Bio-inspired mechanistic insights into CO2 reduction.
Abstract The global energy and environmental concerns related to the excess CO2 concentration in the atmosphere have intensified the research and development regarding CO2 utilization. Due to the high stability and inertness of CO2, CO2 functionalization under mild conditions has been proven to be extremely challenging. Nature has, however, evolved efficient pathways to achieve this difficult transformation. Herein, we compare the mechanisms of CO2 two-electron reduction followed by synthetic catalysts and those by carbon monoxide dehydrogenase and formate dehydrogenase in order to provide more mechanistic insight...
Source: Current Opinion in Chemical Biology - January 9, 2015 Category: Biochemistry Authors: Mondal B, Song J, Neese F, Ye S Tags: Curr Opin Chem Biol Source Type: research

Improving and repurposing biocatalysts via directed evolution.
Abstract Over the last two decades, directed evolution has become a staple in protein engineering and ushered in a new era of industrial biocatalysis. Directed evolution has provided the tools to not only improve the activity of known biocatalysts, but also to endow biocatalysts with chemical reactivities not previously encountered in nature. Here we will discuss the recent successes in the quest to enhance thermostability, stereoselectivity and activity of biocatalysts, as well as to create novel enzymes, over the last two years. PMID: 25579451 [PubMed - as supplied by publisher] (Source: Current Opinion in Chemical Biology)
Source: Current Opinion in Chemical Biology - January 8, 2015 Category: Biochemistry Authors: Denard CA, Ren H, Zhao H Tags: Curr Opin Chem Biol Source Type: research

Artificial metalloenzymes derived from three-helix bundles.
Abstract Three-helix bundles and coiled-coil motifs are well-established de novo designed scaffolds that have been investigated for their metal-binding and catalytic properties. Satisfaction of the primary coordination sphere for a given metal is sufficient to introduce catalytic activity and a given structure may catalyze different reactions dependent on the identity of the incorporated metal. Here we describe recent contributions in the de novo design of metalloenzymes based on three-helix bundles and coiled-coil motifs, focusing on non-heme systems for hydrolytic and redox chemistry. PMID: 25579452 [PubMed...
Source: Current Opinion in Chemical Biology - January 8, 2015 Category: Biochemistry Authors: Tebo AG, Pecoraro VL Tags: Curr Opin Chem Biol Source Type: research

Using non-enzymatic chemistry to influence microbial metabolism.
Abstract The structural manipulation of small molecule metabolites occurs in all organisms and plays a fundamental role in essentially all biological processes. Despite an increasing interest in developing new, non-enzymatic chemical reactions capable of functioning in the presence of living organisms, the ability of such transformations to interface with cellular metabolism and influence biological function is a comparatively underexplored area of research. This review will discuss efforts to combine non-enzymatic chemistry with microbial metabolism. We will highlight recent and historical uses of non-biological ...
Source: Current Opinion in Chemical Biology - January 8, 2015 Category: Biochemistry Authors: Wallace S, Schultz EE, Balskus EP Tags: Curr Opin Chem Biol Source Type: research

DNA-based hybrid catalysis.
fes G Abstract In the past decade, DNA-based hybrid catalysis has merged as a promising novel approach to homogeneous (asymmetric) catalysis. A DNA hybrid catalysts comprises a transition metal complex that is covalently or supramolecularly bound to DNA. The chiral microenvironment and the second coordination sphere interactions provided by the DNA are key to achieve high enantioselectivities and, often, additional rate accelerations in catalysis. Nowadays, current efforts are focused on improved designs, understanding the origin of the enantioselectivity and DNA-induced rate accelerations, expanding the catalytic...
Source: Current Opinion in Chemical Biology - January 8, 2015 Category: Biochemistry Authors: Rioz-Martínez A, Roelfes G Tags: Curr Opin Chem Biol Source Type: research

Use of the confined spaces of apo-ferritin and virus capsids as nanoreactors for catalytic reactions.
Abstract Self-assembled protein cages providing nanosized internal spaces which are capable of encapsulating metal ions/complexes, enzymes/proteins have great potential for use as catalytic nanoreactors in efforts to mimic confined cellular environments for synthetic applications. Despite many uses in biomineralization, drug delivery, bio-imaging and so on, applications in catalysis are relatively rare. Because of their restricted size, protein cages are excellent candidates for use as vessels to exert control over reaction kinetics and product selectivity. Virus capsids with larger internal spaces can encapsulate...
Source: Current Opinion in Chemical Biology - January 8, 2015 Category: Biochemistry Authors: Maity B, Fujita K, Ueno T Tags: Curr Opin Chem Biol Source Type: research

Transition-metal-mediated uncaging in living human cells-an emerging alternative to photolabile protecting groups.
s E Abstract Photolabile protecting groups have been widely used for activation strategies of caged substrates within living cells. However, an alternative uncaging method in which, instead of light, chemical compounds are used as activators (chemical uncaging) is still in its infancy. The recent advances in bioorthogonal reactions mediated by transition metals have shown that bioorthogonal catalysts have the potential to yield such a chemical activator. By now we have seen transition metal compounds that activate caged enzymes, toxigenic prodrugs and other small molecules such as fluorophores within living human ...
Source: Current Opinion in Chemical Biology - January 2, 2015 Category: Biochemistry Authors: Völker T, Meggers E Tags: Curr Opin Chem Biol Source Type: research

Artificial hydrogenases: biohybrid and supramolecular systems for catalytic hydrogen production or uptake.
Abstract There is an urgent need for cheap, abundant and efficient catalysts as an alternative to platinum for hydrogen production and oxidation in (photo)electrolyzers and fuel cells. Hydrogenases are attractive solutions. These enzymes use exclusively nickel and iron in their active sites and function with high catalytic rates at the thermodynamic equilibrium. As an alternative, a number of biomimetic and bioinspired catalysts for H2 production and/or uptake, based on Ni, Fe and Co, have been developed and shown to display encouraging performances. In this review we discuss specifically recent approaches aiming ...
Source: Current Opinion in Chemical Biology - December 29, 2014 Category: Biochemistry Authors: Caserta G, Roy S, Atta M, Artero V, Fontecave M Tags: Curr Opin Chem Biol Source Type: research

Editorial overview: Omics: Methods to monitor and manipulate biological systems: recent advances in 'omics'
PMID: 25549533 [PubMed - as supplied by publisher] (Source: Current Opinion in Chemical Biology)
Source: Current Opinion in Chemical Biology - December 27, 2014 Category: Biochemistry Authors: Cravatt BF, Kodadek T Tags: Curr Opin Chem Biol Source Type: research

Metallopeptide catalysts and artificial metalloenzymes containing unnatural amino acids.
Abstract Metallopeptide catalysts and artificial metalloenzymes built from peptide scaffolds and catalytically active metal centers possess a number of exciting properties that could be exploited for selective catalysis. Control over metal catalyst secondary coordination spheres, compatibility with library based methods for optimization and evolution, and biocompatibility stand out in this regard. A wide range of unnatural amino acids (UAAs) have been incorporated into peptide and protein scaffolds using several distinct methods, and the resulting UAAs containing scaffolds can be used to create novel hybrid metal-...
Source: Current Opinion in Chemical Biology - December 26, 2014 Category: Biochemistry Authors: Lewis JC Tags: Curr Opin Chem Biol Source Type: research

Activity-based protein profiling of microbes.
Abstract Activity-based protein profiling (ABPP) in conjunction with multimodal characterization techniques has yielded impactful findings in microbiology, particularly in pathogen, bioenergy, drug discovery, and environmental research. Using small molecule chemical probes that react irreversibly with specific proteins or protein families in complex systems has provided insights in enzyme functions in central metabolic pathways, drug-protein interactions, and regulatory protein redox, for systems ranging from photoautotrophic cyanobacteria to mycobacteria, and combining live cell or cell extract ABPP with proteomi...
Source: Current Opinion in Chemical Biology - December 19, 2014 Category: Biochemistry Authors: Sadler NC, Wright AT Tags: Curr Opin Chem Biol Source Type: research

Artificial photosynthetic systems for production of hydrogen.
This article summarizes recent advances on studies of artificial photosynthetic systems for photocatalytic production of hydrogen with hydrogenases and their functional mimics including hybrids of natural and artificial components. Because it is highly desired to convert gaseous H2 to an easily storable form, recent progress on storage of hydrogen as liquid or solid form has also been described in this article. PMID: 25531176 [PubMed - as supplied by publisher] (Source: Current Opinion in Chemical Biology)
Source: Current Opinion in Chemical Biology - December 19, 2014 Category: Biochemistry Authors: Fukuzumi S Tags: Curr Opin Chem Biol Source Type: research

Beyond H2: exploiting 2-hydroxypyridine as a design element from [Fe]-hydrogenase for energy-relevant catalysis.
Abstract The unique primary and secondary coordination environments surrounding the active site of hydrogenase enzymes play a crucial role in H2 activation and transfer reactions. [Fe]-hydrogenase contains a 2-hydroxypyridine ligand motif, and many researchers have incorporated this design element into synthetic catalysts. Transition metal complexes supported by 2-hydroxypyridine scaffolds are catalysts for chemical conversion schemes relevant to alternative energy applications and, in addition to hydrogenase-type reactivity, find new uses in other chemical domains. In this review, the current status of 2-hydroxyp...
Source: Current Opinion in Chemical Biology - December 18, 2014 Category: Biochemistry Authors: Moore CM, Dahl EW, Szymczak NK Tags: Curr Opin Chem Biol Source Type: research

Small molecule chemical probes of microRNA function.
Abstract MicroRNAs (miRNAs) are small, non-coding RNAs that control protein expression. Aberrant miRNA expression has been linked to various human diseases, and thus miRNAs have been explored as diagnostic markers and therapeutic targets. Although it is challenging to target RNA with small molecules in general, there have been successful campaigns that have identified small molecule modulators of miRNA function by targeting various pathways. For example, small molecules that modulate transcription and target nuclease processing sites in miRNA precursors have been identified. Herein, we describe challenges in devel...
Source: Current Opinion in Chemical Biology - December 9, 2014 Category: Biochemistry Authors: Velagapudi SP, Vummidi BR, Disney MD Tags: Curr Opin Chem Biol Source Type: research

Light-driven hydrogen production from Photosystem I-catalyst hybrids.
Abstract Solar energy conversion of water into environmentally clean fuels, such as hydrogen, offers one of the best long-term solutions for meeting future global energy needs. In photosynthesis, high quantum yield charge separation is achieved by a series of rapid, photoinitiated electron transfer steps that take place in proteins called reaction centers (RCs). Of current interest are new strategies that couple RC photochemistry to the direct synthesis of energy-rich molecules, offering opportunities to more directly tune the products of photosynthesis and potentially to increase solar energy conversion capacity....
Source: Current Opinion in Chemical Biology - December 9, 2014 Category: Biochemistry Authors: Utschig LM, Soltau SR, Tiede DM Tags: Curr Opin Chem Biol Source Type: research

Construction and screening of vast libraries of natural product-like macrocyclic peptides using in vitro display technologies.
Abstract Macrocyclic structure and backbone N-methylation represent characteristic features of peptidic natural products, which play critical roles in their biological activity. Although natural products have been the traditional source of such peptides, recent developments in synthesizing natural product-like macrocyclic peptides using reconstituted translation systems have enabled us to construct vast trillion-member libraries of non-standard macrocyclic peptides. In addition, a method for displaying such libraries on their corresponding mRNA templates allows us to rapidly screen them for potent ligands against ...
Source: Current Opinion in Chemical Biology - December 4, 2014 Category: Biochemistry Authors: Bashiruddin NK, Suga H Tags: Curr Opin Chem Biol Source Type: research

A reinvigorated era of bacterial secondary metabolite discovery.
Abstract Secondary metabolite discovery from bacteria has become increasingly successful in the last decade due to the advancement of integrated genetic-based, spectrometric-based and informatics-based techniques. Microbes and their unique metabolic outputs have been widely studied since the beginning of modern medicine; however, it is well known that the current repertoire of secondary metabolites, or more commonly natural products, is incomplete and the understanding of natural product-mediated intracellular dialog is in its infancy. Here, we highlight the present state of bacterial metabolomics including compou...
Source: Current Opinion in Chemical Biology - December 1, 2014 Category: Biochemistry Authors: Sidebottom AM, Carlson EE Tags: Curr Opin Chem Biol Source Type: research

Tools for visualizing cell-cell 'interactomes'
Abstract Cellular communication drives diverse aspects of organismal biology ranging from immune function to memory formation. The mechanisms by which cells transact information in vivo, though, are not completely understood. This is due, in part, to a lack of tools for observing collections of cells in their native habitats. New optical probes are being crafted to image networks of cell-cell interactions (i.e., 'interactomes') in tissues and live organisms. Examples of these probes-and their use in visualizing cell contacts and macroscopic cell networks-are highlighted. PMID: 25461730 [PubMed - as supplied b...
Source: Current Opinion in Chemical Biology - December 1, 2014 Category: Biochemistry Authors: Porterfield WB, Prescher JA Tags: Curr Opin Chem Biol Source Type: research

Next-generation sequencing and protein mass spectrometry for the comprehensive analysis of human cellular and serum antibody repertoires.
Abstract Recent developments of high-throughput technologies are enabling the molecular-level analysis and bioinformatic mining of antibody-mediated (humoral) immunity in humans at an unprecedented level. These approaches explore either the sequence space of B-cell receptor repertoires using next-generation deep sequencing (BCR-seq), or the amino acid identities of antibody in blood using protein mass spectrometry (Ig-seq), or both. Generalizable principles about the molecular composition of the protective humoral immune response are being defined, and as such, the field could supersede traditional methods for the...
Source: Current Opinion in Chemical Biology - November 25, 2014 Category: Biochemistry Authors: Lavinder JJ, Horton AP, Georgiou G, Ippolito GC Tags: Curr Opin Chem Biol Source Type: research

Chemical methods for the proteome-wide identification of posttranslationally modified proteins.
Abstract Thousands of proteins are subjected to posttranslational modifications that can have dramatic effects on their functions. Traditional biological methods have struggled to address some of the challenges inherit in the unbiased identification of certain posttranslational modifications. As with many areas of biological discovery, the development of chemoselective and bioorthogonal reactions and chemical probes has transformed our ability to selectively label and enrich a wide variety of posttranslational modifications. Collectively, these efforts are making significant contributions to the goal of mapping th...
Source: Current Opinion in Chemical Biology - November 15, 2014 Category: Biochemistry Authors: Chuh KN, Pratt MR Tags: Curr Opin Chem Biol Source Type: research

Synthesis and screening of small-molecule α-helix mimetic libraries targeting protein-protein interactions.
Synthesis and screening of small-molecule α-helix mimetic libraries targeting protein-protein interactions. Curr Opin Chem Biol. 2014 Nov 15;24C:38-47 Authors: Moon H, Lim HS Abstract α-Helices are the most common protein secondary structure and play a key role in mediating many protein-protein interactions (PPIs) by serving as recognition motifs. Given that aberrant α-helix-mediated PPIs are linked to various disease states, targeting such interactions with small-molecules represents an attractive strategy to develop therapeutic candidates for the related diseases. Over the last dec...
Source: Current Opinion in Chemical Biology - November 15, 2014 Category: Biochemistry Authors: Moon H, Lim HS Tags: Curr Opin Chem Biol Source Type: research

Global profiling of protein lipidation using chemical proteomic technologies.
Abstract Protein lipidation is unique amongst post-translational modifications (PTMs) in enabling direct interaction with cell membranes, and is found in every form of life. Lipidation is important in normal function and in disease, but its intricate interplay with disease context presents a challenging for drug development. Global whole-proteome profiling of protein lipidation lies beyond the range of standard methods, but is well-suited to metabolic tagging with small 'clickable' chemical reporters that do not disrupt metabolism and function; chemoselective reactions are then used to add multifunctional labels e...
Source: Current Opinion in Chemical Biology - November 15, 2014 Category: Biochemistry Authors: Tate EW, Kalesh KA, Lanyon-Hogg T, Storck EM, Thinon E Tags: Curr Opin Chem Biol Source Type: research

15 years of zebrafish chemical screening.
Abstract In 2000, the first chemical screen using living zebrafish in a multi-well plate was reported. Since then, more than 60 additional screens have been published describing whole-organism drug and pathway discovery projects in zebrafish. To investigate the scope of the work reported in the last 14 years and to identify trends in the field, we analyzed the discovery strategies of 64 primary research articles from the literature. We found that zebrafish screens have expanded beyond the use of developmental phenotypes to include behavioral, cardiac, metabolic, proliferative and regenerative endpoints. Additional...
Source: Current Opinion in Chemical Biology - November 15, 2014 Category: Biochemistry Authors: Rennekamp AJ, Peterson RT Tags: Curr Opin Chem Biol Source Type: research

Protein amino-terminal modifications and proteomic approaches for N-terminal profiling.
Abstract Amino-/N-terminal processing is a crucial post-translational modification affecting almost all proteins. In addition to altering the chemical properties of the N-terminus, these modifications affect protein activation, conversion, and degradation, which subsequently lead to diversified biological functions. The study of N-terminal modifications is of increasing interest; especially since modifications such as proteolytic truncation or pyroglutamate formation have been linked to disease processes. During the past decade, mass spectrometry has played an important role in facilitating the investigation of N-...
Source: Current Opinion in Chemical Biology - November 15, 2014 Category: Biochemistry Authors: Lai ZW, Petrera A, Schilling O Tags: Curr Opin Chem Biol Source Type: research

Chemical proteomics approaches to examine novel histone posttranslational modifications.
Abstract Histone posttranslational modifications (PTMs) play key roles in the regulation of many fundamental cellular processes, such as gene transcription, DNA damage repair and chromosome segregation. Significant progress has been made on the detection of a large variety of PTMs on histones. However, the identification of these PTMs' regulating enzymes (i.e. 'writers' and 'erasers') and functional binding partners (i.e. 'readers') have been a relatively slow-paced process. As a result, cellular functions and regulatory mechanisms of many histone PTMs, particularly the newly identified ones, remain poorly underst...
Source: Current Opinion in Chemical Biology - November 15, 2014 Category: Biochemistry Authors: Li X, Li XD Tags: Curr Opin Chem Biol Source Type: research

Live-cell bioorthogonal Raman imaging.
Abstract Live-cell microscopy demands high specificity, sensitivity, and minimal perturbation to the biomolecules of interest. Meeting all these criteria has been challenging in cellular imaging. Toward this goal, a bioorthogonal Raman imaging method has recently emerged by exploiting small Raman reporters that possess Raman signals that do not overlap with the naturally existing biomolecules in the cells. The Raman reporters are metabolically incorporated into the target biomolecules for direct visualization. Herein, we review recent advances in the methodological development and the proof-of-concept applications...
Source: Current Opinion in Chemical Biology - November 15, 2014 Category: Biochemistry Authors: Hong S, Lin L, Xiao M, Chen X Tags: Curr Opin Chem Biol Source Type: research

TNFR1-activated NF-κB signal transduction: regulation by the ubiquitin/proteasome system.
TNFR1-activated NF-κB signal transduction: regulation by the ubiquitin/proteasome system. Curr Opin Chem Biol. 2014 Nov 12;23C:71-77 Authors: Wertz IE Abstract The Tumor Necrosis Factor Receptor-1 (TNFR1) is a central regulator of inflammation, cell death, and cellular proliferation. As such, alterations in TNFR1 signaling are associated with numerous diseases ranging from autoimmune syndromes to cancer. Understanding the regulation of TNFR1 signaling is therefore of considerable importance. The transduction of signaling events in the TNFR1 pathway - from ligand binding through transcriptional r...
Source: Current Opinion in Chemical Biology - November 12, 2014 Category: Biochemistry Authors: Wertz IE Tags: Curr Opin Chem Biol Source Type: research

Covalent protein modification: the current landscape of residue-specific electrophiles.
Abstract Functional amino acids that play critical roles in catalysis and regulation are known to display elevated nucleophilicity and can be selectively targeted for covalent modification by reactive electrophiles. Chemical-proteomic platforms, such as activity-based protein profiling (ABPP), exploit this reactivity by utilizing chemical probes to covalently modify active-site residues to inform on the functional state of enzymes within complex proteomes. These and other applications rely on the availability of a diverse array of electrophiles and detailed knowledge of the reactivity and amino-acid selectivity of...
Source: Current Opinion in Chemical Biology - November 11, 2014 Category: Biochemistry Authors: Shannon DA, Weerapana E Tags: Curr Opin Chem Biol Source Type: research

Proteome sequencing goes deep.
Abstract Advances in mass spectrometry (MS) have transformed the scope and impact of protein characterization efforts. Identifying hundreds of proteins from rather simple biological matrices, such as yeast, was a daunting task just a few decades ago. Now, expression of more than half of the estimated ∼20000 human protein coding genes can be confirmed in record time and from minute sample quantities. Access to proteomic information at such unprecedented depths has been fueled by strides in every stage of the shotgun proteomics workflow-from sample processing to data analysis-and promises to revolutionize our un...
Source: Current Opinion in Chemical Biology - November 8, 2014 Category: Biochemistry Authors: Richards AL, Merrill AE, Coon JJ Tags: Curr Opin Chem Biol Source Type: research

In vivo continuous directed evolution.
Abstract The development and application of methods for the laboratory evolution of biomolecules has rapidly progressed over the last few decades. Advancements in continuous microbe culturing and selection design have facilitated the development of new technologies that enable the continuous directed evolution of proteins and nucleic acids. These technologies have the potential to support the extremely rapid evolution of biomolecules with tailor-made functional properties. Continuous evolution methods must support all of the key steps of laboratory evolution - translation of genes into gene products, selection or ...
Source: Current Opinion in Chemical Biology - November 7, 2014 Category: Biochemistry Authors: Badran AH, Liu DR Tags: Curr Opin Chem Biol Source Type: research

Editorial Overview: Molecular immunology: Targeting the immune system.
PMID: 25467126 [PubMed - as supplied by publisher] (Source: Current Opinion in Chemical Biology)
Source: Current Opinion in Chemical Biology - November 7, 2014 Category: Biochemistry Authors: Groettrup M, Ovaa H Tags: Curr Opin Chem Biol Source Type: research

Catching a DUB in the act: novel ubiquitin-based active site directed probes.
We describe recent advances and discuss future directions in reagent development for studying DUBs. PMID: 25461387 [PubMed - as supplied by publisher] (Source: Current Opinion in Chemical Biology)
Source: Current Opinion in Chemical Biology - November 3, 2014 Category: Biochemistry Authors: Ekkebus R, Flierman D, Geurink PP, Ovaa H Tags: Curr Opin Chem Biol Source Type: research

Chemical reporters for exploring ADP-ribosylation and AMPylation at the host-pathogen interface.
Abstract Bacterial pathogens secrete protein toxins and effectors that hijack metabolites to covalently modify host proteins and interfere with their function during infection. Adenosine metabolites, such as nicotinamide adenine dinucleotide (NAD) and adenosine triphosphate (ATP), have in particular been co-opted by these secreted virulence factors to reprogram host pathways. While some host targets for secreted virulence factors have been identified, other toxin and effector substrates have been elusive, which require new methods for their characterization. In this review, we focus on chemical reporters based on ...
Source: Current Opinion in Chemical Biology - October 27, 2014 Category: Biochemistry Authors: Westcott NP, Hang HC Tags: Curr Opin Chem Biol Source Type: research

Advances in the directed evolution of proteins.
Abstract Natural evolution has produced a great diversity of proteins that can be harnessed for numerous applications in biotechnology and pharmaceutical science. Commonly, specific applications require proteins to be tailored by protein engineering. Directed evolution is a type of protein engineering that yields proteins with the desired properties under well-defined conditions and in a practical time frame. While directed evolution has been employed for decades, recent creative developments enable the generation of proteins with previously inaccessible properties. Novel selection strategies, faster techniques, t...
Source: Current Opinion in Chemical Biology - October 10, 2014 Category: Biochemistry Authors: Lane MD, Seelig B Tags: Curr Opin Chem Biol Source Type: research

Semi-synthesis of chemokines.
Abstract Protein ligation allows the introduction of a wide range of modifications into proteins that are not accessible by mutagenesis. This includes non-proteinogenic amino acids and even backbone modification. This review summarizes recent reports on modified chemokine variants by ligation technologies and includes the development of the first protein with a full secondary structure motif exchanged by a helix that exclusively consists of β-amino acids. Furthermore the first protein activatable by light by rearrangement of a depsi-peptide bond is described. Combining different ligation methods, immobilizati...
Source: Current Opinion in Chemical Biology - October 6, 2014 Category: Biochemistry Authors: Beck-Sickinger AG, Panitz N Tags: Curr Opin Chem Biol Source Type: research

Serine/threonine ligation for the chemical synthesis of proteins.
Abstract Advances in the development of efficient peptide ligation methods have enabled the total synthesis of complex proteins to be successfully undertaken. Recently, a Ser/Thr ligation has emerged as a new tool in synthetic protein chemistry. The chemoselective reaction between an N-terminal serine or threonine of an unprotected peptide segment and a C-terminal salicylaldehyde ester of another unprotected peptide segment gives rise to an N,O-benzylidene acetal linked product, which upon acidolysis produces a native peptide bond at the site of ligation. Ser/Thr ligation has been used for the synthesis of the hum...
Source: Current Opinion in Chemical Biology - October 6, 2014 Category: Biochemistry Authors: Lee CL, Li X Tags: Curr Opin Chem Biol Source Type: research

New chemistries for chemoselective peptide ligations and the total synthesis of proteins.
Abstract The identification of fast, chemoselective bond-forming reactions is one of the major contemporary challenges in chemistry. The requirements of the native chemical ligation - an N-terminal cysteine and C-terminal thioesters - have encouraged a search for alternative amide-forming ligation reactions. Among successful alternatives to native chemical ligation, are the α-ketoacid-hydroxylamine ligation with 5-oxaproline and, serine/threonine ligation, and potassium acyltrifluoroborate (KAT) ligation. In addition, the KAT ligation, along with the non-amide forming alkyne-azide ligation, is very useful fo...
Source: Current Opinion in Chemical Biology - October 6, 2014 Category: Biochemistry Authors: Harmand TJ, Murar CE, Bode JW Tags: Curr Opin Chem Biol Source Type: research

Sortase-mediated ligations for the site-specific modification of proteins.
Abstract Sortase-mediated ligation (SML) is one of the most commonly used techniques for the site-specific modification of proteins. Here, a brief overview on advantages and limitations of this technology in comparison with other chemoselective protein modification techniques is provided and successful approaches that extend the application range of SML are discussed. PMID: 25299574 [PubMed - as supplied by publisher] (Source: Current Opinion in Chemical Biology)
Source: Current Opinion in Chemical Biology - October 6, 2014 Category: Biochemistry Authors: Schmohl L, Schwarzer D Tags: Curr Opin Chem Biol Source Type: research

Decoration of proteins with sugar chains: recent advances in glycoprotein synthesis.
Abstract Chemical or chemoenzymatic synthesis is an emerging approach to produce homogeneous glycoproteins, which are hard to obtain by conventional biotechnology methods. Recent advances in the synthetic methodologies for the decoration of protein molecules with oligosaccharides provide several remarkable syntheses of homogeneous glycoproteins. This short review highlights several of the latest syntheses of glycoproteins including therapeutically important glycoproteins, a highly glycosylated protein, and unnatural glycoproteins in order to illustrate the power of the modern glycoprotein synthesis. Structurally d...
Source: Current Opinion in Chemical Biology - October 4, 2014 Category: Biochemistry Authors: Okamoto R, Izumi M, Kajihara Y Tags: Curr Opin Chem Biol Source Type: research

More than add-on: chemoselective reactions for the synthesis of functional peptides and proteins.
Abstract The quest to enlarge the molecular space of functional biomolecules has led to the discovery of selective, mild and high-yielding chemical reactions for the modification of peptides and proteins. These conjugation methods have recently become even more advanced with the advent of modern biochemical techniques such as unnatural protein expression or enzymatic reactions that allow the site-specific modification of proteins. Within this overview, we will highlight recent examples that describe the site-specific functionalization of proteins. These examples go beyond the straightforward attachment of a given ...
Source: Current Opinion in Chemical Biology - October 3, 2014 Category: Biochemistry Authors: Schumacher D, Hackenberger CP Tags: Curr Opin Chem Biol Source Type: research

Recent extensions to native chemical ligation for the chemical synthesis of peptides and proteins.
Abstract Native chemical ligation continues to play a pivotal role in the synthesis of increasingly complex peptide and protein targets twenty years after its initial report. This opinion article will highlight a number of recent, powerful extensions of the technology that have expanded the scope of the reaction, accelerated ligation rates, enabled chemoselective post-ligation modifications, and streamlined the ligation of multiple peptide fragments. These advances have facilitated the synthesis of a number of impressive protein targets to date and hold great promise for the continued application of native chemica...
Source: Current Opinion in Chemical Biology - October 3, 2014 Category: Biochemistry Authors: Malins LR, Payne RJ Tags: Curr Opin Chem Biol Source Type: research

Towards applications of synthetic genetic polymers in diagnosis and therapy.
Abstract Aptamers are a class of single-stranded nucleic acid ligands that can bind their targets with high specificity and affinities rivalling those of antibodies. First described over 20 years ago by Tuerk & Gold [1] and Ellington & Szostak [2] (who coined the name), their promise as both diagnostic and therapeutic agents remains to be realised. Key problems include the generally low biostability of the standard DNA/RNA or mixed RNA/2'F-DNA backbones under physiological conditions, limited chemical diversity of functional groups on the natural nucleobases, and the difficulty in reliably discovering apta...
Source: Current Opinion in Chemical Biology - October 3, 2014 Category: Biochemistry Authors: Taylor AI, Arangundy-Franklin S, Holliger P Tags: Curr Opin Chem Biol Source Type: research

Integration of biological parts toward the synthesis of a minimal cell.
Abstract Various approaches are taken to construct synthetic cells in the laboratory, a challenging goal that became experimentally imaginable over the past two decades. The construction of protocells, which explores scenarios of the origin of life, has been the original motivations for such projects. With the advent of the synthetic biology era, bottom-up engineering approaches to synthetic cells are now conceivable. The modular design emerges as the most robust framework to construct a minimal cell from natural molecular components. Although significant advances have been made for each piece making this complex ...
Source: Current Opinion in Chemical Biology - October 3, 2014 Category: Biochemistry Authors: Caschera F, Noireaux V Tags: Curr Opin Chem Biol Source Type: research

Targeting B-cell lymphomas with inhibitors of the MALT1 paracaspase.
Abstract The paracaspase MALT1 is an Arg-specific protease that cleaves multiple substrates to promote lymphocyte proliferation and survival. The catalytic activity of MALT1 is normally tightly regulated by antigen receptor triggering, which promotes MALT1 activation by its inducible monoubiquitination-dependent dimerization. Constitutive MALT1 activity is a hallmark of specific subsets of B-cell lymphomas, which are characterized by chromosomal translocations or point mutations that activate MALT1 or its upstream regulators. Recent findings suggest that such lymphomas may be sensitive to treatment with MALT1 inhi...
Source: Current Opinion in Chemical Biology - October 3, 2014 Category: Biochemistry Authors: Hailfinger S, Lenz G, Thome M Tags: Curr Opin Chem Biol Source Type: research

Synthetic relaxins.
Abstract The relaxin subfamily of peptides within the human insulin superfamily consists of seven members including relaxin-2 and relaxin-3. The former is a pleiotropic hormone that is a vasodilator and cardiac stimulant in the cardiovascular system and an antifibrotic agent whereas the latter is primarily a neuropeptide involved in stress and metabolic control. Both possess the unique three-disulfide heterodimeric peptide structure of insulin. Consequently, the synthesis, both chemical and biological, of relaxin-2 and relaxin-3 has long represented a special challenge to further understanding their structural and...
Source: Current Opinion in Chemical Biology - October 1, 2014 Category: Biochemistry Authors: Hossain MA, Wade JD Tags: Curr Opin Chem Biol Source Type: research

Mirror image proteins.
Abstract Proteins composed entirely of unnatural d-amino acids and the achiral amino acid glycine are mirror image forms of their native l-protein counterparts. Recent advances in chemical protein synthesis afford unique and facile synthetic access to domain-sized mirror image d-proteins, enabling protein research to be conducted through 'the looking glass' and in a way previously unattainable. d-Proteins can facilitate structure determination of their native l-forms that are difficult to crystallize (racemic X-ray crystallography); d-proteins can serve as the bait for library screening to ultimately yield pharmac...
Source: Current Opinion in Chemical Biology - October 1, 2014 Category: Biochemistry Authors: Zhao L, Lu W Tags: Curr Opin Chem Biol Source Type: research

Asymmetric catalysis with short-chain peptides.
Abstract Within this review article we describe recent developments in asymmetric catalysis with peptides. Numerous peptides have been established in the past two decades that catalyze a wide variety of transformations with high stereoselectivities and yields, as well as broad substrate scope. We highlight here catalytically active peptides, which have addressed challenges that had thus far remained elusive in asymmetric catalysis: enantioselective synthesis of atropoisomers and quaternary stereogenic centers, regioselective transformations of polyfunctional substrates, chemoselective transformations, catalysis in...
Source: Current Opinion in Chemical Biology - September 29, 2014 Category: Biochemistry Authors: Lewandowski B, Wennemers H Tags: Curr Opin Chem Biol Source Type: research

Experimental fitness landscapes to understand the molecular evolution of RNA-based life.
Abstract In evolutionary biology, the relationship between genotype and Darwinian fitness is known as a fitness landscape. These landscapes underlie natural selection, so understanding them would greatly improve quantitative prediction of evolutionary outcomes, guiding the development of synthetic living systems. However, the structure of fitness landscapes is essentially unknown. Our ability to experimentally probe these landscapes is physically limited by the number of different sequences that can be identified. This number has increased dramatically in the last several years, leading to qualitatively new invest...
Source: Current Opinion in Chemical Biology - September 27, 2014 Category: Biochemistry Authors: Athavale SS, Spicer B, Chen IA Tags: Curr Opin Chem Biol Source Type: research

Human T cells use CD1 and MR1 to recognize lipids and small molecules.
Abstract For decades immunologists thought that T cells solely recognize peptides bound to Major Histocompatibility Complex (MHC) proteins. Therefore, nearly all medical technology that seeks to measure and manipulate human T cells during immunization, infection, allergy and autoimmune diseases relies on peptide antigens. Newer insights into αβ and γδ T cell activation by CD1 or MR1 proteins greatly expand the biochemical range of T cell antigens to include lipids and non-peptidic small molecules. Moving beyond in vitro studies, the recent development of human CD1a, CD1b, CD1c and MR1 tetram...
Source: Current Opinion in Chemical Biology - September 27, 2014 Category: Biochemistry Authors: Layre E, de Jong A, Moody DB Tags: Curr Opin Chem Biol Source Type: research

Use of enhanced interleukin-2 formulations for improved immunotherapy against cancer.
Abstract The use of interleukin-2 (IL-2) for the stimulation of an effector immune response against metastatic cancer dates back to the early 1980s. Administration of unmodified IL-2, either alone or together with antigen-specific approaches, has resulted in remarkably long-term survival of some patients suffering from metastatic melanoma. However, such treatment is usually hampered by the appearance of toxic adverse effects, which has motivated the engineering of modified IL-2 formulations showing reduced toxicity while being more potent at stimulating anti-tumor effector immune cells. In this review we summarize...
Source: Current Opinion in Chemical Biology - September 27, 2014 Category: Biochemistry Authors: Rosalia RA, Arenas-Ramirez N, Bouchaud G, Raeber ME, Boyman O Tags: Curr Opin Chem Biol Source Type: research