1,154 results match your criteria noncanonical amino


Genetic Incorporation of  ε-N-benzoyllysine by Engineering Methanomethylophilus alvus Pyrrolysyl-tRNA Synthetase.

Chembiochem 2021 Jun 12. Epub 2021 Jun 12.

University of California San Francisco, Pharmaceutical Chemistry, 555 Mission Bay Blvd South, 94158, San Francisco, UNITED STATES.

Protein post-translational modifications regulate protein structure and function. Lysine benzoylation is a new type of histone mark with unique physiological relevance. To construct proteins with this modification site-specifically introduced, here we generated orthogonal tRNA Pyl -MaBzKRS pairs by engineering  Methanomethylophilus alvus  pyrrolysyl-tRNA synthetase, allowing the genetic incorporation of ε-N-benzoyllysine (BzK) into proteins with high efficiency in  E. Read More

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Insight into the sequence-specific elements leading to increased DNA bending and ligase-mediated circularization propensity by antitumor trabectedin.

J Comput Aided Mol Des 2021 Jun 9. Epub 2021 Jun 9.

Area of Pharmacology, Department of Biomedical Sciences and "Unidad Asociada IQM-CSIC", School of Medicine and Health Sciences, University of Alcalá, 28805, Alcalá de Henares, Madrid, Spain.

DNA curvature is the result of a combination of both intrinsic features of the double helix and external distortions introduced by the environment and the binding of proteins or drugs. The propensity of certain double-stranded DNA (dsDNA) sequences to bend is essential in crucial biological processes, such as replication and transcription, in which proteins are known to either recognize noncanonical DNA conformations or promote their formation upon DNA binding. Trabectedin (Yondelis®) is a clinically used antitumor drug which, following covalent bond formation with the 2-amino group of guanine, induces DNA curvature and enhances the circularization ratio, upon DNA ligation, of several dsDNA constructs but not others. Read More

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Sustainable one-pot chemo-enzymatic synthesis of chiral furan amino acid from biomass via magnetic solid acid and threonine aldolase.

Bioresour Technol 2021 May 29;337:125344. Epub 2021 May 29.

Key Laboratory of Industrial Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi 214122, Jiangsu, China. Electronic address:

Sustainable synthesis of valuable noncanonical amino acids from renewable feedstocks is of great importance. Here, a feasible chemo-enzymatic procedure was developed for the synthesis of chiral β-(2-furyl)serine from biomass catalyzed by a solid acid catalyst and immobilized E. coli whole-cell harboring l-threonine aldolase. Read More

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Functional Consequences of Mutations in Myeloproliferative Neoplasms.

Hemasphere 2021 Jun 1;5(6):e578. Epub 2021 Jun 1.

Ludwig Institute for Cancer Research, Brussels, Belgium.

Driver mutations occur in Janus kinase 2 (), thrombopoietin receptor (), and calreticulin () in BCR-ABL1 negative myeloproliferative neoplasms (MPNs). From mutations leading to one amino acid substitution in JAK2 or MPL, to frameshift mutations in CALR resulting in a protein with a different C-terminus, all the mutated proteins lead to pathologic and persistent JAK2-STAT5 activation. The most prevalent mutation, JAK2 V617F, is associated with the 3 entities polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF), while and mutations are associated only with ET and MF. Read More

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Sense codon reassignment enables viral resistance and encoded polymer synthesis.

Science 2021 06;372(6546):1057-1062

Medical Research Council Laboratory of Molecular Biology, Cambridge, UK.

It is widely hypothesized that removing cellular transfer RNAs (tRNAs)-making their cognate codons unreadable-might create a genetic firewall to viral infection and enable sense codon reassignment. However, it has been impossible to test these hypotheses. In this work, following synonymous codon compression and laboratory evolution in , we deleted the tRNAs and release factor 1, which normally decode two sense codons and a stop codon; the resulting cells could not read the canonical genetic code and were completely resistant to a cocktail of viruses. Read More

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Photophysical Properties of Noncanonical Amino Acid 7-Fluorotryptophan Sharply Different from Those of Canonical Derivative Tryptophan: Spectroscopic and Quantum Chemical Calculations.

J Phys Chem B 2021 Jun 3. Epub 2021 Jun 3.

School of Chemical Sciences, Indian Association for the Cultivation of Sciences, Kolkata 700032, India.

Due to the limited number of naturally existing canonical amino acids, several noncanonical amino acids have been designed to understand the diverse complex biological functions. Fluorinated amino acids are one of the important noncanonical amino acids that have been used to understand the different complex processes of proteins. In this study, the photophysical properties of the noncanonical amino acid 7-fluorotryptophan (7F-Trp) in different solvents have been investigated using extensive spectroscopic as well as quantum chemical calculation methods and compared with those of tryptophan (Trp). Read More

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Stereoselective Synthesis of b-Branched Aromatic a-Amino Acids via Biocatalytic Dynamic Kinetic Resolution.

Angew Chem Int Ed Engl 2021 May 30. Epub 2021 May 30.

The Scripps Research Institute, Chemistry, 130 Scripps Way, 33458, Jupiter, UNITED STATES.

b -branched noncanonical amino acids are valuable molecules in modern drug development efforts. However, they are still challenging to prepare due to the need to set multiple stereocenters in a stereoselective fashion and contemporary methods to achieve this often relies on the use of rare transition metal catalysis with designer ligand. Here, we report a biocatalytic transamination method to prepare a broad range of aromatic b -branched a -amino acids that proceeds with high diastereo- and enantioselectivity. Read More

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Discovery of Hyperstable Noncanonical Plant-Derived Epidermal Growth Factor Receptor Agonist and Analogs.

J Med Chem 2021 Jun 20;64(11):7746-7759. Epub 2021 May 20.

School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.

Here, we report the discovery of the first plant-derived and noncanonical epidermal growth factor receptor (EGFR) agonist, the 36-residue bleogen pB1 from of the Cactaceae family. We show that bleogen pB1 is a low-affinity EGFR agonist using a suite of chemical, biochemical, cellular, and animal experiments which include incisor eruption and wound-healing mouse models. A focused positional scanning pB1 library of Ala- and d-amino acid scans yielded a high-affinity pB1 analog, [K29k]pB1, with a 60-fold-improved EGFR affinity and mitogenicity. Read More

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Full incorporation of the noncanonical amino acid hydroxylysine as a surrogate for lysine in green fluorescent protein.

Bioorg Med Chem 2021 May 9;41:116207. Epub 2021 May 9.

Universität des Saarlandes, Biologische Experimentalphysik, Naturwissenschaftlich-Technische Fakultät, B2 1, Campus, 66123 Saarbrücken, Germany. Electronic address:

The canonical set of amino acids leads to an exceptionally wide range of protein functionality, nevertheless, this set still exhibits limitations. The incorporation of noncanonical amino acids into proteins can enlarge its functional scope. Although proofreading will counteract the charging of tRNAs with other amino acids than the canonical ones, the translation machinery may still accept noncanonical amino acids as surrogates and incorporate them at the canonically prescribed locations within the protein sequence. Read More

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Novel Mixed NOP/Opioid Receptor Peptide Agonists.

J Med Chem 2021 May 17;64(10):6656-6669. Epub 2021 May 17.

Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Via Luigi Borsari 46, Ferrara 44121, Italy.

The nociceptin/orphanin FQ (N/OFQ)/N/OFQ receptor (NOP) system controls different biological functions including pain and cough reflex. Mixed NOP/opioid receptor agonists elicit similar effects to strong opioids but with reduced side effects. In this work, 31 peptides with the general sequence [Tyr/Dmt,Xaa]N/OFQ(1-13)-NH were synthesized and pharmacologically characterized for their action at human recombinant NOP/opioid receptors. Read More

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Amino acid analog induces stress response in marine .

Appl Environ Microbiol 2021 May 14. Epub 2021 May 14.

Biological Sciences Department, California Polytechnic State University, San Luis Obispo, CA 93407, USA

Characterizing the cell-level metabolic trade-offs that phytoplankton exhibit in response to changing environmental conditions is important for predicting the impact of these changes on marine food web dynamics and biogeochemical cycling. The time-selective proteome-labeling approach, bioorthogonal noncanonical amino acid tagging (BONCAT), has potential to provide insight into differential allocation of resources at the cellular level, especially when coupled with proteomics. However, the application of this technique in marine phytoplankton remains limited. Read More

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Selective MAP1LC3C (LC3C) autophagy requires noncanonical regulators and the C-terminal peptide.

J Cell Biol 2021 Jul 14;220(7). Epub 2021 May 14.

Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH.

LC3s are canonical proteins necessary for the formation of autophagosomes. We have previously established that two paralogs, LC3B and LC3C, have opposite activities in renal cancer, with LC3B playing an oncogenic role and LC3C a tumor-suppressing role. LC3C is an evolutionary late gene present only in higher primates and humans. Read More

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The human WNT5A isoforms display similar patterns of expression but distinct and overlapping activities in normal human osteoblasts.

J Cell Biochem 2021 May 13. Epub 2021 May 13.

Department of Biology, University of North Carolina Greensboro, Greensboro, North Carolina, USA.

WNT5A activates noncanonical Wnt signaling pathways and has critical functions in early development, differentiation, and tissue homeostasis. Two major WNT5A protein isoforms, which in this study we term WNT5A-L(A) and WNT5A-S(B), have been identified that differ by 18 AA at their amino terminus. Functional differences between the isoforms have been indicated in studies utilizing cancer cell lines but the activities of the isoforms in normal cells and during differentiation have not been explored. Read More

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Quantitative Proteomics Reveals that Hsp90 Inhibition Dynamically Regulates Global Protein Synthesis in Leishmania mexicana.

mSystems 2021 May 11;6(3). Epub 2021 May 11.

Department of Biosciences, Durham University, Durham, United Kingdom.

Heat shock protein 90 (Hsp90) is a conserved molecular chaperone responsible for the folding and maturation of nascent proteins. Hsp90 is regarded as a master regulator of protein homeostasis in the cell, and its inhibition affects the functions of a large array of client proteins. The classical Hsp90 inhibitor tanespimycin has shown potent antileishmanial activity. Read More

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Protein Synthesis in Semipermeable Artificial Cells.

ACS Synth Biol 2021 05 10;10(5):1237-1244. Epub 2021 May 10.

Research School of Chemistry, Australian National University, Canberra, ACT 2601, Australia.

A novel cell free protein synthesis (CFPS) system utilizing layer-by-layer (LbL) polymer assembly was developed to reduce the operational cost of conventional CFPS. This yielded an encapsulated cell system, dubbed "eCells", that successfully performs CFPS and allows cost-effective incorporation of noncanonical amino acids into proteins. The use of eCells in CFPS circumvents the need for traditional cell lysate preparation and purification of amino acyl-tRNA synthetases (aaRS) while still retaining the small scale of an reaction. Read More

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Unprecedented Noncanonical Features of the Nonlinear Nonribosomal Peptide Synthetase Assembly Line for WS9326A Biosynthesis.

Angew Chem Int Ed Engl 2021 May 7. Epub 2021 May 7.

Seoul National University, College of Pharmacy, KOREA, REPUBLIC OF.

Systematic inactivation of nonribosomal peptide synthetase (NRPS) domains and translocation of the thioesterase (TE) domain revealed several unprecedented nonlinear NRPS assembly processes during the biosynthesis of the cyclodepsipeptide WS9326A in Streptomyces sp. SNM55. First, two sets of type ΙΙ TE (TEΙΙ)-like enzymes mediate the shuttling of activated amino acids between two sets of stand-alone adenylation (A)-thiolation (T) didomain modules and an 'A-less' condensation (C)-T module with distinctive specificities and flexibilities. Read More

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Coordination of Redox Ions within a Membrane-Binding Peptide: A Tale of Aromatic Rings.

J Phys Chem Lett 2021 May 3;12(18):4392-4399. Epub 2021 May 3.

Department of Applied Science, William & Mary, Williamsburg, Virginia 23185, United States.

The amino-terminal-copper-and-nickel-binding (ATCUN) motif, a tripeptide sequence ending with a histidine, confers important functions to proteins and peptides. Few high-resolution studies have been performed on the ATCUN motifs of membrane-associated proteins and peptides, limiting our understanding of how they stabilize Cu/Ni in membranes. Here, we leverage solid-state NMR to investigate metal-binding to piscidin-1 (P1), a host-defense peptide featuring F1F2H3 as its ATCUN motif. Read More

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Recent Advances in Biocatalysis with Chemical Modification and Expanded Amino Acid Alphabet.

Chem Rev 2021 May 22;121(10):6173-6245. Epub 2021 Apr 22.

Department of Systems Biotechnology, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea.

The two main strategies for enzyme engineering, directed evolution and rational design, have found widespread applications in improving the intrinsic activities of proteins. Although numerous advances have been achieved using these ground-breaking methods, the limited chemical diversity of the biopolymers, restricted to the 20 canonical amino acids, hampers creation of novel enzymes that Nature has never made thus far. To address this, much research has been devoted to expanding the protein sequence space via chemical modifications and/or incorporation of noncanonical amino acids (ncAAs). Read More

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Dual Site-Selective Presentation of Functional Handles on Protein-Engineered Cowpea Chlorotic Mottle Virus-Like Particles.

Bioconjug Chem 2021 May 16;32(5):958-963. Epub 2021 Apr 16.

Eindhoven University of Technology, Institute for Complex Molecular Systems, PO Box 513 (STO 3.41), 5600 MB Eindhoven, The Netherlands.

Protein cages hold much promise as carrier systems in nanomedicine, due to their well-defined size, cargo-loading capacity, and inherent biodegradability. In order to make them suitable for drug delivery, they have to be stable under physiological conditions. In addition, often surface modifications are required, for example, to improve cell targeting or reduce the particle immunogenicity by PEGylation. Read More

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Generation of Fluorescent Versions of Saccharomyces cerevisiae RPA to Study the Conformational Dynamics of Its ssDNA-Binding Domains.

Methods Mol Biol 2021 ;2281:151-168

Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO, USA.

Replication protein A (RPA) is an essential single-stranded DNA (ssDNA)-binding protein that sequesters ssDNA and protects it from nucleolytic degradation. The RPA-ssDNA nucleoprotein acts as a hub to recruit over two dozen DNA metabolic enzymes onto ssDNA to coordinate DNA replication, repair, and recombination. RPA functions as a heterotrimer composed of RPA70, RPA32, and RPA14 subunits and has multiple DNA-binding and protein-interaction domains. Read More

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January 2021

Deciphering the mechanisms of CC-122 resistance in DLBCL via a genome-wide CRISPR screen.

Blood Adv 2021 04;5(7):2027-2039

Bristol Myers Squibb, San Diego, CA.

CC-122 is a next-generation cereblon E3 ligase-modulating agent that has demonstrated promising clinical efficacy in patients with relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL). Mechanistically, CC-122 induces the degradation of IKZF1/3, leading to T-cell activation and robust cell-autonomous killing in DLBCL. We report a genome-wide CRISPR/Cas9 screening for CC-122 in a DLBCL cell line SU-DHL-4 with follow-up mechanistic characterization in 6 DLBCL cell lines to identify genes regulating the response to CC-122. Read More

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A synthetic 5,3-cross-link in the cell wall of rod-shaped Gram-positive bacteria.

Proc Natl Acad Sci U S A 2021 Mar;118(11)

Department of Chemistry, Scripps Research, La Jolla, CA 92037;

Gram-positive bacteria assemble a multilayered cell wall that provides tensile strength to the cell. The cell wall is composed of glycan strands cross-linked by nonribosomally synthesized peptide stems. Herein, we modify the peptide stems of the Gram-positive bacterium with noncanonical electrophilic d-amino acids, which when in proximity to adjacent stem peptides form novel covalent 5,3-cross-links. Read More

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Introducing noncanonical amino acids for studying and engineering bacterial microcompartments.

Curr Opin Microbiol 2021 Jun 1;61:67-72. Epub 2021 Apr 1.

Cell and Molecular Biology Program, University of Arkansas, Fayetteville, AR, USA; Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, AR, USA. Electronic address:

Bacterial microcompartments (BMCs) with selectively permeable shells and encapsulated enzyme cores are well-suited candidates for nano-bioreactors because of their advantages of enhancing pathway flux and protection against toxic products. To better study and engineer protein-based BMCs, a series of protein chemistry approaches are adopted. As one of the most advanced techniques, genetic code expansion can introduce various noncanonical amino acids (ncAAs) with diverse functional groups into target proteins, thus providing powerful tools for protein studies and engineering. Read More

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Discovery of Protein Modifications Using Differential Tandem Mass Spectrometry Proteomics.

J Proteome Res 2021 04 22;20(4):1835-1848. Epub 2021 Mar 22.

Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10021, United States.

Recent studies have revealed diverse amino acid, post-translational, and noncanonical modifications of proteins in diverse organisms and tissues. However, their unbiased detection and analysis remain hindered by technical limitations. Here, we present a spectral alignment method for the identification of protein modifications using high-resolution mass spectrometry proteomics. Read More

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Native Ubiquitin Structural Changes Resulting from Complexation with β-Methylamino-l-alanine (BMAA).

J Am Soc Mass Spectrom 2021 Apr 18;32(4):895-900. Epub 2021 Mar 18.

Chemistry Program, Department of Biomedical and Chemical Engineering and Sciences, Florida Institute of Technology, Melbourne, Florida 32904, United States.

The objective of this research was to investigate potential changes to unfolding energy barriers for ubiquitin in the presence of the noncanonical amino acid β-methylamino-l-alanine (BMAA). Although BMAA has been implicated in neurodegenerative disease, its specific role remains unclear. We hypothesized that formation of a ubiquitin + BMAA noncovalent complex would alter the protein's unfolding dynamics in comparison with native ubiquitin alone or in noncovalent complexes with other amino acids. Read More

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Functionalizing DNA nanostructures with natural cationic amino acids.

Bioact Mater 2021 Sep 27;6(9):2946-2955. Epub 2021 Feb 27.

Institute of Respiratory Diseases, Xinqiao Hospital, Third Military Medical University, 183 Xinqiao Street, Chongqing, 400037, China.

Complexing self-assembled DNA nanostructures with various functional guest species is the key to unlocking new and exciting biomedical applications. Cationic guest species not only induce magnesium-free DNA to self-assemble into defined structures but also endow the final complex nanomaterials with new properties. Herein, we propose a novel strategy that employs naturally occurring cationic amino acids to induce DNA self-assembly into defined nanostructures. Read More

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September 2021

Genetic Encoding of Three Distinct Noncanonical Amino Acids Using Reprogrammed Initiator and Nonsense Codons.

ACS Chem Biol 2021 04 16;16(4):766-774. Epub 2021 Mar 16.

We recently described an orthogonal initiator tRNA (tRNA) that can initiate protein synthesis with noncanonical amino acids (ncAAs) in response to the UAG nonsense codon. Here, we report that a mutant of tRNA (tRNA) can efficiently initiate translation in response to the UAU tyrosine codon, giving rise to proteins with an ncAA at their N-terminus. We show that, in cells expressing tRNA, UAU can function as a dual-use codon that selectively encodes ncAAs at the initiating position and predominantly tyrosine at elongating positions. Read More

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Studying protein folding in health and disease using biophysical approaches.

Emerg Top Life Sci 2021 May;5(1):29-38

National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing 100101, China.

Protein folding is crucial for normal physiology including development and healthy aging, and failure of this process is related to the pathology of diseases including neurodegeneration and cancer. Early thermodynamic and kinetic studies based on the unfolding and refolding equilibrium of individual proteins in the test tube have provided insight into the fundamental principles of protein folding, although the problem of predicting how any given protein will fold remains unsolved. Protein folding within cells is a more complex issue than folding of purified protein in isolation, due to the complex interactions within the cellular environment, including post-translational modifications of proteins, the presence of macromolecular crowding in cells, and variations in the cellular environment, for example in cancer versus normal cells. Read More

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Determinants of genome-wide distribution and evolution of uORFs in eukaryotes.

Nat Commun 2021 02 17;12(1):1076. Epub 2021 Feb 17.

State Key Laboratory of Protein and Plant Gene Research, Center for Bioinformatics, School of Life Sciences, Peking University, Beijing, China.

Upstream open reading frames (uORFs) play widespread regulatory functions in modulating mRNA translation in eukaryotes, but the principles underlying the genomic distribution and evolution of uORFs remain poorly understood. Here, we analyze ~17 million putative canonical uORFs in 478 eukaryotic species that span most of the extant taxa of eukaryotes. We demonstrate how positive and purifying selection, coupled with differences in effective population size (N), has shaped the contents of uORFs in eukaryotes. Read More

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February 2021

A high-performance genetically encoded fluorescent biosensor for imaging physiological peroxynitrite.

Cell Chem Biol 2021 Jan 27. Epub 2021 Jan 27.

Department of Chemistry, University of California, Riverside, Riverside, CA 92521, USA; Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908, USA; Center for Membrane and Cell Physiology, University of Virginia, Charlottesville, VA 22908, USA; Department of Chemistry, University of Virginia, Charlottesville, VA 22904, USA; The UVA Cancer Center, University of Virginia, Charlottesville, VA 22908, USA. Electronic address:

Peroxynitrite is a reactive nitrogen species (RNS) that plays critical roles in signal transduction, stress response, and numerous human diseases. Advanced molecular tools that permit the selective, sensitive, and noninvasive detection of peroxynitrite are essential for understanding its pathophysiological functions. Here, we present pnGFP-Ultra, a high-performance, reaction-based, genetically encodable biosensor for imaging peroxynitrite in live cells. Read More

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January 2021