery to the target, efficacy, and ultimately clinical translation...
December 15, 2018: Trends in Biochemical Sciences
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