R.B. Leveson-Gower
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[ASAP] Genetically Encoded Phosphine Ligand for Metalloprotein Design
R.B. Leveson-GowerLmrR
Artificial enzymes for artificial photosynthesis
R.B. Leveson-GowerHeterogeneous catalysis = artificial enzymes
Nature Catalysis, Published online: 17 November 2022; doi:10.1038/s41929-022-00873-5
Artificial enzymes capable of catalysing significant transformations are highly desired but usually suffer from limitations in structural design and poor efficiency. Now, a monolayered metal–organic framework is reported as an editable biomimetic platform to achieve exceptional artificial photosynthesis performance.Asymmetric C-Alkylation of Nitroalkanes via Enzymatic Photoredox Catalysis
R.B. Leveson-Gowergot a recemisable stereocentre in your compound? Just change H to Me (Y)
[ASAP] Engineering a Conformationally Switchable Artificial Metalloprotein
[ASAP] Cu-Catalyzed Enantioselective Hydrogermylation: Asymmetric Synthesis of Unnatural β‑Germyl α‑Amino Acids
R.B. Leveson-Goweranyone wanna get germy????
Using enzymes to tame nitrogen-centred radicals for enantioselective hydroamination
Nature Chemistry, Published online: 14 November 2022; doi:10.1038/s41557-022-01083-z
Expanding the biocatalysis toolbox for C–N bond formation is of great value. Now, a biocatalytic amination strategy using a new-to-nature mechanism involving nitrogen-centred radicals has been developed. The transformations are enabled by synergistic photoenzymatic catalysis, providing intra- and intermolecular hydroamination products with high yields and levels of enantioselectivity.Molecular flavin catalysts for C–H functionalisation and derivatisation of dehydroamino acids
DOI: 10.1039/D2SC04341F, Edge Article
Molecular flavin photocatalysts enable the oxidative functionalisation of diene and dehydroamino acid substrates. Covalent catalyst–substrate adducts are formed under the catalysis conditions and react with the persistent radical TEMPO.
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Mutability‐Landscape‐Guided Engineering of l‐Threonine Aldolase Revealing the Prelog Rule in Mediating Diastereoselectivity of C−C Bond Formation
The Prelog rule in l-threonine aldolase holds that when the Cα anion of PLP-Gly attacks the carbonyl carbon atom of the aldehyde from the re-face, the (2S,3S)-configured product is formed, whereas attack from the si-face forms the (2S,3R)-configured product. Guided by this rule, mutants of LTA with improved diastereoselectivity of 99.2 % syn and 97.4 % anti were obtained.
Abstract
l-threonine aldolase (LTA) catalyzes C−C bond synthesis with moderate diastereoselectivity. In this study, with LTA from Cellulosilyticum sp (CpLTA) as an object, a mutability landscape was first constructed by performing saturation mutagenesis at substrate access tunnel amino acids. The combinatorial active-site saturation test/iterative saturation mutation (CAST/ISM) strategy was then used to tune diastereoselectivity. As a result, the diastereoselectivity of mutant H305L/Y8H/V143R was improved from 37.2 % syn to 99.4 % syn . Furthermore, the diastereoselectivity of mutant H305Y/Y8I/W307E was inverted to 97.2 % anti . Based on insight provided by molecular dynamics simulations and coevolution analysis, the Prelog rule was employed to illustrate the diastereoselectivity regulation mechanism of LTA, holding that the asymmetric formation of the C−C bond was caused by electrons attacking the carbonyl carbon atom of the substrate aldehyde from the re or si face. The study would be useful to expand LTA applications and guide engineering of other C−C bond-forming enzymes.
Near-Infrared Photoredox Catalyzed Tryptophan Functionalization for Peptide Stapling and Protein Labeling in Complex Tissue Environments
Selecting Better Biocatalysts by Complementing Recoded Bacteria
An in vivo selection strategy is presented, in which bacteria addicted to non-canonical amino acids (ncAAs) are complemented by enzymes that can yield these building blocks from synthetic precursors. As growth rates under selective conditions correlate with enzyme activities, serial passaging elicited better biocatalysts from populations harboring enzyme libraries. The platform was used to improve the activity of carbamoylases for ncAA-precursors.
Abstract
In vivo selections are powerful tools for the directed evolution of enzymes. However, the need to link enzymatic activity to cellular survival makes selections for enzymes that do not fulfill a metabolic function challenging. Here, we present an in vivo selection strategy that leverages recoded organisms addicted to non-canonical amino acids (ncAAs) to evolve biocatalysts that can provide these building blocks from synthetic precursors. We exemplify our platform by engineering carbamoylases that display catalytic efficiencies more than five orders of magnitude higher than those observed for the wild-type enzyme for ncAA-precursors. As growth rates of bacteria under selective conditions correlate with enzymatic activities, we were able to elicit improved variants from populations by performing serial passaging. By requiring minimal human intervention and no specialized equipment, we surmise that our strategy will become a versatile tool for the in vivo directed evolution of diverse biocatalysts.
In Vivo Biocatalytic Cascades Featuring an Artificial‐Enzyme‐Catalysed New‐to‐Nature Reaction
We report in vivo biocatalytic cascade reactions comprising a combination of canonical enzyme-catalysed reactions with an artificial-enzyme-catalysed new-to-nature reaction. The artificial enzyme contains a genetically encoded unnatural catalytic residue, which catalyses the formation of a hydrazone product from biosynthetically produced benzaldehydes in E. coli.
Abstract
Artificial enzymes utilizing the genetically encoded non-proteinogenic amino acid p-aminophenylalanine (pAF) as a catalytic residue are able to react with carbonyl compounds through an iminium ion mechanism to promote reactions that have no equivalent in nature. Herein, we report an in vivo biocatalytic cascade that is augmented with such an artificial enzyme-catalysed new-to-nature reaction. The artificial enzyme in this study is a pAF-containing evolved variant of the lactococcal multidrug-resistance regulator, designated LmrR_V15pAF_RMH, which efficiently converts benzaldehyde derivatives produced in vivo into the corresponding hydrazone products inside E. coli cells. These in vivo biocatalytic cascades comprising an artificial-enzyme-catalysed reaction are an important step towards achieving a hybrid metabolism.
[ASAP] Tailoring Protein–Polymer Conjugates as Efficient Artificial Enzymes for Aqueous Asymmetric Aldol Reactions
R.B. Leveson-Gowersame as that ACS catal paper???
[ASAP] How to Stabilize Carbenes in Enzyme Active Sites without Metal Ions
A versatile artificial metalloenzyme scaffold enabling direct bioelectrocatalysis in solution
Utilizing Biocatalysis and an Unprecedented Sulfolane-mediated Reductive Acetal Opening to Access Nemtabrutinib from Cyrene
[ASAP] Development of a P450 Fusion Enzyme for Biaryl Coupling in Yeast
Site-selective Chlorination of Pyrrolic Heterocycles by Flavin Dependent Enzyme PrnC
Facile, green, and functional group-tolerant reductions of carboxylic acids…in water
R.B. Leveson-GowerI want a paper with an ellipsis in the title!
[ASAP] Peptide Carbocycles: From −SS– to −CC– via a Late-Stage “Snip-and-Stitch”
[ASAP] Analysis of Sheep and Goat IAPP Provides Insight into IAPP Amyloidogenicity and Cytotoxicity
R.B. Leveson-GowerHuman > Sheep
Late‐Stage Modification of Oligopeptides by Nickel‐Catalyzed Stereoselective Radical Addition to Dehydroalanine
Radical addition to the dehydroalanine (Dha) residue of a peptide could diversify the peptide sequence with noncanonical residues, but this strategy is currently limited by the lack of control over the stereochemistry. This work addresses this important challenge by applying chiral nickel catalysts to control the stereoselective radical addition to Dha on oligopeptides.
Abstract
Radical addition to dehydroalanine (Dha) represents an appealing, modular strategy to access non-canonical peptide analogues for drug discovery. Prior studies on radical addition to the Dha residue of peptides and proteins have demonstrated outstanding functional group compatibility, but the lack of stereoselectivity has limited the synthetic utility of this approach. Herein, we address this challenge by employing chiral nickel catalysts to control the stereoselectivity of radical addition to Dha on oligopeptides. The conditions accommodate a variety of primary and secondary electrophiles to introduce polyethylene glycol, biotin, halo-tag, and hydrophobic and hydrophilic side chains to the peptide. The reaction features catalyst control to largely override substrate-based control of stereochemical outcome for modification of short peptides. We anticipate that the discovery of chiral nickel complexes that confer catalyst control will allow rapid, late-stage modification of peptides featuring nonnatural sidechains.
[ASAP] Repurposing a Nitric Oxide Transport Hemoprotein Nitrophorin 2 for Olefin Cyclopropanation
Why the reaction order of biomolecular reaction should be 2.33 instead of 2?
R.B. Leveson-Gowerlol the title is supposed to say bimolecular
Enzymatic Late‐Stage Halogenation of Peptides
Late-stage halogenation of peptides has become feasible using a highly flexible halogenase that catalyses bromination of a wide range of amides and peptides. Upon optimization studies, even longer peptides carrying a terminal tryptophan residue were reasonably accepted leading to high conversions and remarkable selectivity. This novel bioorthogonal approach was exemplified by halogenating an RGD peptide derivative in the final step.
Abstract
The late-stage site-selective derivatisation of peptides has many potential applications in structure-activity relationship studies and postsynthetic modification or conjugation of bioactive compounds. The development of orthogonal methods for C−H functionalisation is crucial for such peptide derivatisation. Among them, biocatalytic methods are increasingly attracting attention. Tryptophan halogenases emerged as valuable catalysts to functionalise tryptophan (Trp), while direct enzyme-catalysed halogenation of synthetic peptides is yet unprecedented. Here, it is reported that the Trp 6-halogenase Thal accepts a wide range of amides and peptides containing a Trp moiety. Increasing the sequence length and reaction optimisation made bromination of pentapeptides feasible with good turnovers and a broad sequence scope, while regioselectivity turned out to be sequence dependent. Comparison of X-ray single crystal structures of Thal in complex with d-Trp and a dipeptide revealed a significantly altered binding mode for the peptide. The viability of this bioorthogonal approach was exemplified by halogenation of a cyclic RGD peptide.
Ensemble-function relationships to dissect mechanisms of enzyme catalysis
Coordination Switch Drives Selective C−S Bond Formation by the Non‐Heme Sulfoxide Synthases
Calculations suggest that a coordination switch of the sulfoxide intermediate is involved in the catalysis of ergothioneine synthase (EgtB). This coordination switch from S to O is driven by the S/π nonbonding electrostatic interactions, which efficiently promotes the observed stereoselective C−S bond formation while bypassing cysteine dioxygenation.
Abstract
The non-heme iron ergothioneine synthase (EgtB) is a sulfoxide synthase that catalyzes oxidative C−S bond formation in the synthesis of ergothioneine, which plays roles against oxidative stress in cells. Despite extensive experimental and computational studies of the catalytic mechanisms of EgtB, the root causes for the selective C−S bond formation remain elusive. Using quantum mechanics/molecular mechanics (QM/MM) calculations, we show herein that a coordination switch of the sulfoxide intermediate is involved in the catalysis of the non-heme iron EgtB. This coordination switch from the S to the O atom is driven by the S/π electrostatic interactions, which efficiently promotes the observed stereoselective C−S bond formation while bypassing cysteine dioxygenation. The present mechanism is in agreement with all available experimental data, including regioselectivity, stereoselectivity and KIE results. This match underscores the critical role of coordination switching in the catalysis of non-heme enzymes.
[ASAP] Expanding the Reactivity of Flavin-Dependent Halogenases toward Olefins via Enantioselective Intramolecular Haloetherification and Chemoenzymatic Oxidative Rearrangements
Enantioselective Single and Dual a-C–H Bond Functionalization of Cyclic Amines via Enzymatic Carbene Transfer
Photoexcited Enzymes for Asymmetric Csp3−Csp3 Cross‐Electrophile Couplings
The combination of photochemistry with enzyme catalysis offers exciting opportunities to induce new reactivities and to create novel enzymes for reactions other than their native ones. Recently, Hyster and co-workers demonstrated this for a photoenzymatic asymmetric Csp 3−Csp 3 cross-electrophile coupling, a reactivity previously unknown to enzymes.
Abstract
Enzymes have several advantages over conventional catalysts for organic synthesis. Over the last two decades, much effort has been made to further extend the scope of biocatalytic reactions available to synthetic chemists, particularly by expanding the repertoire of enzymes for abiological transformations. In this regard, exciting new developments in the area of photobiocatalysis enable now the introduction of non-natural reactivity in enzymes to solve long-standing synthetic challenges. A recently described example from the Hyster group demonstrates in an unprecedented way how the combination of photochemistry with enzyme catalysis empowers the catalytic asymmetric construction of Csp 3−Csp 3 bonds with high chemo- and enantioselectivity.