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Current Opinion in Chemical Biology

Grace W Chong, Amruta A Karbelkar, Mohamed Y El-Naggar
Microorganisms can acquire energy from the environment by extending their electron transport chains to external solid electron donors or acceptors. This process, known as extracellular electron transfer (EET), is now being heavily pursued for wiring microbes to electrodes in bioelectrochemical renewable energy technologies. Recent studies highlight the crucial role of multi-heme cytochromes in facilitating biotic-abiotic EET both for cellular electron export and uptake. Here we explore progress in understanding the range and function of these biological electron conduits in the context of fuel-to-electricity and electricity-to-bioproduct conversion...
July 14, 2018: Current Opinion in Chemical Biology
Jochen Blumberger
I review recent experimental measurements probing electron transfer (ET) and electron transport (ETp) through multi-heme cytochromes (MHCs) as well as their theoretical interpretation. Examples include pump-probe spectroscopy of Ru-labeled MHCs aimed at determining heme-heme ET rates in MHCs and the measurement of the I-V characteristics of MHCs in bioelectronic junctions. While the ET mechanism appears to be well established for MHCs in aqueous solution, the ETp mechanism in bioelectronic junctions such as STM remains elusive partly due to the complexities of the electrode-protein interface...
July 13, 2018: Current Opinion in Chemical Biology
Richard L Hesketh, Kevin M Brindle
Hyperpolarization of 13 C-labeled substrates can increase their 13 C NMR signal by more than 10000-fold, which has allowed magnetic resonance imaging (MRI) of metabolic reactions in vivo. This has already provided a unique insight into the dysregulated metabolic pathways and microenvironment of tumors. Perhaps the best known of the cancer-associated metabolic aberrations is the Warburg effect, which has been imaged in patients using hyperpolarized [1-13 C]pyruvate. In clinical oncology there is a requirement to diagnose tumors earlier, better determine their aggressiveness and prognosis, identify novel treatment targets and detect response to treatment earlier...
July 11, 2018: Current Opinion in Chemical Biology
Robert P Hausinger, Benoît Desguin, Matthias Fellner, Joel A Rankin, Jian Hu
A novel organometallic cofactor, nickel pyridinium-3,5-dithiocarboxylic acid mononucleotide, was recently discovered in lactate racemase (LarA) of Lactobacillus plantarum. This review summarizes the substantial progress made in uncovering the function of this cofactor as a transient hydride acceptor in the LarA mechanism. The latest developments related to cofactor biosynthesis reveal insights into a pathway in which LarB serves as a nicotinic acid adenine dinucleotide hydrolase/carboxylase, LarE acts as a sacrificial sulfur transferase, and LarC functions as a nickel insertase, forming the nickel-pincer nucleotide cofactor that becomes covalently tethered to LarA in some bacteria...
July 9, 2018: Current Opinion in Chemical Biology
Xushen Xiong, Xiaoyu Li, Chengqi Yi
Chemical modifications to rRNA, tRNA and mRNA provide a new regulatory layer of gene expression, which is termed as the `epitranscriptome'. N1 -methyladenosine (m1 A), first characterized more than 50 years ago, is a well-known modification in rRNA and tRNA. m1 A in these abundant non-coding RNAs plays important roles in maintaining their biological functions. Recent studies also reveal that m1 A is present in both nuclear-encoded and mitochondrial-encoded mRNA and is dynamically regulated by environmental and developmental conditions; m1 A is found in a subset of nuclear-encoded long non-coding RNAs as well...
July 9, 2018: Current Opinion in Chemical Biology
Hao Lu, James N Iuliano, Peter J Tonge
Time-dependent target occupancy is a function of both the thermodynamics and kinetics of drug-target interactions. However, while the optimization of thermodynamic affinity through approaches such as structure-based drug design is now relatively straight forward, less is understood about the molecular interactions that control the kinetics of drug complex formation and breakdown since this depends on both the ground and transition state energies on the binding reaction coordinate. In this opinion we highlight several recent examples that shed light on current approaches that are elucidating the factors that control the life-time of the drug-target complex...
July 6, 2018: Current Opinion in Chemical Biology
Matthias Schiedel, Stuart J Conway
Lysine acetylation has emerged as a key post-translational modification found at many sites throughout the cell. It plays an important role in epigenetic processes, and more generally in the regulation of protein stability and interactions. Acetyl groups are installed by lysine acetyltransferases and removed by lysine deacetylases. Acetylated lysine residues function as binding sites for bromodomains, which are epigenetic reader protein modules that mediate protein-protein interactions. Progress in the development of small molecules that interfere with lysine acetylation has stimulated intensive research activity in diverse therapeutic areas...
June 26, 2018: Current Opinion in Chemical Biology
Malý Pavel, van Grondelle Rienk
Photosystems, the machines of photosynthesis, are highly complex and energetically disordered pigment-protein structures. Yet, they perform their function, be it highly efficient energy transfer and charge separation or the ability to switch between light-harvesting and photoprotective states, extremely well. In this opinioned review we describe the interplay of disorder and exciton delocalization in photosynthetic light harvesting. By discussing recent research advances on grounds of well-established concepts, we demonstrate that not only is the excitation delocalization a robust phenomenon, but that it in fact enables the light-harvesting function in the disordered environment...
June 26, 2018: Current Opinion in Chemical Biology
Yuki Goto, Hiroaki Suga
Peptides bearing non-proteinogenic structures characteristic of natural products have great potential as leads of pharmaceuticals. In the biosynthetic pathways of ribosomally synthesized and post-translationally modified peptides (RiPPs), the non-proteinogenic structures are generated by enzymatic structural modification on precursor peptides encoded in genetic information. The plasticity of this pathway, in which alterations of the precursor genes directly resulted in variation of the products by the process of modularly functioning enzymes, have greatly facilitated both in vivo and in vitro engineering of the pathways...
June 26, 2018: Current Opinion in Chemical Biology
Brendan Prideaux, Anne Lenaerts, Véronique Dartois
Mass spectrometry imaging (MSI) is a powerful label-free technique for visualizing drug and metabolite distributions in biological tissues. In this review, we discuss recent developments in MSI and spatial profiling technologies to visualize and quantify drug distributions in tissues. We also present recent examples of applications of these technologies for assessing drug distribution within tissues and individual cells. Finally, we focus on an emerging technique coupling laser capture microdissection (LCM) to quantitative mass spectrometry, which combines the respective advantages of imaging and conventional liquid chromatography mass spectrometry, and thus enables spatially resolved drug quantification...
June 26, 2018: Current Opinion in Chemical Biology
Bentley M Wingert, Carlos J Camacho
The new generation of post-genomic targets, such as protein-protein interactions (PPIs), often require new chemotypes not well represented in current compound libraries. This is one reason for why traditional high throughput screening (HTS) approaches are not more successful in delivering medicinal chemistry starting points for PPIs. In silico screening methods of an expanded chemical space are then potential alternatives for developing novel chemical probes to modulate PPIs. In this review, we report on the state-of-the-art pipelines for virtual screening, emphasizing prospectively validated methods capable of addressing the challenge of drugging difficult targets in the human interactome...
June 16, 2018: Current Opinion in Chemical Biology
Jitka Dadová, Sébastien Rg Galan, Benjamin G Davis
Dehydroalanine has emerged in recent years as a non-proteinogenic residue with strong chemical utility in proteins for the study of biology. In this review we cover the several methods now available for its flexible and site-selective incorporation via a variety of complementary chemical and biological techniques and examine its reactivity, allowing both creation of modified protein side-chains through a variety of bond-forming methods (C-S, C-N, C-Se, C-C) and as an activity-based probe in its own right. We illustrate its utility with selected examples of biological and technological discovery and application...
June 15, 2018: Current Opinion in Chemical Biology
Beatriz Del Blanco, Angel Barco
During development, chromatin changes contribute to establishing and maintaining the distinct gene-expression profiles of each individual cell type in a multicellular organism. This feat is especially remarkable in the human brain considering the sheer number of distinct cell types that make up this organ. This epigenetic programing is sensitive to environmental influences such as the presence of toxicants, diet, temperature, maternal behavior and many other external factors that can lead to sustained differences in neuronal gene expression...
June 15, 2018: Current Opinion in Chemical Biology
Xu Ran, Jason E Gestwicki
Protein-protein interactions (PPI) were once considered 'undruggable', but clinical successes, driven by advanced methods in drug discovery, have challenged that notion. Here, we review the last three years of literature on PPI inhibitors to understand what is working and why. From the 66 recently reported PPI inhibitors, we found that the average molecular weight was significantly greater than 500Da, but that this trend was driven, in large part, by the contribution of peptide-based compounds. Despite differences in average molecular weight, we found that compounds based on small molecules or peptides were almost equally likely to be potent inhibitors (KD <1μM)...
June 13, 2018: Current Opinion in Chemical Biology
Amber C Bonds, Nicole S Sampson
Mycobacterium tuberculosis (Mtb) is the epitome of persistent. Mtb is the pathogen that causes tuberculosis, the leading cause of death by infection worldwide. The success of this pathogen is due in part to its clever ability to adapt to its host environment and its effective manipulation of the host immune system. A major contributing factor to the survival and virulence of Mtb is its acquisition and metabolism of host derived lipids including cholesterol. Accumulating evidence suggests that the catabolism of cholesterol during infection is highly regulated by cholesterol catabolites...
June 12, 2018: Current Opinion in Chemical Biology
Robert H Scannevin
Neurodegenerative diseases can arise from a multitude of different pathological drivers, however protein misfolding appears to be a common molecular feature central to several disorders. Protein folding, and attainment of correct secondary and tertiary structure, is essential for proper protein function. Protein misfolding gives rise to structural perturbations that can result in loss of protein function or a gain of toxic function, such as through aggregation, either of which can initiate and propagate biological responses that are deleterious to cells...
June 11, 2018: Current Opinion in Chemical Biology
Anthony Lee, Shawn Sun, Alan Sandler, Tien Hoang
Therapeutic antibodies have advanced the clinical management of multiple diseases including cancer. Cancer immunotherapy has been a focal point of recent clinical research with the success of checkpoint inhibitor antibodies, particularly those that target the PD-L1/PD-1 pathway. These antibodies that target specific steps of the cancer-immunity cycle show improved anti-tumor response, progression-free survival and overall survival versus standard therapy across multiple tumor types. Despite these advancements, not all patients experience durable response from checkpoint inhibition treatment...
June 7, 2018: Current Opinion in Chemical Biology
Stewart L Fisher, Andrew J Phillips
Targeted protein degradation is an emerging strategy for drug discovery that employs small molecules to catalyze the ubiquitination of target proteins, ultimately causing their degradation by the proteasome. Current degrader designs employ hetero-bivalent molecules to recruit E3 ubiquitin ligases such as VHL, Cereblon, and the IAPs to the target protein to be ubiquitinated. In this review, we describe some of the foundational studies underpinning the use of heterobivalent degraders for targeted protein degradation...
June 7, 2018: Current Opinion in Chemical Biology
Zi Yao, Brendan S Zhang, Jennifer A Prescher
Bioluminescent probes are powerful tools for visualizing biology in live tissues and whole animals. Recent years have seen a surge in the number of new luciferases, luciferins, and related tools available for bioluminescence imaging. Many were crafted using classic methods of optical probe design and engineering. Here we highlight recent advances in bioluminescent tool discovery and development, along with applications of the probes in cells, tissues, and organisms. Collectively, these tools are improving in vivo imaging capabilities and bolstering new research directions...
June 4, 2018: Current Opinion in Chemical Biology
Herschel Mukherjee, Neil P Grimster
Over the past decade targeted covalent inhibitors have undergone a renaissance due to the clinical validation and regulatory approval of several small molecule therapeutics that are designed to irreversibly modify their target protein. Invariably, these compounds rely on the serendipitous placement of a cysteine residue proximal to the small molecule binding site; while this strategy has afforded numerous successes, it necessarily limits the number of proteins that can be targeted by this approach. This drawback has led several research groups to develop novel methodologies that target non-cysteine residues for covalent modification...
May 29, 2018: Current Opinion in Chemical Biology
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