LongLarf

Nature Chemistry, Published online: 01 June 2023; doi:10.1038/s41557-023-01224-y

Ribosomal incorporation of non-α-amino acid monomers into proteins is largely restricted to in vitro translation. Now, pyrrolysyl-transfer RNA synthetase variants have been shown to acylate tRNAs with α-thio acids, malonic acids, and N-formyl amino acids. This work represents a key step towards the programmed ribosomal synthesis of sequence-defined non-protein polymers in cellulo.

Nature, Published online: 31 May 2023; doi:10.1038/s41586-023-06000-z

Quinuclidine-pyridone and sulfonamide-pyridone ligands enable transannular γ-methylene C–H arylation of cycloalkane carboxylic acids with a range of ring sizes, bringing us closer to molecular editing of saturated carbocycles.

Synlett
DOI: 10.1055/s-0042-1751444

Dual light-excited ketone/transition-metal catalysis is a rapidly developing field of photochemistry. It allows for versatile functionalizations of C–H or C–X bonds enabled by triplet ketone acting as a hydrogen-atom-abstracting agent, a single-electron acceptor, or a photosensitizer. This review summarizes recent developments of synthetically useful transformations promoted by the synergy between triplet ketone and transition-metal catalysis.1 Introduction2 Triplet Ketone Catalysis via Hydrogen Atom Transfer2.1 Triplet Ketones with Nickel Catalysis2.2 Triplet Ketones with Copper Catalysis2.3 Triplet Ketones with Other Transition-Metal Catalysis3 Triplet Ketone Catalysis via Single-Electron Transfer4 Triplet Ketone Catalysis via Energy Transfer5 Conclusions
[...]

Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

Cooperative chemoenzymatic catalysis has emerged as a uniquely powerful strategy for the synthesis of value-added small molecules and materials. This review will present a selection of recent notable accomplishments in this research area followed by a brief perspective on its promising future.

Abstract

The application of enzymes in synthetic organic chemistry has emerged as a powerful means to generate molecular complexity in a highly selective, efficient, and sustainable manner. While enzymes have increasingly been incorporated into synthetic sequences for numerous academic and industrial applications on their own and in sequential processes, their utility in cooperative catalysis with small molecule catalytic platforms has recently drawn increased attention across the field of organic synthesis. In this review, we present a selection of notable accomplishments in cooperative chemoenzymatic catalysis and provide a perspective on its future directions.

Joining ribosomal subunits with a small RNA linker has recently given rise to tethered ribosomes. Their ability to process orthogonal mRNAs (o-mRNA) independent of endogenous ribosomes allowed the identification of otherwise lethal, gain-of-function mutations. Thus, engineering tethered ribosomes promises to significantly expand the scope of building blocks amenable to translation and, ultimately, enable the sequence-selective synthesis of tailor-made (bio)polymers.

Abstract

The ribosome is the core element of the translational apparatus and displays unrivaled fidelity and efficiency in the synthesis of long polymers with defined sequences and diverse compositions. Repurposing ribosomes for the assembly of nonproteinogenic (bio)polymers is an enticing prospect with implications for fundamental science, bioengineering and synthetic biology alike. Here, we review tethered ribosomes, which feature inseparable large and small subunits that can be evolved for novel function without interfering with native translation. Following a tutorial summary of ribosome structure, function, and biogenesis, we introduce design and optimization strategies for the creation of orthogonal and tethered ribosomes. We also highlight studies, in which (rational) engineering efforts of these designer ribosomes enabled the evolution of new functions. Lastly, we discuss future prospects and challenges that remain for the ribosomal synthesis of tailor-made (bio)polymers.

Towards efficient electrocatalysis of C−N coupling reactions, the accumulation of critical intermediates, i.e., N-containing and C-containing intermediates, must be facilitated. Taking the direct electrosynthesis of cyclohexanone oxime as an example, Fe can serve as an ideal electrode because it can accumulate adsorbed hydroxylamine and cyclohexanone, which is supported by DFT calculations and in situ characterizations.

Abstract

Synthesis of cyclohexanone oxime via the cyclohexanone-hydroxylamine process is widespread in the caprolactam industry, which is an upstream industry for nylon-6 production. However, there are two shortcomings in this process, harsh reaction conditions and the potential danger posed by explosive hydroxylamine. In this study, we presented a direct electrosynthesis of cyclohexanone oxime using nitrogen oxides and cyclohexanone, which eliminated the usage of hydroxylamine and demonstrated a green production of caprolactam. With the Fe electrocatalysts, a production rate of 55.9 g h⁻¹ g_cat ⁻¹ can be achieved in a flow cell with almost 100 % yield of cyclohexanone oxime. The high efficiency was attributed to their ability of accumulating adsorbed hydroxylamine and cyclohexanone. This study provides a theoretical basis for electrocatalyst design for C−N coupling reactions and illuminates the tantalizing possibility to upgrade the caprolactam industry towards safety and sustainability.

The first Cu(I)-peptoid complex is presented here. This complex is based on a helical peptoid incorporating 2,2’-bipyridine (Bipy) ligands pre-organized on the same side of the helix. Interplay between the first and second coordination spheres is demonstrated, where the first coordination sphere is provided by the two Bipy ligands and the second by the helical structure, enabling the high stability of Cu(I).

Abstract

Stabilization of Cu(I) is ubiquitous within native copper proteins. Understanding how to stabilize Cu(I) within synthetic biomimetic systems is therefore desired towards biological applications. Peptoids are an important class of peptodomimetics, that can bind metal ions and stabilize them in their high oxidation state. Thus, to date, they were not used for Cu(I) binding. Here we show how the helical peptoid hexamer, having two 2,2’-bipyridine (Bipy) groups that face the same side of the helix, forms the intramolecular air stable Cu(I) complex. Further study of the binding site by rigorous spectroscopic techniques suggests that Cu(I) is tetracoordinated, binding to only three N atoms from the Bipy ligands and to the N-terminus of the peptoid's backbone. A set of control peptoids and experiments indicates that the Cu(I) stability and selectivity are dictated by the intramolecular binding, forced by the helicity of the peptoid, which can be defined as the second coordination sphere of the metal center.

Nature Chemistry, Published online: 22 May 2023; doi:10.1038/s41557-023-01205-1

In vitro screening of a ribosomally synthesized macrocyclic peptide library containing cyclic γ2,4-amino acids (cγAA) afforded the discovery of potent inhibitors of the SARS-CoV-2 main protease (Mpro). A co-crystal structure revealed the contribution of this cγAA to Mpro binding and the proteolytic stability of these macrocycles.

Benzolactone enamides, a number of which incorporate a methylated oxime moiety, are produced by a range of organisms, and constitute a family of cytotoxic natural products. Here, we determine how this capped oxime group is installed during assembly of the model polyketide lobatamide by a modular trans-AT polyketide synthase and provide molecular insight into the responsible mono-oxygenase domain by X-ray crystallography.

Abstract

Modular trans-acyltransferase polyketide synthases (trans-AT PKSs) are enzymatic assembly lines that biosynthesize complex polyketide natural products. Relative to their better studied cis-AT counterparts, the trans-AT PKSs introduce remarkable chemical diversity into their polyketide products. A notable example is the lobatamide A PKS, which incorporates a methylated oxime. Here we demonstrate biochemically that this functionality is installed on-line by an unusual oxygenase-containing bimodule. Furthermore, analysis of the oxygenase crystal structure coupled with site-directed mutagenesis allows us to propose a model for catalysis, as well as identifying key protein-protein interactions that support this chemistry. Overall, our work adds oxime-forming machinery to the biomolecular toolbox available for trans-AT PKS engineering, opening the way to introducing such masked aldehyde functionalities into diverse polyketides.

Abstract

3-Aminopiperidines are a valuable motif present in small molecule pharmaceuticals and bioactive natural products. Synthesis of these moieties via olefin diamination would be an attractive approach, however significant challenges remain with regards to both regioselectivity and exogenous nucleophile scope. Herein, we report a metal-free olefin diamination via a “heterocyclic group transfer“ (HGT) reaction of I(III) N-HVI reagents, giving rise to 3-aminopiperidines with high selectivity. The HGT strategy leverages heteroarenes as oxidatively masked amine nucleophiles, giving rise to (hetero)arylonium salt products which are isolated via simple trituration and provide a versatile handle for downstream diversification. This represents only the second 6-endo selective I(III)-mediated diamination reaction and mechanistic studies indicate ring opening of an intermediate aziridinium ion is responsible for the 6-endo selectivity.

We present the application of the genetic code expansion technique to achieve the site-specific modification of the sensing region of a nanopore. The rationally designed conformation of unnatural amino acid (UAA) residues provides a favorable geometric orientation for the interactions of peptides and pore. The chemical environment of the sensing region facilitates the direct discrimination of the mixtures of peptides containing hydrophobic amino acids.

Abstract

Conventional protein engineering methods for modifying protein nanopores are typically limited to 20 natural amino acids, which restrict the diversity of the nanopores in structure and function. To enrich the chemical environment inside the nanopore, we employed the genetic code expansion (GCE) technique to site-specifically incorporate the unnatural amino acid (UAA) into the sensing region of aerolysin nanopores. This approach leveraged the efficient pyrrolysine-based aminoacyl-tRNA synthetase-tRNA pair for a high yield of pore-forming protein. Both molecular dynamics (MD) simulations and single-molecule sensing experiments demonstrated that the conformation of UAA residues provided a favorable geometric orientation for the interactions of target molecules and the pore. This rationally designed chemical environment enabled the direct discrimination of multiple peptides containing hydrophobic amino acids. Our work provides a new framework for endowing nanopores with unique sensing properties that are difficult to achieve using classical protein engineering approaches.

Introducing a new bioconjugation method by employing aqueous 1,3-dipolar cycloaddition reaction between nitrile oxide and dehydroalanine is shown. This approach facilitates a mild and fast protein modification without disruption of protein function. In addition, this can be applicable to the installation of a fluorescent molecule on the protein.

Abstract

Here we describe a novel catalyst-free 1,3-dipolar cycloaddition bioconjugation approach for chemical modification of proteins. The dehydroalanine (Dha)-containing protein reacts with nitrile oxides generated in situ through 1,3-dipolar cycloaddition in fully aqueous-buffered systems. This leads to the formation of a new isoxazoline ring at a pre-defined site (Dha) of the protein. Furthermore, the 1-pyrene isoxazoline-installed annexin V acts as a fluorescent probe, which successfully labels the outer cellular membranes of human cholangiocarcinoma (HuCCA-1) cells for detection of apoptosis.

Science, Volume 380, Issue 6646, Page 706-712, May 2023.

Pt(II)−NHC complexes are used in alkene hydrosilylation reactions. Some of the examined compounds display excellent catalytic activity, outperforming Pt(0)−NHC pre-catalysts. Our study explores the catalyst structure-activity relationship and provides new mechanistic insights into this industrially important transformation. A sustainable protocol, featuring efficient platinum removal, allows us to access a series of organosilanes in very good to excellent yields.

Abstract

Herein, we report the catalytic activity of a series of platinum(II) pre-catalysts, bearing N-heterocyclic carbene (NHC) ligands, in the alkene hydrosilylation reaction. Their structural and electronic properties are fully investigated using X-ray diffraction analysis and nuclear magnetic resonance spectroscopy (NMR). Next, our study presents a structure-activity relationship within this group of pre-catalysts and gives mechanistic insights into the catalyst activation step. An exceptional catalytic performance of one of the complexes is observed, reaching a turnover number (TON) of 970 000 and a turnover frequency (TOF) of 40 417 h⁻¹ at 1 ppm catalyst loading. Finally, an attractive solvent-free and open-to-air alkene hydrosilylation protocol, featuring efficient platinum removal (reduction of residual Pt from 582 ppm to 5.8 ppm), is disclosed.