Advances in synthesis of biotin and assembly of lipoic acid.
Abstract Although biotin and lipoic acid are two universally conserved cofactors essential for intermediary metabolism, their synthetic pathways have become known only in recent years. Both pathways have unusual features. Biotin synthesis in Escherichia coli requires a methylation that is later removed whereas lipoic acid is assembled on the enzymes where it is required for activity by two different pathways. PMID: 30236800 [PubMed - as supplied by publisher] (Source: Current Opinion in Chemical Biology)
Source: Current Opinion in Chemical Biology - September 17, 2018 Category: Biochemistry Authors: Cronan JE Tags: Curr Opin Chem Biol Source Type: research

Insights into the physiology of ammonia-oxidizing microorganisms.
Abstract Nitrification is the aerobic process of the nitrogen cycle that converts ammonia to nitrate and is facilitated by ammonia-oxidizing and nitrite-oxidizing microorganisms. Ammonia-oxidizers are unique chemolithotrophs that evolved specialized networks of electron carriers to generate proton motive force using ammonia as a sole energy source as well as mechanisms to tolerate cytotoxic intermediates of their metabolism. Cultivation and genome sequencing of ammonia-oxidizing bacteria (AOB), archaea (AOA), and comammox bacteria (i.e. COMplete AMMonia OXidizers) have revealed new enzymology, mechanisms to tolera...
Source: Current Opinion in Chemical Biology - September 17, 2018 Category: Biochemistry Authors: Stein LY Tags: Curr Opin Chem Biol Source Type: research

Control of electron transfer in nitrogenase.
Abstract The bacterial enzyme nitrogenase achieves the reduction of dinitrogen (N2) to ammonia (NH3) utilizing electrons, protons, and energy from the hydrolysis of ATP. Building on earlier foundational knowledge, recent studies provide molecular-level details on how the energy of ATP hydrolysis is utilized, the sequencing of multiple electron transfer events, and the nature of energy transduction across this large protein complex. Here, we review the state of knowledge about energy transduction in nitrogenase. PMID: 30205289 [PubMed - as supplied by publisher] (Source: Current Opinion in Chemical Biology)
Source: Current Opinion in Chemical Biology - September 8, 2018 Category: Biochemistry Authors: Seefeldt LC, Peters JW, Beratan DN, Bothner B, Minteer SD, Raugei S, Hoffman BM Tags: Curr Opin Chem Biol Source Type: research

Expansion of the genetic code via expansion of the genetic alphabet.
Abstract Current methods to expand the genetic code enable site-specific incorporation of non-canonical amino acids (ncAAs) into proteins in eukaryotic and prokaryotic cells. However, current methods are limited by the number of codons possible, their orthogonality, and possibly their effects on protein synthesis and folding. An alternative approach relies on unnatural base pairs to create a virtually unlimited number of genuinely new codons that are efficiently translated and highly orthogonal because they direct ncAA incorporation using forces other than the complementary hydrogen bonds employed by their natural...
Source: Current Opinion in Chemical Biology - September 8, 2018 Category: Biochemistry Authors: Dien VT, Morris SE, Karadeema RJ, Romesberg FE Tags: Curr Opin Chem Biol Source Type: research

Editorial overview: Synthetic biomolecules.
PMID: 30201441 [PubMed - as supplied by publisher] (Source: Current Opinion in Chemical Biology)
Source: Current Opinion in Chemical Biology - September 7, 2018 Category: Biochemistry Authors: Payne RJ, Winssinger N Tags: Curr Opin Chem Biol Source Type: research

Chemical cross-linking with mass spectrometry: a tool for systems structural biology.
Abstract Biological processes supporting life are orchestrated by a highly dynamic array of protein structures and interactions comprising the interactome. Defining the interactome, visualizing how structures and interactions change and function to support life is essential to improved understanding of fundamental molecular processes, but represents a challenge unmet by any single analytical technique. Chemical cross-linking with mass spectrometry provides identification of proximal amino acid residues within proteins and protein complexes, yielding low resolution structural information. This approach has predomin...
Source: Current Opinion in Chemical Biology - August 30, 2018 Category: Biochemistry Authors: Chavez JD, Bruce JE Tags: Curr Opin Chem Biol Source Type: research

Chemical proteomics for subcellular proteome analysis.
Abstract Protein functions are tightly regulated by their subcellular localization and dynamic alteration. Chemical proteomics offers convenience and efficiency for profiling protein features in a native context. In this review, we summarize the recent progress of subcellular-compartment-focused chemical proteomics which do not rely on organelle fractionation. Organelle-specific activity-based protein profiling (ABPP) and engineered ascorbate peroxidase (APEX) have been developed for proteome analysis within organelles and even sub-organelles. In parallel, our lab designed organelle-localizable reactive molecules ...
Source: Current Opinion in Chemical Biology - August 28, 2018 Category: Biochemistry Authors: Zhu H, Tamura T, Hamachi I Tags: Curr Opin Chem Biol Source Type: research

Insights into the enzymatic formation, chemical features, and biological role of the flavin-N5-oxide.
Abstract Flavoenzymes are versatile catalysts that mostly facilitate redox reactions such as the oxygenation of organic substrates. Commonly, flavin monooxygenases employ a flavin-C4a-(hydro)peroxide as oxygenating species. Recently, however, a modified N5-functionalized flavin cofactor featuring a distinct nitrone moiety - the flavin-N5-oxide - was reported for the first time as oxygenating species in the bacterial enzyme EncM that catalyzes the dual oxidation of a reactive poly-β-ketone substrate. Meanwhile, additional flavoenzymes have been reported that form the flavin-N5-oxide...
Source: Current Opinion in Chemical Biology - August 27, 2018 Category: Biochemistry Authors: Saleem-Batcha R, Teufel R Tags: Curr Opin Chem Biol Source Type: research

Recent advances in the chemical synthesis of N-linked glycoproteins.
Abstract Glycoproteins have many biological roles. Due to the heterogeneity of natural glycoproteins in the sugar part resulting in glycoforms the evaluation of the biochemical roles of individual glycans remains difficult to investigate. Since pure glycoforms are still not accessible via recombinant or chromatographic methods, the synthesis of proteins with uniform posttranslational modifications using ligation methods or glycan remodeling are currently the best options for accessing these targets. Recent developments in chemical protein synthesis, the assembly of N-glycans and the use of enzymatic procedures hav...
Source: Current Opinion in Chemical Biology - August 22, 2018 Category: Biochemistry Authors: Carlo U, Yasuhiro K Tags: Curr Opin Chem Biol Source Type: research

Ribosomal incorporation of unnatural amino acids: lessons and improvements from fast kinetics studies.
Abstract Technologies for genetically programming ribosomal incorporation of unnatural amino acids are expanding and have created many exciting applications. However, these applications are generally limited by low efficiencies of the unnatural incorporations. Here we review our current mechanistic understanding of these limitations delineated from in vitro fast kinetics. Rate limitation occurs by different mechanisms, depending on the classes of the unnatural amino acids and the tRNA adaptors. This new understanding has led to several ways of improving the incorporation efficiencies, as well as challenges of dogm...
Source: Current Opinion in Chemical Biology - August 17, 2018 Category: Biochemistry Authors: Wang J, Forster AC Tags: Curr Opin Chem Biol Source Type: research

The challenge of synthetic biology. Synthetic Darwinism and the aperiodic crystal structure.
Abstract 'Grand Challenges' offer ways to discover flaws in existing theory without first needing to guess what those flaws are. Our grand challenge here is to reproduce the Darwinism of terran biology, but on molecular platforms different from standard DNA. Access to Darwinism distinguishes the living from the non-living state. However, theory suggests that any biopolymer able to support Darwinism must (a) be able to form Schrödinger's `aperiodic crystal', where different molecular components pack into a single crystal lattice, and (b) have a polyelectrolyte backbone. In 1953, the descriptive biology of Wats...
Source: Current Opinion in Chemical Biology - August 8, 2018 Category: Biochemistry Authors: Karalkar NB, Benner SA Tags: Curr Opin Chem Biol Source Type: research

Synthesis at the interface of virology and genetic code expansion.
Abstract How a virus efficiently invades its host cell and masterfully engineers its properties provides valuable lessons and resources for the emerging discipline of synthetic biology, which seeks to create engineered biological systems with novel functions. Recently, the toolbox of synthetic biology has also been enriched by the genetic code expansion technology, which has provided access to a large assortment of unnatural amino acids with novel chemical functionalities that can be site-specifically incorporated into proteins in living cells. The synergistic interplay of these two disciplines holds much promise ...
Source: Current Opinion in Chemical Biology - August 4, 2018 Category: Biochemistry Authors: Kelemen RE, Erickson SB, Chatterjee A Tags: Curr Opin Chem Biol Source Type: research

Application of non-canonical crosslinking amino acids to study protein-protein interactions in live cells.
Abstract The genetic incorporation of non-canonical amino acids (ncAAs) equipped with photo-crosslinking and chemical crosslinking moieties has found broad application in the study of protein-protein interactions from a unique perspective in live cells. We highlight here applications of photo-activatable ncAAs to map protein interaction surfaces and to capture protein-protein interactions, and we describe recent efforts to efficiently couple photo-crosslinking with mass spectrometric analysis. In addition, we describe recent advances in the development and application of ncAAs for chemical crosslinking, including ...
Source: Current Opinion in Chemical Biology - August 2, 2018 Category: Biochemistry Authors: Coin I Tags: Curr Opin Chem Biol Source Type: research

In vitro genetic code reprogramming and expansion to study protein function and discover macrocyclic peptide ligands.
Abstract The ability to introduce non-canonical amino acids into peptides and proteins is facilitated by working within in vitro translation systems. Non-canonical amino acids can be introduced into these systems using sense codon reprogramming, stop codon suppression, and by breaking codon degeneracy. Here, we review how these techniques have been used to create proteins with novel properties and how they facilitate sophisticated studies of protein function. We also discuss how researchers are using in vitro translation experiments with non-canonical amino acids to explore the tolerance of the translation apparat...
Source: Current Opinion in Chemical Biology - August 2, 2018 Category: Biochemistry Authors: Richardson SL, Dods KK, Abrigo NA, Iqbal ES, Hartman MC Tags: Curr Opin Chem Biol Source Type: research

From coherent to vibronic light harvesting in photosynthesis.
Abstract Photosynthetic organisms are a remarkable example of nanoscale engineering and have mastered the process of solar energy harvesting over billions of years of evolution. Therefore, researchers seek insights from the light collection mechanisms of photosynthetic machinery. The initial energy transfer stage of photosynthesis, which begins with light absorption and leads to charge separation, is remarkably robust in conditions of strong energetic disorder, extreme physiological temperatures, and low light flux - very different from conventional solar conversion materials [1-3]. However, determin...
Source: Current Opinion in Chemical Biology - August 2, 2018 Category: Biochemistry Authors: Jumper CC, Rafiq S, Wang S, Scholes GD Tags: Curr Opin Chem Biol Source Type: research

Editorial Overview: Non-invasive molecular imaging: dedicated to the memory of Professor Roger Tsien.
PMID: 30075836 [PubMed - in process] (Source: Current Opinion in Chemical Biology)
Source: Current Opinion in Chemical Biology - August 1, 2018 Category: Biochemistry Authors: Adams S, Rao J Tags: Curr Opin Chem Biol Source Type: research

Chemistry meets epigenetics: from chromatin tools to small molecules affecting the readout of our genomes.
PMID: 30075837 [PubMed - in process] (Source: Current Opinion in Chemical Biology)
Source: Current Opinion in Chemical Biology - August 1, 2018 Category: Biochemistry Authors: Fischle W, Schwarzer D Tags: Curr Opin Chem Biol Source Type: research

A new era for electron bifurcation.
Abstract Electron bifurcation, or the coupling of exergonic and endergonic oxidation-reduction reactions, was discovered by Peter Mitchell and provides an elegant mechanism to rationalize and understand the logic that underpins the Q cycle of the respiratory chain. Thought to be a unique reaction of respiratory complex III for nearly 40 years, about a decade ago Wolfgang Buckel and Rudolf Thauer discovered that flavin-based electron bifurcation is also an important component of anaerobic microbial metabolism. Their discovery spawned a surge of research activity, providing a basis to understand flavin-based bifurca...
Source: Current Opinion in Chemical Biology - August 1, 2018 Category: Biochemistry Authors: Peters JW, Beratan DN, Bothner B, Dyer RB, Harwood CS, Heiden ZM, Hille R, Jones AK, King PW, Lu Y, Lubner CE, Minteer SD, Mulder DW, Raugei S, Schut GJ, Seefeldt LC, Tokmina-Lukaszewska M, Zadvornyy OA, Zhang P, Adams MW Tags: Curr Opin Chem Biol Source Type: research

Genetic code expansion via integration of redundant amino acid assignment by finely tuning tRNA pools.
Abstract In all translation systems, the genetic code assigns codons to amino acids as building blocks of polypeptides, defining their chemical, structural and physiological properties. The canonical genetic code, however, utilizes only 20 proteinogenic amino acids redundantly encoded in 61 codons. In order to expand the building block repertoire, this redundancy was reduced by tuning composition of the transfer RNA (tRNA) mixture in vitro. Depletion of particular tRNAs from the total tRNA mixture or its reconstitution with in vitro-transcribed tRNASNNs (S = C or G, N = U, C, A or G) di...
Source: Current Opinion in Chemical Biology - July 30, 2018 Category: Biochemistry Authors: Tajima K, Katoh T, Suga H Tags: Curr Opin Chem Biol Source Type: research

Next-generation genetic code expansion.
Abstract Engineering of the translation apparatus has permitted the site-specific incorporation of nonstandard amino acids (nsAAs) into proteins, thereby expanding the genetic code of organisms. Conventional approaches have focused on porting tRNAs and aminoacyl-tRNA synthetases (aaRS) from archaea into bacterial and eukaryotic systems where they have been engineered to site-specifically encode nsAAs. More recent work in genome engineering has opened up the possibilities of whole genome recoding, in which organisms with alternative genetic codes have been constructed whereby codons removed from the genetic code ca...
Source: Current Opinion in Chemical Biology - July 30, 2018 Category: Biochemistry Authors: Arranz-Gibert P, Vanderschuren K, Isaacs FJ Tags: Curr Opin Chem Biol Source Type: research

Context effects of genetic code expansion by stop codon suppression.
Abstract Genetic code expansion enables the incorporation of unnatural amino acids into proteins thereby augmenting their physical and chemical properties. This is achieved by the reassignment of codons from their original sense to incorporate unnatural amino acids. The most commonly used methodology is stop codon suppression, which has resulted in numerous successful studies and applications in recent years. In these studies, many observations have been accumulated indicating that stop codon suppression efficiency depends on various cellular, operon and mRNA context effects. Predominant among these are mRNA conte...
Source: Current Opinion in Chemical Biology - July 28, 2018 Category: Biochemistry Authors: Chemla Y, Ozer E, Algov I, Alfonta L Tags: Curr Opin Chem Biol Source Type: research

Creation of unnatural base pairs for genetic alphabet expansion toward synthetic xenobiology.
Abstract Artificial extra base pairs (unnatural base pairs, UBPs) expand the genetic alphabet of DNA, thus broadening entire biological systems in the central dogma. UBPs function as third base pairs in replication, transcription, and/or translation, and have created a new research area, synthetic xenobiology, providing genetic engineering tools to generate novel DNAs, RNAs, and proteins with increased functionalities. Several UBPs have been developed and applied to PCR technology, DNA aptamer generation, and semi-synthetic organism creation. Among them, we developed a series of UBPs and demonstrated unique quanti...
Source: Current Opinion in Chemical Biology - July 27, 2018 Category: Biochemistry Authors: Hamashima K, Kimoto M, Hirao I Tags: Curr Opin Chem Biol Source Type: research

Upgrading aminoacyl-tRNA synthetases for genetic code expansion.
‡ A Abstract Synthesis of proteins with non-canonical amino acids via genetic code expansion is at the forefront of synthetic biology. Progress in this field has enabled site-specific incorporation of over 200 chemically and structurally diverse amino acids into proteins in an increasing number of organisms. This has been facilitated by our ability to repurpose aminoacyl-tRNA synthetases to attach non-canonical amino acids to engineered tRNAs. Current efforts in the field focus on overcoming existing limitations to the simultaneous incorporation of multiple non-canonical amino acids or amino acids that differ from...
Source: Current Opinion in Chemical Biology - July 27, 2018 Category: Biochemistry Authors: Vargas-Rodriguez O, Sevostyanova A, Söll D, Crnković A Tags: Curr Opin Chem Biol Source Type: research

Harnessing the power of an expanded genetic code toward next-generation biopharmaceuticals.
Abstract Synthetic biology has been revolutionizing the biopharmaceutical industry from drug discovery, clinical development to the manufacturing of biopharmaceuticals. As one of its most promising areas, genetic incorporation of noncanonical amino acids (ncAA) into proteins via an expanded genetic code emerged with great promise in the pharmaceutical industry recently with multiple therapeutic candidates tested in human clinical trials and one approved veterinary drug. Expanded building blocks enable proteins to have new or modified functions, providing ample opportunities for innovative or improved medicines. He...
Source: Current Opinion in Chemical Biology - July 27, 2018 Category: Biochemistry Authors: Kang M, Lu Y, Chen S, Tian F Tags: Curr Opin Chem Biol Source Type: research

Evolutionary tuning impacts the design of bacterial tRNAs for the incorporation of unnatural amino acids by ribosomes.
Abstract In order to function on the ribosome with uniform rate and adequate accuracy, each bacterial tRNA has evolved to have a characteristic sequence and set of modifications that compensate for the differing physical properties of its esterified amino acid and its codon-anticodon interaction. The sequence of the T-stem of each tRNA compensates for the differential effect of the esterified amino acid on the binding and release of EF-Tu during decoding. The sequence and modifications in the anticodon loop and core of tRNA impact the codon-anticodon strength and the ability of the tRNA to bend during codon recogn...
Source: Current Opinion in Chemical Biology - July 27, 2018 Category: Biochemistry Authors: Uhlenbeck OC, Schrader JM Tags: Curr Opin Chem Biol Source Type: research

Recent advances in the optical control of protein function through genetic code expansion.
Abstract In nature, biological processes are regulated with precise spatial and temporal resolution at the molecular, cellular, and organismal levels. In order to perturb and manipulate these processes, optically controlled chemical tools have been developed and applied in living systems. The use of light as an external trigger provides spatial and temporal control with minimal adverse effects. Incorporation of light-responsive amino acids into proteins in cells and organisms with an expanded genetic code has enabled the precise activation/deactivation of numerous, diverse proteins, such as kinases, nucleases, pro...
Source: Current Opinion in Chemical Biology - July 26, 2018 Category: Biochemistry Authors: Courtney T, Deiters A Tags: Curr Opin Chem Biol Source Type: research

Supramolecular strategies for protein immobilization and modification.
Abstract Protein immobilization and modification are widely used techniques in the fields of chemical biology and biomaterials science. While covalent strategies based on small molecules are traditionally used, supramolecular chemistry offers numerous useful opportunities for guiding the modification locations on complex protein landscapes and introducing different degrees of reversibility into the products. In this opinion, we highlight recent advances in using supramolecular interactions, particularly host-guest chemistry, for controlling protein modification and immobilization. We discuss supramolecular strateg...
Source: Current Opinion in Chemical Biology - July 21, 2018 Category: Biochemistry Authors: Finbloom JA, Francis MB Tags: Curr Opin Chem Biol Source Type: research

Modulating the masters: chemical tools to dissect CBP and p300 function.
Abstract Dysregulation of transcription is found in nearly every human disease, and as a result there has been intense interest in developing new therapeutics that target regulators of transcription. CREB binding protein (CBP) and its paralogue p300 are attractive targets due to their function as `master coactivators'. Although inhibitors of several CBP/p300 domains have been identified, the selectivity of many of these compounds has remained underexplored. Here, we review recent successes in the development of chemical tools targeting several CBP/p300 domains with selectivity acceptable for use as chemical probes...
Source: Current Opinion in Chemical Biology - July 16, 2018 Category: Biochemistry Authors: Breen ME, Mapp AK Tags: Curr Opin Chem Biol Source Type: research

Nature's conductors: what can microbial multi-heme cytochromes teach us about electron transport and biological energy conversion?
Abstract 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-electric...
Source: Current Opinion in Chemical Biology - July 14, 2018 Category: Biochemistry Authors: Chong GW, Karbelkar AA, El-Naggar MY Tags: Curr Opin Chem Biol Source Type: research

Editorial overview: Next generation therapeutics.
PMID: 30017613 [PubMed - as supplied by publisher] (Source: Current Opinion in Chemical Biology)
Source: Current Opinion in Chemical Biology - July 14, 2018 Category: Biochemistry Authors: Whitty A, Tonge PJ Tags: Curr Opin Chem Biol Source Type: research

Electron transfer and transport through multi-heme proteins: recent progress and future directions.
Abstract 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. PMID: 3...
Source: Current Opinion in Chemical Biology - July 13, 2018 Category: Biochemistry Authors: Blumberger J Tags: Curr Opin Chem Biol Source Type: research

Magnetic resonance imaging of cancer metabolism with hyperpolarized 13C-labeled cell metabolites.
Abstract Hyperpolarization of 13C-labeled substrates can increase their 13C 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 [1-13C]pyruvate. In clinical oncology there is a requirement to diagnose tumors earlier, better determine their aggressiveness and prognosis, identify novel treat...
Source: Current Opinion in Chemical Biology - July 11, 2018 Category: Biochemistry Authors: Hesketh RL, Brindle KM Tags: Curr Opin Chem Biol Source Type: research

N1-methyladenosine methylome in messenger RNA and non-coding RNA.
Abstract Chemical modifications to rRNA, tRNA and mRNA provide a new regulatory layer of gene expression, which is termed as the `epitranscriptome'. N1-methyladenosine (m1A), first characterized more than 50 years ago, is a well-known modification in rRNA and tRNA. m1A in these abundant non-coding RNAs plays important roles in maintaining their biological functions. Recent studies also reveal that m1A is present in both nuclear-encoded and mitochondrial-encoded mRNA and is dynamically regulated by environmental and developmental conditions; m1A is found in a subset of nuclear-encoded long non-coding RNAs as well. ...
Source: Current Opinion in Chemical Biology - July 9, 2018 Category: Biochemistry Authors: Xiong X, Li X, Yi C Tags: Curr Opin Chem Biol Source Type: research

Structure-kinetic relationships that control the residence time of drug-target complexes: insights from molecular structure and dynamics.
Abstract 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 th...
Source: Current Opinion in Chemical Biology - July 6, 2018 Category: Biochemistry Authors: Lu H, Iuliano JN, Tonge PJ Tags: Curr Opin Chem Biol Source Type: research

Imaging and spatially resolved quantification of drug distribution in tissues by mass spectrometry.
Abstract 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 conventi...
Source: Current Opinion in Chemical Biology - June 26, 2018 Category: Biochemistry Authors: Prideaux B, Lenaerts A, Dartois V Tags: Curr Opin Chem Biol Source Type: research

Engineering of RiPP pathways for the production of artificial peptides bearing various non-proteinogenic structures.
Abstract 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 ...
Source: Current Opinion in Chemical Biology - June 26, 2018 Category: Biochemistry Authors: Goto Y, Suga H Tags: Curr Opin Chem Biol Source Type: research

Interplay of disorder and delocalization in photosynthetic light harvesting.
Abstract 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 ...
Source: Current Opinion in Chemical Biology - June 26, 2018 Category: Biochemistry Authors: Pavel M, Rienk VG Tags: Curr Opin Chem Biol Source Type: research

Small molecules as tools to study the chemical epigenetics of lysine acetylation.
Abstract 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 ...
Source: Current Opinion in Chemical Biology - June 26, 2018 Category: Biochemistry Authors: Schiedel M, Conway SJ Tags: Curr Opin Chem Biol Source Type: research

Improving small molecule virtual screening strategies for the next generation of therapeutics.
Abstract 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 capa...
Source: Current Opinion in Chemical Biology - June 16, 2018 Category: Biochemistry Authors: Wingert BM, Camacho CJ Tags: Curr Opin Chem Biol Source Type: research

Impact of environmental conditions and chemicals on the neuronal epigenome.
Abstract 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. Here, we review a number of studies that demonstrate the existen...
Source: Current Opinion in Chemical Biology - June 15, 2018 Category: Biochemistry Authors: Del Blanco B, Barco A Tags: Curr Opin Chem Biol Source Type: research

Synthesis of modified proteins via functionalization of dehydroalanine.
is BG Abstract 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 ...
Source: Current Opinion in Chemical Biology - June 15, 2018 Category: Biochemistry Authors: Dadová J, Galan SR, Davis BG Tags: Curr Opin Chem Biol Source Type: research

Inhibitors of protein-protein interactions (PPIs): an analysis of scaffold choices and buried surface area.
Abstract 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 we...
Source: Current Opinion in Chemical Biology - June 13, 2018 Category: Biochemistry Authors: Ran X, Gestwicki JE Tags: Curr Opin Chem Biol Source Type: research

More than cholesterol catabolism: regulatory vulnerabilities in Mycobacterium tuberculosis.
Abstract 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. We review what is k...
Source: Current Opinion in Chemical Biology - June 12, 2018 Category: Biochemistry Authors: Bonds AC, Sampson NS Tags: Curr Opin Chem Biol Source Type: research

Therapeutic strategies for targeting neurodegenerative protein misfolding disorders.
Abstract 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. Several neurodegenerative diseases, such as Alzheim...
Source: Current Opinion in Chemical Biology - June 11, 2018 Category: Biochemistry Authors: Scannevin RH Tags: Curr Opin Chem Biol Source Type: research

Targeted protein degradation and the enzymology of degraders.
Abstract 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. We also present a framework for degraders as programmable essential activators of ubiquitin...
Source: Current Opinion in Chemical Biology - June 7, 2018 Category: Biochemistry Authors: Fisher SL, Phillips AJ Tags: Curr Opin Chem Biol Source Type: research

Recent progress in therapeutic antibodies for cancer immunotherapy.
Abstract 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. Ongoing resea...
Source: Current Opinion in Chemical Biology - June 7, 2018 Category: Biochemistry Authors: Lee A, Sun S, Sandler A, Hoang T Tags: Curr Opin Chem Biol Source Type: research

Advances in bioluminescence imaging: new probes from old recipes.
Abstract 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. PMID: 29879594 [PubMed - as...
Source: Current Opinion in Chemical Biology - June 4, 2018 Category: Biochemistry Authors: Yao Z, Zhang BS, Prescher JA Tags: Curr Opin Chem Biol Source Type: research

Beyond cysteine: recent developments in the area of targeted covalent inhibition.
Abstract 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 residu...
Source: Current Opinion in Chemical Biology - May 29, 2018 Category: Biochemistry Authors: Mukherjee H, Grimster NP Tags: Curr Opin Chem Biol Source Type: research

Opportunities and guidelines for discovery of orally absorbed drugs in beyond rule of 5 space.
Abstract Recent years have seen a dramatic increase in the number of drugs approved in chemical space outside of Lipinski's rule of 5, that is in what has been termed beyond rule of 5 (bRo5) space. The development of three major classes of oral drugs that treat HIV and HCV infections and the growing evidence that novel, difficult targets can be accessed has prompted research into understanding design of drugs displaying cell permeability, solubility and ultimately oral bioavailability in bRo5 space. Studies have found a consistent outer property limit for a reasonable chance of de novo designing oral bioavailabili...
Source: Current Opinion in Chemical Biology - May 24, 2018 Category: Biochemistry Authors: Poongavanam V, Doak BC, Kihlberg J Tags: Curr Opin Chem Biol Source Type: research

Advances and challenges in bacterial compound accumulation assays for drug discovery.
Abstract The identification of potent in vitro inhibitors of essential bacterial targets is relatively straightforward, however vanishingly few of these molecules have Gram-negative antibacterial potency and spectrum because of a failure to accumulate inside the bacteria. The Gram-negative bacterial cell envelope provides a formidable barrier to entry and couples with efflux pumps to prevent compound accumulation. Assays to measure the cellular permeation, efflux and accumulation of compounds in bacteria continue to be innovated and refined to guide drug discovery. Important advances in the label-free detection of...
Source: Current Opinion in Chemical Biology - May 24, 2018 Category: Biochemistry Authors: Six DA, Krucker T, Leeds JA Tags: Curr Opin Chem Biol Source Type: research