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Unnatural amino acid

K M Sharnabai, M Krishnamurthy, N R Sagar, L Santhosh, Sureshbabu V Vommina
An efficient oxidative chlorination of thiols to Nα-protected amino alkyl sulfonyl azides is delineated. The reaction involves in situ generation of sulfonyl chloride employing N-chlorosuccinimide and tetrabutylammonium chloride-water in acetonitrile, followed by the reaction with sodium azide. The protocol is simple, straight forward, mild and high yielding. Amino acids with simple as well as bifunctional side chains were used to obtain Nα-protected amino alkyl sulfonyl azides. Further, sulfonyl azides were utilized to synthesize unnatural amino acids via Cu(OAc)2...
November 30, 2016: Protein and Peptide Letters
Heng Chi, Timothy A Keiderling
ß-sheet conformation is promoted in peptides with amphiphilic design, and stable ß-turn formation is favored with the unnatural amino acid DPro followed by a flexible residue, such as Gly. A 19-residue peptide (B3) was synthesized with alternating hydrophobic and hydrophilic residues connected by symmetrical DPro-Gly and Gly-DPro turns. B3 forms an oligomeric aggregate, rich in ß-sheet conformation, which reversibly transforms into unordered structure on heating as evidenced by its temperature dependent IR spectra...
November 29, 2016: Chembiochem: a European Journal of Chemical Biology
Johnathan C Maza, Christina A Howard, Megha A Vipani, Christopher R Travis, Douglas D Young
The ability to introduce or modify protein function has widespread application to multiple scientific disciplines. The introduction of unique unnatural amino acids represents an excellent mechanism to incorporate new functionality; however, this approach is limited by ability of the translational machinery to recognize and incorporate the chemical moiety. To overcome this potential limitation, we aimed to exploit the functionality of existing unnatural amino acids to perform bioorthogonal reactions to introduce the desired protein modification, altering its function...
November 16, 2016: Bioorganic & Medicinal Chemistry Letters
Eden Ozer, Yonatan Chemla, Orr Schlesinger, Haim Yuval Aviram, Inbal Riven, Gilad Haran, Lital Alfonta
Proteins play a crucial role in all living organisms, with the twenty natural amino acids as their building blocks. Unnatural amino acids are synthetic derivatives of these natural building blocks. These amino acids have unique chemical or physical properties as a result of their specific side chain residues. Their incorporation into proteins through ribosomal translation in response to one of the stop codons has opened a new way to manipulate and study proteins by enabling new functionalities, thus expending the genetic code...
November 24, 2016: Biotechnology and Bioengineering
Wei Jiang, Chao-Zhen Xu, Si-Zhi Jiang, Tang-Duo Zhang, Shi-Zhen Wang, Bai-Shan Fang
L-tert-Leucine (L-Tle) and its derivatives are extensively used as crucial building blocks for chiral auxiliaries, pharmaceutically active ingredients, and ligands. Combining with formate dehydrogenase (FDH) for regenerating the expensive coenzyme NADH, leucine dehydrogenase (LeuDH) is continually used for synthesizing L-Tle from α-keto acid. A multilevel factorial experimental design was executed for research of this system. In this work, an efficient optimization method for improving the productivity of L-Tle was developed...
November 19, 2016: Applied Biochemistry and Biotechnology
Nir Qvit, Samuel J S Rubin, Travis J Urban, Daria Mochly-Rosen, Eric R Gross
Natural endogenously occurring peptides exhibit desirable medicinal properties, but are often limited in application by rapid proteolysis and inadequate membrane permeability. However, editing naturally occurring peptide sequences to develop peptidomimetic analogs created a promising class of therapeutics that can augment or inhibit molecular interactions. Here, we discuss a variety of chemical modifications, including l to d isomerization, cyclization, and unnatural amino acid substitution, as well as design strategies, such as attachment to cell-penetrating peptides, which are used to develop peptidomimetics...
November 14, 2016: Drug Discovery Today
Yutao Tian, Marius Aursnes, Trond Vidar Hansen, Jørn Eivind Tungen, Jason D Galpin, Lilia Leisle, Christopher A Ahern, Rong Xu, Stefan H Heinemann, Toshinori Hoshi
Docosahexaenoic acid (DHA), a polyunsaturated ω-3 fatty acid enriched in oily fish, contributes to better health by affecting multiple targets. Large-conductance Ca(2+)- and voltage-gated Slo1 BK channels are directly activated by nanomolar levels of DHA. We investigated DHA-channel interaction by manipulating both the fatty acid structure and the channel composition through the site-directed incorporation of unnatural amino acids. Electrophysiological measurements show that the para-group of a Tyr residue near the ion conduction pathway has a critical role...
November 29, 2016: Proceedings of the National Academy of Sciences of the United States of America
Karin Halbmair, Janine Wegner, Ulf Diederichsen, Marina Bennati
We present the performance of nanometer-range pulse electron paramagnetic resonance distance measurements (pulsed electron-electron double resonance/double electron-electron resonance, PELDOR/DEER) on a transmembrane WALP24 peptide labeled with the semirigid unnatural amino acid 4-(3,3,5,5-tetra-methyl-2,6-dioxo-4-oxylpiperazin-1-yl)-l-phenylglycine (TOPP). Distances reported by the TOPP label are compared to the ones reported by the more standard MTSSL spin label, commonly employed in protein studies. Using high-power pulse electron paramagnetic resonance spectroscopy at Q-band frequencies (34 GHz), we show that in contrast to MTSSL, our label reports one-peak, sharp (Δr ≤ 0...
November 8, 2016: Biophysical Journal
Krzysztof P Bzymek, Kendra A Avery, Yuelong Ma, David A Horne, John C Williams
Herein, multiple crystal structures of meditope peptide derivatives incorporating natural and unnatural amino acids bound to the cetuximab Fab domain are presented. The affinity of each derivative was determined by surface plasmon resonance and correlated to the atomic structure. Overall, it was observed that the hydrophobic residues in the meditope peptide, Phe3, Leu5 and Leu10, could accommodate a number of moderate substitutions, but these invariably reduced the overall affinity and half-life of the interaction...
November 1, 2016: Acta Crystallographica. Section F, Structural Biology Communications
Ayami Kita, Nobumasa Hino, Sakiko Higashi, Kohji Hirota, Ryohei Narumi, Jun Adachi, Kazuaki Takafuji, Kenji Ishimoto, Yoshiaki Okada, Kensaku Sakamoto, Takeshi Tomonaga, Seiji Takashima, Hiroyuki Mizuguchi, Takefumi Doi
The site-specific incorporation of cross-linkable designer amino acids into proteins is useful for covalently bonding protein complexes upon exposure to light. This technology can be used to study networks of protein-protein interactions in living cells; however, to date it has only been applicable for use with a narrow range of cell types, due to the limited availability of plasmid-based transfection protocols. In the present study, we achieved adenovirus-based expression of a variant of an archaeal pyrrolysyl-tRNA synthetase and UAG-recognising tRNA pair, which was used to incorporate unnatural amino acids into proteins at sites defined by in-frame UAG codons within genes...
November 11, 2016: Scientific Reports
Jehad Almaliti, Ayad A Al-Hamashi, Ahmed T Negmeldin, Christin L Hanigan, Lalith Perera, Mary Kay H Pflum, Robert A Casero, L M Viranga Tillekeratne
A number of analogues of the marine-derived histone deacetylase inhibitor largazole incorporating major structural changes in the depsipeptide ring were synthesized. Replacing the thiazole-thiazoline fragment of largazole with a bipyridine group gave analogue 7 with potent cell growth inhibitory activity and an activity profile similar to that of largazole, suggesting that conformational change accompanying switching hybridization from sp3 to sp2at C-7 is well tolerated. Analogue 7 was more class I selective compared to largazole, with at least 464-fold selectivity for class I HDAC proteins over class II HDAC6 compared to a 22-fold selectivity observed with largazole...
November 3, 2016: Journal of Medicinal Chemistry
Andreas Lerchen, Tobias Knecht, Constantin G Daniliuc, Frank Glorius
Herein, we report an unprecedented regioselective and entirely atom-economic cobalt(III)-catalyzed method for the non-annulative, intermolecular carboamination of alkenes. The methodology enables the direct synthesis of unnatural amino acid derivatives and proceeds under redox-neutral conditions with a completely regioselective C-C bond and C-N bond formation. Furthermore, this reaction exemplifies the inherently different mechanistic behavior of the Cp*Co(III) catalyst and its Cp*Rh(III) counterpart, especially towards β-H-elimination...
October 27, 2016: Angewandte Chemie
Tao Peng, Howard C Hang
Over the past years, fluorescent proteins (e.g., green fluorescent proteins) have been widely utilized to visualize recombinant protein expression and localization in live cells. Although powerful, fluorescent protein tags are limited by their relatively large sizes and potential perturbation to protein function. Alternatively, site-specific labeling of proteins with small-molecule organic fluorophores using bioorthogonal chemistry may provide a more precise and less perturbing method. This approach involves site-specific incorporation of unnatural amino acids (UAAs) into proteins via genetic code expansion, followed by bioorthogonal chemical labeling with small organic fluorophores in living cells...
November 2, 2016: Journal of the American Chemical Society
Georg Wandrey, Joel Wurzel, Kyra Hoffmann, Tobias Ladner, Jochen Büchs, Lorenz Meinel, Tessa Lühmann
BACKGROUND: Genetic code expansion has developed into an elegant tool to incorporate unnatural amino acids (uAA) at predefined sites in the protein backbone in response to an amber codon. However, recombinant production and yield of uAA comprising proteins are challenged due to the additional translation machinery required for uAA incorporation. RESULTS: We developed a microtiter plate-based high-throughput monitoring system (HTMS) to study and optimize uAA integration in the model protein enhanced green fluorescence protein (eGFP)...
2016: Journal of Biological Engineering
Lei Wang
The genetic code can be expanded to include unnatural amino acids (Uaas) by engineering orthogonal components involved in protein translation. To be compatible with live cells, side chains of Uaas have been limited to either chemically inert or bio-orthogonal (i.e., nonreactive toward biomolecules) functionalities. To introduce bioreactivity into live systems, the genetic code has recently been engineered to encode a new class of Uaas, the bioreactive Uaas. These Uaas, after being incorporated into proteins, specifically react with target natural amino acid residues via proximity-enabled bioreactivity, enabling the selective formation of new covalent linkages within and between proteins both in vitro and in live systems...
October 6, 2016: New Biotechnology
Shubhendu Palei, Henning D Mootz
Cyclic peptides are highly desired molecules not only for basic research but also for many biomedical and pharmacological applications. Due to their potentially superior physicochemical properties as compared to their linear counterparts, they are considered as ideal candidates for studying protein-protein interactions, among others. Most of the methods developed in recent years to prepare cyclic peptides focus either on a synthetic or a recombinant route. While the former provides access to diversified, noncanonical peptides, including unnatural and D-amino acid, for example, the latter can harness the power of genetic randomization to generate and select from large peptide libraries...
2017: Methods in Molecular Biology
Shaoquan Lin, Naoya Kumagai, Masakatsu Shibasaki
α,α-Disubstituted α-amino acids have attracted increasing interest due to their potential utility as building blocks of unnatural peptides. Herein we document an enantioselective entry to this class of compounds through the direct catalytic addition of acetonitrile to α-iminoesters bearing an N-thiophosphinoyl group. Chiral N-heterocyclic carbene complexes of [Ir(cod)(OMe)]2 catalytically rendered the catalytic generation of α-cyanocarbanions from acetonitrile in combination with Barton's base, followed by enantioselective addition to the imino carbonyl group, delivering a variety of enantioenriched α-cyanomethylated α,α-disubstituted α-amino acid derivatives...
October 18, 2016: Organic & Biomolecular Chemistry
Meilin Tian, Shixin Ye
Allostery is essential to neuronal receptor function, but its transient nature poses a challenge for characterization. The N-terminal domains (NTDs) distinct from ligand binding domains are a major locus for allosteric regulation of NMDA receptors (NMDARs), where different modulatory binding sites have been observed. The inhibitor ifenprodil, and related phenylethanoamine compounds specifically targeting GluN1/GluN2B NMDARs have neuroprotective activity. However, whether they use differential structural pathways than the endogenous inhibitor Zn(2+) for regulation is unknown...
October 7, 2016: Scientific Reports
Quan Gou, Yu-Wen Yang, Zi-Ning Liu, Jun Qin
The first example of intermolecular amination of unactivated C(sp(3) )-H bonds by cyclic alkylamines mediated by Cu(OAc)2 /O2 is reported. This method avoids the use of benzoyloxyamines as the aminating reagent, which are normally prepared from alkylamines in extra steps. A variety of unnatural β(2, 2) -amino acid analogues are synthesized by this simple and efficient procedure. This approach offers a solution to the previous unmet challenge of C(sp(3) )-H/N-H activation for the formation of C(sp(3) )-N bonds...
November 2, 2016: Chemistry: a European Journal
Yi Yang, Haiping Song, Peng R Chen
Protein-protein interactions (PPIs) play pivotal roles in regulation of many biological processes. Conventional methods are capable of investigating stable and strong interactions within protein complexes, but remain difficult for studying dynamic, transient, and weak PPIs. Herein we review photo-affinity unnatural amino acids that can be site-specifically incorporated into a protein of interest to covalently trap noncovalent PPIs under living conditions. A newly developed cleavable photocrosslinker from our group will also be introduced, which facilitated the prey-bait separation for better enrichment and identification of photocrosslinked PPI complexes...
September 26, 2016: IUBMB Life
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