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Journal: Journal of the American Chemical Society


Chemically modified proteins are invaluable tools for studying the molecular details of biological processes, and they also hold great potential as new therapeutic agents. Several methods have been developed for the site-specific modification of proteins, one of the most widely used being expressed protein ligation (EPL) in which a recombinant α-thioester is ligated to an N-terminal Cys-containing peptide. Despite the widespread use of EPL, the generation and isolation of the required recombinant protein α-thioesters remain challenging. We describe here a new method for the preparation and purification of recombinant protein α-thioesters using engineered versions of naturally split DnaE inteins. This family of autoprocessing enzymes is closely related to the inteins currently used for protein α-thioester generation, but they feature faster kinetics and are split into two inactive polypeptides that need to associate to become active. Taking advantage of the strong affinity between the two split intein fragments, we devised a streamlined procedure for the purification and generation of protein α-thioesters from cell lysates and applied this strategy for the semisynthesis of a variety of proteins including an acetylated histone and a site-specifically modified monoclonal antibody.

Concepts: Protein biosynthesis, Molecular biology, Molecular genetics, DNA, Intein, Proteins, Peptide bond, Protein


Selective catalytic synthesis of Z-olefins has been challenging. Here we describe a method to produce 1,2-disubstituted olefins in high Z selectivity via reductive cross-coupling of alkyl halides with terminal arylalkynes . The method employs inexpensive and non-toxic catalyst (iron(II) bromide) and reductant (zinc). The substrate scope encompasses primary, secondary, and tertiary alkyl halides, and the reaction tolerates a large number of functional groups. The utility of the method is demonstrated in the synthesis of several pharmaceutically relevant molecules. Mechanistic study suggests that the reaction proceeds through an iron-catalyzed anti-selective carbozincation pathway.

Concepts: Hydrohalogenation, Functional group, Chemical reaction, Alkene, Functional groups, Alkane


Complete structural elucidation of natural products is often challenging due to structural complexity and limited availability. This is true for present-day secondary metabolites, but even more for exceptionally preserved secondary metabolites of ancient organisms that potentially provide insights into the evolutionary history of natural products. Here we report the full structure and absolute configuration of the borolithochromes, enigmatic boron-containing pigments from a Jurassic putative red alga, from samples of less than 50 µg using microcryoprobe NMR, CD spectroscopy, and DFT calculations, and reveal their polyke-tide origin. The pigments are identified as spiroborates with two pentacyclic sec-butyl-trihydroxy-methyl-benzo[gh]tetraphen-one ligands and less substituted deriva-tives. The configuration of the sec-butyl group is found to be (S). Because the exceptional benzo[gh]tetraphene scaffold is otherwise only observed in the recently discovered polyke-tide clostrubin from a present-day Clostridium bacterium, the Jurassic borolithochromes now can be unambiguously linked to the modern polyketide, providing evidence that the fossil pigments are almost originally preserved secondary metabolites and suggesting that the pigments in fact may have been produced by an ancient bacterium. The borolithochromes differ fundamentally from previously described boronated polyketides and represent the first boronated aromatic polyketides found so far. Our results demonstrate the potential of microcryoprobe NMR in the analysis of previously little-explored secondary metabolites from ancient organisms and reveal the evolutionary significance of clostrubin-type polyketides.

Concepts: Organism, Cyanobacteria, Bacteria, DNA, Photosynthesis, Fungus, Evolution, Metabolism


The concepts of excited-state aromaticity and anti-aromaticity have in recent years with increasing frequency been invoked to rationalize the photochemistry of cyclic conjugated organic compounds, with the long-term goal of using these concepts to improve the reactivities of such compounds toward different photochemical transformations. In this regard, it is of particular interest to assess how the presence of a benzene motif affects photochemical reactivity, as benzene is well known to completely change its aromatic character in its lowest excited states. Here, we investigate how a benzene motif influences the photoinduced electrocyclization of dithienylethenes, a major class of molecular switches. Specifically, we report on the synthesis of a dithienylbenzene switch where the typical non-aromatic, ethene-like motif bridging the two thienyl units is replaced by a benzene motif, and show that this compound undergoes electrocyclization upon irradiation with UV-light. Furthermore, through a detailed quantum chemical analysis, we demonstrate that the electrocyclization is driven jointly and synergistically by the loss of aromaticity in this motif from the formation of a reactive, anti-aromatic excited state during the initial photoexcitation, and by the subsequent relief of this anti-aromaticity as the reaction progresses from the Franck-Condon region. Overall, we conclude that photoinduced changes in aromaticity facilitate the electrocyclization of dithienylbenzene switches.


Synthetic assembly within living cells represents an innovative way to explore purely chemical tools that can direct and control cellular behaviour. We use a simple and modular platform that is broadly accessible and yet incorporates highly intricate molecular recognition, immolative and rearrangement chemistry. Short bi-modular peptide sequences undergo a programmed sequence of events that can be tailored within the living intracellular environment. Each sequential stage of the pathways beginning with the cellular uptake, intracellular transport and localization imposes distinct structural changes that result in the assembly of fibrillar architectures inside cells. The observation of apoptosis, which is charac-terized by the binding of Annexin V, demonstrates that programmed cell death can be promoted by the peptide assembly. Higher complexity of the assemblies was also achieved by co-assembly of two different sequences, resulting in intrinsi-cally fluorescent architectures. As such, we demonstrate that the in-situ construction of architectures within cells will broaden the community’s perspective towards how structure formation can impact a living system.


Blood transfusions are critically important in many medical procedures but the presence of antigens on red blood cells (RBCs, erythrocytes) means that careful blood-typing must be carried out prior to transfusion to avoid adverse and sometimes fatal reactions following transfusion. Enzymatic removal of the terminal N-acetylgalactosamine or galactose of A- or B- antigens, respectively, yields universal O-type blood, but is inefficient. Starting with the family 98 glycoside hydrolase from Streptococcus pneumoniae SP3-BS71 (Sp3GH98), which cleaves the entire terminal trisaccharide antigenic determinants of both A- and B-antigens from some of the linkages on RBC surface glycans, through several rounds of evolution, we developed variants with vastly improved activity towards some of the linkages that are resistant to cleavage by the wild-type enzyme. The resulting enzyme effects more complete removal of blood group antigens from cell surfaces, demonstrating the potential for engineering enzymes to generate antigen-null blood from donors of various types.

Concepts: Malaria, Transfusion reaction, Blood type, Blood transfusion, ABO blood group system, Hematology, Blood, Red blood cell


We describe the design, synthesis, and antitumor activity of an 18 carbon α,ω-dicarboxylic acid monoconjugated via an ester linkage to paclitaxel (PTX). This 1,18-octadecanedioic acid-PTX (ODDA-PTX) prodrug readily forms a noncovalent complex with human serum albumin (HSA). Preservation of the terminal carboxylic acid moiety on ODDA-PTX enables binding to HSA in the same manner as native long-chain fatty acids (LCFAs), within hydrophobic pockets, maintaining favorable electrostatic contacts between the ω-carboxylate of ODDA-PTX and positively charged amino acid residues of the protein. This carrier strategy for small molecule drugs is based on naturally evolved interactions between LCFAs and HSA, demonstrated here for PTX. ODDA-PTX shows differentiated pharmacokinetics, higher maximum tolerated doses and increased efficacy in vivo in multiple subcutaneous murine xenograft models of human cancer, as compared to two FDA-approved clinical formulations, Cremophor EL-formulated paclitaxel (crPTX) and Abraxane (nanoparticle albumin-bound (nab)-paclitaxel).


Superomniphobic surfaces display contact angles > 150° and low contact angle hysteresis with essentially all contacting liquids. In this work, we report surfaces that display superomniphobicity with a range of different non-Newtonian liquids, in addition to super-omniphobicity with a wide range of Newtonian liquids. Our surfaces possess hierarchical scales of re-entrant texture that significantly reduces the solid-liquid contact area. Virtually all liquids including concentrated organic and inorganic acids, bases and solvents, as well as, vis-coelastic polymer solutions can easily roll-off and bounce on our surfaces. Consequently, they serve as effective chemical shields against virtually all liquids - organic or inorganic, polar or non-polar, Newtonian or non-Newtonian.

Concepts: Viscosity, Solubility, Newtonian fluid, Oxygen, Hysteresis, Angle, Contact angle, Non-Newtonian fluid


Lithium-ion conducting solid electrolytes hold the promise for enabling high-energy battery chemistries and circumventing safety issues of conventional lithium batteries. Achieving the combination of high ionic conductivity and broad electrochemical window in solid electrolytes is a grand challenge for the synthesis of battery materials. Herein we show an enhancement of room-temperature lithium-ion conductivity of 3 orders of magnitude by creating nanostructured Li3PS4. This material has a wide (5 V) electrochemical window and superior chemical stability against lithium metal. The nanoporous structure of Li3PS4 reconciles two vital effects that enhance ionic conductivity: (1) The reduced dimension to nanometer-sized framework stabilizes the high conduction beta phase that occurs at elevated temperatures; and (2) The high surface-to-bulk ratio of nanoporous β-Li3PS4 promotes surface conduction. Manipulating the ionic conductivity of solid electrolytes has far-reaching implications for materials design and synthesis in a broad range of applications such as batteries, fuel-cells, sensors, photovoltaic systems, and so forth.

Concepts: Physical chemistry, Lithium-ion battery, Metal, Electrolysis, Lithium battery, Battery, Electrochemistry, Lithium


We report selective electrocatalytic reduction of carbon dioxide (CO2) to carbon monoxide (CO) on gold (Au) nanoparticles (NPs) in 0.5 M KHCO3 at 25℃. Among monodisperse 4-, 6-, 8-, and 10-nm NPs tested, the 8 nm Au NPs show the maximum Faradaic efficiency (FE) (up to 90% at -0.67 V vs. reversible hydrogen electrode, RHE). Density functional theory (DFT) calculations suggest that the presence of dominant edge sites over corner sites (active for the competitive H2 evolution reaction) on the Au NP surface facilitates the stabilization of the reduction intermediates, such as COOH*, and the formation of CO. This mechanism is further supported by the fact that Au NPs embedded in a matrix of butyl-3-methylimidazolium hexafluorophosphate for more efficient COOH* stabilization exhibit even higher reaction activity (3 A/g mass activity) and selectivity (97% FE) at -0.52 V (vs. RHE). The work demonstrates the great potentials of using monodisperse Au NPs to optimize the available reaction intermediate binding sites for efficient and selective electrocatalytic reduction of CO2 to CO.

Concepts: Electrochemistry, Hydrogen, Redox, Iron, Oxygen, Carbon monoxide, Carbon, Carbon dioxide