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Current Opinion in Chemical Biology

Vivian T Dien, Sydney E Morris, Rebekah J Karadeema, Floyd E Romesberg
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 counterparts...
September 8, 2018: Current Opinion in Chemical Biology
Lance C Seefeldt, John W Peters, David N Beratan, Brian Bothner, Shelley D Minteer, Simone Raugei, Brian M Hoffman
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.
September 8, 2018: Current Opinion in Chemical Biology
Richard J Payne, Nicolas Winssinger
No abstract text is available yet for this article.
September 7, 2018: Current Opinion in Chemical Biology
Juan D Chavez, James E Bruce
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...
August 30, 2018: Current Opinion in Chemical Biology
Hao Zhu, Tomonori Tamura, Itaru Hamachi
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...
August 28, 2018: Current Opinion in Chemical Biology
Raspudin Saleem-Batcha, Robin Teufel
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...
August 27, 2018: Current Opinion in Chemical Biology
Unverzagt Carlo, Kajihara Yasuhiro
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 have provided access to many glycoproteins with modifications as well as their analogs...
August 23, 2018: Current Opinion in Chemical Biology
Jinfan Wang, Anthony C Forster
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 dogma on rate-limiting steps in protein synthesis in natural cells...
August 17, 2018: Current Opinion in Chemical Biology
Nilesh B Karalkar, Steven A Benner
'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...
August 8, 2018: Current Opinion in Chemical Biology
Rachel E Kelemen, Sarah B Erickson, Abhishek Chatterjee
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...
August 4, 2018: Current Opinion in Chemical Biology
Chanelle C Jumper, Shahnawaz Rafiq, Siwei Wang, Gregory D Scholes
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]...
August 2, 2018: Current Opinion in Chemical Biology
Stacie L Richardson, Kara K Dods, Nicolas A Abrigo, Emil S Iqbal, Matthew Ct Hartman
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 apparatus to artificial building blocks...
August 2, 2018: Current Opinion in Chemical Biology
Irene Coin
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 protein stapling, photo-control of protein conformation, two-dimensional crosslinking, and stabilization of transient and low-affinity protein-protein interactions...
August 2, 2018: Current Opinion in Chemical Biology
John W Peters, David N Beratan, Brian Bothner, R Brian Dyer, Caroline S Harwood, Zachariah M Heiden, Russ Hille, Anne K Jones, Paul W King, Yi Lu, Carolyn E Lubner, Shelley D Minteer, David W Mulder, Simone Raugei, Gerrit J Schut, Lance C Seefeldt, Monika Tokmina-Lukaszewska, Oleg A Zadvornyy, Peng Zhang, Michael Ww Adams
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 bifurcation, forging fundamental parallels with Mitchell's Q cycle and leading to the proposal of metal-based bifurcating enzymes...
August 1, 2018: Current Opinion in Chemical Biology
Pol Arranz-Gibert, Koen Vanderschuren, Farren J Isaacs
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 can be repurposed as new sense codons dedicated for incorporation of nsAAs...
July 30, 2018: Current Opinion in Chemical Biology
Kenya Tajima, Takayuki Katoh, Hiroaki Suga
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 tRNASNN s (S = C or G, N = U, C, A or G) divided a codon box to encode two amino acids, expanding the repertoire to 23...
July 30, 2018: Current Opinion in Chemical Biology
Yonatan Chemla, Eden Ozer, Itay Algov, Lital Alfonta
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...
July 28, 2018: Current Opinion in Chemical Biology
Olke C Uhlenbeck, Jared M Schrader
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 recognition...
July 27, 2018: Current Opinion in Chemical Biology
Mingchao Kang, Yingchun Lu, Sigeng Chen, Feng Tian
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...
July 27, 2018: Current Opinion in Chemical Biology
Oscar Vargas-Rodriguez, Anastasia Sevostyanova, Dieter Söll, Ana Crnković
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 the l-α-amino acid structure (e...
July 27, 2018: Current Opinion in Chemical Biology
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