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Unnatural amino acid

O Stephen Ojo, Brunello Nardone, Stefania F Musolino, Andrew R Neal, Liam Wilson, Tomas Lebl, Alexandra M Z Slawin, David B Cordes, James E Taylor, James H Naismith, Andrew D Smith, Nicholas J Westwood
Alternative sources of potential feedstock chemicals are of increasing importance as the availability of oil decreases. The biopolymer lignin is viewed as a source of useful mono-aromatic compounds as exemplified by the industrial scale production of vanillin from this biomass. Alternative lignin-derived aromatics are available in pure form but to date examples of the use of these types of compounds are rare. Here we address this issue by reporting the conversion of an aromatic keto-alcohol to the anti- and syn-isomers of Descurainolide A...
December 15, 2017: Organic & Biomolecular Chemistry
Mary Rose Hilaire, Bei Ding, Debopreeti Mukherjee, Jianxin Chen, Feng Gai
Herein, we combine several methods to characterize the fibrils formed by a TTR105-115 mutant in which Leu111 is replaced by the unnatural amino acid aspartic acid 4-methyl ester. We find that this mutant peptide exhibits significantly different aggregation behavior than the wild-type peptide: (1) it forms fibrils with a much faster rate, (2) its fibrils lack the long-range helical twists observed in TTR105-115 fibrils, (3) its fibrils exhibit a giant far-UV circular dichroism signal, and (4) its fibrils give rise to an unusual amide I' band consisting of four distinct and sharp peaks...
December 14, 2017: Journal of the American Chemical Society
Pravin C Patil, Frederick A Luzzio, Jarrid M Ronnebaum
The interchangeability of the isoindolinone group as a nitrogen protecting group for amino acid intermediates is demonstrated by the preparation of several natural and unnatural α-amino acid derivatives using a two-carbon N-isoindolinone (phthalimidine) scaffold. Using a selective benzylic oxidation, the N-isoindolinone group is then converted to the N-phthaloyl group for convenient removal (65-98%). For preparation of the isoindolinone products which were to be the substrates for benzylic oxidation, a range of side chains were installed on the isoindolinone-protected glycine equivalent on deprotonation to demonstrate the utility of the N-protected isoindolinone synthon (51-93%)...
September 20, 2017: Tetrahedron Letters
Simone A Costa, Joseph R Simon, Miriam Amiram, Lei Tang, Stefan Zauscher, Eric M Brustad, Farren J Isaacs, Ashutosh Chilkoti
Hydrogel particles are versatile materials that provide exquisite, tunable control over the sequestration and delivery of materials in pharmaceutics, tissue engineering, and photonics. The favorable properties of hydrogel particles depend largely on their size, and particles ranging from nanometers to micrometers are used in different applications. Previous studies have only successfully fabricated these particles in one specific size regime and required a variety of materials and fabrication methods. A simple yet powerful system is developed to easily tune the size of polypeptide-based, thermoresponsive hydrogel particles, from the nano- to microscale, using a single starting material...
December 11, 2017: Advanced Materials
Felix Faschinger, Martin Ertl, Mirjam Zimmermann, Andreas Horner, Markus Himmelsbach, Wolfgang Schöfberger, Günther Knör, Hermann J Gruber
In this study, two new terpyridine-based EuIII complexes were synthesized, the structures of which were optimized for luminescence resonance energy-transfer (LRET) experiments. The complexes showed high quantum yields (32 %); a single long lifetime (1.25 ms), which was not influenced by coupling to protein; very high stability in the presence of chelators such as ethylenediamine-N,N,N',N'-tetraacetate and ethylene glycol-bis(2-aminoethylether)-N,N,N',N'-tetraacetic acid; and no interaction with cofactors such as adenosine triphosphate and guanosine triphosphate...
December 2017: ChemistryOpen
Mira D Liu, Elliot A Warner, Charlotte E Morrissey, Caitlyn W Fick, Taia S Wu, Marya Y Ornelas, Gabriela V Ochoa, Brendan Zhang, Colin M Rathbun, William B Porterfield, Jennifer A Prescher, Aaron Morgan Leconte
Directed evolution has proven to be an invaluable tool for protein engineering; however, there is still a need for developing new approaches to continue to improve the efficiency and efficacy of these methods. Here, we demonstrate a new method for library design that applies a previously developed bioinformatic method, Statistical Coupling Analysis (SCA). SCA uses homologous enzymes to identify amino acid positions that are mutable, functionally important, and engage in synergistic interactions between amino acids...
December 11, 2017: Biochemistry
Jitka Dadová, Kuan-Jung Wu, Patrick G Isenegger, James C Errey, Gonçalo J L Bernardes, Justin M Chalker, Lluís Raich, Carme Rovira, Benjamin G Davis
Biomimicry valuably allows the understanding of the essential chemical components required to recapitulate biological function, yet direct strategies for evaluating the roles of amino acids in proteins can be limited by access to suitable, subtly-altered unnatural variants. Here we describe a strategy for dissecting the role of histidine residues in enzyme active sites using unprecedented, chemical, post-translational side-chain-β,γ C-N bond formation. Installation of dehydroalanine (as a "tag") allowed the testing of nitrogen conjugate nucleophiles in "aza-Michael"-1,4-additions (to "modify")...
November 22, 2017: ACS Central Science
William D G Brittain, Steven L Cobb
The Negishi cross-coupling is a powerful C-C bond-forming reaction widely utilised in many areas of organic synthesis. This review details the use of Negishi cross-couplings in the synthesis of unnatural amino acids. The application of this reaction in the preparation of aromatic, heteroaromatic, and, complex amino acid derivatives are reviewed and presented herein.
December 4, 2017: Organic & Biomolecular Chemistry
Pál Csuka, Vivienn Juhász, Szabolcs Kohári, Alina Filip, Andrea Varga, Péter Sátorhelyi, László Csaba Bencze, Hazel A Barton, Csaba Paizs, Laszlo Poppe
A number of class I lyase-like enzymes including aromatic ammonia-lyases and aromatic 2,3-aminomutases containing the electrophilic 3,5-dihydro-5-methylidene-4H-imidazol-4-one (MIO) catalytic moiety. This study reveals that Pseudomonas fluorescens R124 strain isolated from a nutrient limited cave encodes a histidine ammonia-lyase (HAL), a tyrosine/phenylalanine/histidine ammonia-lyase (XAL) and a phenylalanine 2,3-aminomutase (PAM), and demonstrates that an organism under nitrogen-limited conditions can develop novel nitrogen fixation and transformation pathways to enrich the possibility of the nitrogen metabolism by gaining a PAM via horizontal gene transfer...
November 28, 2017: Chembiochem: a European Journal of Chemical Biology
Yorke Zhang, Jerod L Ptacin, Emil C Fischer, Hans R Aerni, Carolina E Caffaro, Kristine San Jose, Aaron W Feldman, Court R Turner, Floyd E Romesberg
Since at least the last common ancestor of all life on Earth, genetic information has been stored in a four-letter alphabet that is propagated and retrieved by the formation of two base pairs. The central goal of synthetic biology is to create new life forms and functions, and the most general route to this goal is the creation of semi-synthetic organisms whose DNA harbours two additional letters that form a third, unnatural base pair. Previous efforts to generate such semi-synthetic organisms culminated in the creation of a strain of Escherichia coli that, by virtue of a nucleoside triphosphate transporter from Phaeodactylum tricornutum, imports the requisite unnatural triphosphates from its medium and then uses them to replicate a plasmid containing the unnatural base pair dNaM-dTPT3...
November 29, 2017: Nature
Piotr Minkiewicz, Anna Iwaniak, Małgorzata Darewicz
Contemporary peptide science exploits methods and tools of bioinformatics, and cheminformatics. These approaches use different languages to describe peptide structures-amino acid sequences and chemical codes (especially SMILES), respectively. The latter may be applied, e.g., in comparative studies involving structures and properties of peptides and peptidomimetics. Progress in peptide science "in silico" may be achieved via better communication between biologists and chemists, involving the translation of peptide representation from amino acid sequence into SMILES code...
November 27, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Chengcheng Zhang, Kuo-Shyan Lin, François Bénard
Melanoma is a deadly disease at late metastatic stage, and early diagnosis and accurate staging remain the key aspects for managing melanoma. The melanocortin 1 receptor (MC1 R) is overexpressed in primary and metastatic melanomas, and its endogenous ligand, the α-melanocyte-stimulating hormone (αMSH), has been extensively studied for the development of MC1 R-targeted molecular imaging and therapy of melanoma. Natural αMSH is not well suited for this purpose due to low stability in vivo. Unnatural amino acid substitutions substantially stabilized the peptide, while cyclization via lactam bridge and metal coordination further improved binding affinity and stability...
January 2017: Molecular Imaging
Alessandro Contini, Nicola Ferri, Raffaella Bucci, Maria Giovanna Lupo, Emanuela Erba, Maria Luisa Gelmi, Sara Pellegrino
Rac1 GTPase interaction with guanine nucleotide exchange factor Tiam1 is involved in several cancer types and cardiovascular diseases. Although small molecules interfering with their protein-protein interaction (PPI) were identified and studied, the ability of small peptides and peptide mimics acting as Rac1/Tiam1 PPI inhibitors has not been yet explored. Using computational alanine scanning (CAS), the "hot" interfacial residues have been determined allowing the design of a small library of putative PPI inhibitors...
November 27, 2017: Biopolymers
Sarah A Almahboub, Tanja Narancic, Marc Devocelle, Shane T Kenny, William Palmer-Brown, Cormac Murphy, Jasmina Nikodinovic-Runic, Kevin E O'Connor
Terminal modification of peptides is frequently used to improve their hydrophobicity. While N-terminal modification with fatty acids (lipidation) has been reported previously, C-terminal lipidation is limited as it requires the use of linkers. Here we report the use of a biocatalyst for the production of an unnatural fatty amino acid, (S)-2-aminooctanoic acid (2-AOA) with enantiomeric excess > 98% ee and the subsequent use of 2-AOA to modify and improve the activity of an antimicrobial peptide. A transaminase originating from Chromobacterium violaceum was employed with a conversion efficiency 52-80% depending on the ratio of amino group donor to acceptor...
November 25, 2017: Applied Microbiology and Biotechnology
Subhendu Sekhar Bag, Afsana Yashmeen
We report herein the uracil-di-aza-amino acid (U(r)AA) as a new family of molecular scaffold to induce β-hairpin structure with H-bonded β-sheet conformation in a short peptide. This has been demonstrated in two conceptual fluorescent pentapeptides wherein triazolylpyrenyl alanine and/or triazolylmethoxynapthyl alanine ((TPy)AlaDo and/or (TMNap)AlaDo) are embedded into two arms of the uracil-amino acid via an intervening leucine. Conformational analysis by CD, IR, variable temperature and 2D NMR spectroscopy reveals the β-hairpin structures for both the peptides...
November 10, 2017: Bioorganic & Medicinal Chemistry Letters
Fernando P Cossío, Andrea Ruiz-Olalla, Maria de Gracia Retamosa, Abel de Cózar, Tamara Bello
A new three-component diastereo- and enantioselective cyclization reaction is described. The reaction takes place between a ketone, a carboxylic acid and a nitroalkene to yield a bicyclic octahydro-2H-indol-2-one scaffold possessing three chiral centers. This reaction involves a rearrangement of the nitro group under simple thermal conditions. A plausible mechanism is proposed for this new reaction based on DFT calculations and isotope labeling experiments. A new concise enantioselective synthesis of alkaloid (+)-pancracine is presented as an example of the potential of this novel organocatalytic cyclization reaction in the synthesis of natural products...
November 9, 2017: Angewandte Chemie
Qun Zhou
Antibody-drug conjugates (ADCs) have become a promising class of antitumor agents with four conjugates being approved by regulatory agencies for treating cancer patients. To improve the conventional conjugations that are currently applied to generate these heterogeneous products, various site-specific approaches have been developed. These methods couple cytotoxins or chemotherapeutic drugs to specifically defined sites in antibody molecules including cysteine, glutamine, unnatural amino acids, short peptide tags, and glycans...
November 9, 2017: Biomedicines
Stefanie A Baril, Amber L Koenig, Mackenzie W Krone, Katherine I Albanese, Cyndi Qixin He, Ga Young Lee, Kendall N Houk, Marcey L Waters, Eric M Brustad
Trimethyllysine (Kme3) reader proteins are targets for inhibition due to their role in mediating gene expression. Although all such reader proteins bind Kme3 in an aromatic cage, the driving force for binding may differ; some readers exhibit evidence for cation-π interactions whereas others do not. We report a general unnatural amino acid mutagenesis approach to quantify the contribution of individual tyrosines to cation binding using the HP1 chromodomain as a model system. We demonstrate that two tyrosines (Y24 and Y48) bind to a Kme3-histone tail peptide via cation-π interactions, but linear free energy trends suggest they do not contribute equally to binding...
November 20, 2017: Journal of the American Chemical Society
Tatiana Radchenko, Andreas Brink, Yves Siegrist, Christopher Kochansky, Alison Bateman, Fabien Fontaine, Luca Morettoni, Ismael Zamora
Interest in using peptide molecules as therapeutic agents due to high selectivity and efficacy is increasing within the pharmaceutical industry. However, most peptide-derived drugs cannot be administered orally because of low bioavailability and instability in the gastrointestinal tract due to protease activity. Therefore, structural modifications peptides are required to improve their stability. For this purpose, several in-silico software tools have been developed such as PeptideCutter or PoPS, which aim to predict peptide cleavage sites for different proteases...
2017: PloS One
Ivana Drienovská, Lur Alonso-Cotchico, Pietro Vidossich, Agustí Lledós, Jean-Didier Maréchal, Gerard Roelfes
The design of artificial metalloenzymes is a challenging, yet ultimately highly rewarding objective because of the potential for accessing new-to-nature reactions. One of the main challenges is identifying catalytically active substrate-metal cofactor-host geometries. The advent of expanded genetic code methods for the in vivo incorporation of non-canonical metal-binding amino acids into proteins allow to address an important aspect of this challenge: the creation of a stable, well-defined metal-binding site...
October 1, 2017: Chemical Science
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