Braca

Selective modification of lysine residues is challenging due to their similar intrinsic reactivity. Inspired by enzymatic recognition, ligand-guided electrophiles enable site-selective labeling and functionalization, while ligand-guided catalyses achieve regioselective installation of bio-relevant post-translational modifications. Together, these advances establish a framework for programmable protein modification and synthetic epigenetics.

ABSTRACT

Lysine post-translational modifications (PTMs) play crucial roles in regulating protein structures, interactions, and cellular signaling. Precise study of PTM functions requires homogeneous proteins with modifications at defined sites; however, selective chemical modification is challenging because multiple lysines undergo similar chemistry yet exhibit variable reactivity depending on their local environments. Early chemical strategies exploited intrinsic reactivity differences, which are effective for exposed lysines but limited for low-reactivity or sterically hindered sites. In contrast, enzymes achieve high selectivity through substrate recognition and spatial organization. Inspired by this enzymatic principle, chemical approaches have been developed, including ligand-directed chemistry, proximity-enabled modification, and on-demand generation of highly reactive electrophiles. Recent advances in ligand-guided catalysis now enable regioselective and catalytic installation of biorelevant, authentic PTMs, providing a platform for programmable lysine modification and synthetic epigenetics.

Nature Synthesis, Published online: 22 May 2026; doi:10.1038/s44160-026-01091-8

Unactivated alkanes are difficult to use in enantioselective synthesis. Now a copper-catalysed radical S–C cross-coupling strategy enables their direct conversion into sulfur-stereogenic alkyl sulfilimines with high enantioselectivity. Two complementary methods using photo- and thermal chemistry combine hydrogen atom transfer with enantioselective copper-mediated S-stereocentre formation and chirality-transferring radical substitution.

Nature Synthesis, Published online: 22 May 2026; doi:10.1038/s44160-026-01080-x

Sijia Dong, Assistant Professor at Northeastern University, talks to Nature Synthesis about the computational studies and design of photoenzymatic catalysts.

Nature Synthesis, Published online: 22 May 2026; doi:10.1038/s44160-026-01087-4

The combination of biocatalysts with electro- and photocatalysis provides a compelling route towards sustainable chemical and energy production driven by renewable electricity or light. We reflect on the challenges and opportunities associated with combining these technologies.

Nature Synthesis, Published online: 15 May 2026; doi:10.1038/s44160-026-01074-9

The enantiodiscrimination between two minimally different alkyl substituents is synthetically challenging. Here a photobiocatalytic strategy combines thiamine diphosphate-dependent enzymes with visible-light-driven photoredox catalysis for the enantioselective synthesis of all-carbon quaternary stereocentres. The process can distinguish between methyl and ethyl groups, through the enantioselective cross-coupling of prochiral alkyl radicals with enzymatic thiamine-derived ketyl radicals.

Modern protein design methods based on deep learning allow generation of customized protein scaffolds with diverse geometries and functionalities. Here, we capitalize on these recent advances to develop hyper-thermostable de novo CO2 reductases featuring a cobalt porphyrin IX cofactor (CoPPIX). CoPPIX containing enzymes were assembled in vivo through media supplementation with cobalt salts and assessed for photocatalytic CO2 reductase activity. We identified two cysteine-ligated designs that exhibit high activity (>1000 turnovers at rates of up to 25 min-1) while suppressing competing hydrogen evolution pathways. A 2.1 [A] crystal structure shows close agreement to the design model with the Co-Cys bond programmed as intended. This study showcases the power of computational protein design in developing artificial enzymes to activate challenging molecules such as CO2.

Genetic code expansion introduces new-to-nature chemical moieties into ribosomally synthesized proteins. In practice, the scope of functional groups that can be accessed using this method is often limited by noncanonical amino acid (ncAA) availability. Producing ncAAs directly in cells can circumvent poor ncAA uptake or commercial unavailability, but limited enzymes suitable for this application exist. In vitro evolution campaigns have been remarkably successful in yielding synthetically useful "ncAA synthases." However, these enzymes are optimized for preparative-scale synthesis and their activities often do not translate well to cellular biosynthesis. Thus, expanding strategies to engineer enzymes specifically for ncAA production within cells will benefit further implementation of genetic code expansion. Here, we use phage-assisted noncontinuous and continuous evolution to evolve enzymes for improved synthesis of non-canonical tyrosine derivatives in E. coli. Using simple serial passaging, we uncovered mutations that doubled the production of an expensive ncAA, 3-methoxytyrosine, by tyrosine phenol lyase, and furthermore evolved variants that enable 3-iodotyrosine biosynthesis, a transformation the parent enzyme is unable to catalyze. Additionally, we evolved a recently reported tyrosine synthase for improved production of 3-halogenated tyrosines, identifying variants that exhibit high activity even at low substrate concentrations owing to a [~]8-fold reduction in KM. Our results demonstrate that phage assisted evolution can be used to rapidly improve the activity of enzymes for ncAA production in cells.

Alkyl phosphonates are valuable motifs that can be prepared by phosphonylations of various common functional groups. However, direct phosphonylations of C(sp³)–H bonds are limited to activated positions. Herein, we report an iron-photocatalyzed phosphonylation of unactivated C(sp³)–H bonds using a novel phosphite radical trap, which is equipped with an oxidizing radical leaving group to enable effective photocatalyst turnover.

ABSTRACT

Alkyl phosphonate esters are valuable motifs that have broad synthetic utility and are commonly found in bioactive molecules. Therefore, many methods have been developed to enable efficient phosphonylations of organic molecules, typically involving the construction of C(sp³)–P bonds by substitutions of common functional groups with phosphorus(III) reagents. However, direct phosphonylations of unactivated C(sp³)–H bonds are rare and currently lack the substrate generality required for late-stage introduction of phosphonate groups into complex molecules. Herein, we report a photoinduced C(sp³)–H phosphonylation of unactivated alkanes using a hydrogen atom transfer (HAT) strategy with an iron photocatalyst. Key to the success of the process was the development of a novel mandelonitrile-derived phosphite radical trap, which is equipped with an oxidizing phenylacetonitrile radical leaving group that enables effective turnover of the photocatalyst. The method displays good functional group tolerance, high selectivity for phosphonylations of sterically unhindered C─H bonds, and was found to be applicable to regioselective late-stage installation of phosphonate esters into complex molecules.

Disulfides are versatile, nontoxic alternatives to metal photocatalysts. This review explores their role as photoactivated thiyl-radical precursors and bifunctional catalysts (HAT/electron shuttling) in diverse transformations. Strategies for electronic tuning and development into recyclable heterogeneous materials are highlighted for sustainable, green photochemistry.

The facile photolysis of the sulfur-sulfur bond in disulfides has emerged as a powerful and versatile strategy in organic chemistry. This review surveys the rapidly growing field of disulfide-mediated photoreactions, including both catalytic and cocatalytic systems, as well as their roles across homogeneous and developing heterogeneous platforms. We highlight how electronically tuned disulfides function as photoactivated thiyl-radical precursors and, in many cases, as bifunctional radical mediators that enable hydrogen-atom transfer (HAT), electron shuttling, and polarity-matched radical trapping. Representative reaction classes include anti-Markovnikov hydrofunctionalizations of alkenes, oxidative alkene oxygenation and CC cleavage, hydrophosphinylation, hydrofluoroalkylation, decarboxylative transformations, C(sp³)–H functionalizations, and alkene/alkyne isomerizations. The review discusses the strategies for translating molecular disulfide chemistry into recyclable heterogeneous materials and polymer-supported catalysts. The photochemical flexibility and tunability of disulfides through electronic modification, combined with their commercial availability and low toxicity, position them as attractive alternatives to expensive precious-metal photoredox catalysts for advancing industrially viable and sustainable photochemistry.

Nature, Published online: 29 April 2026; doi:10.1038/s41586-026-10328-7

A Review of de novo protein design highlights key methodological advances and achievements, current challenges and future applications.

Nature Catalysis, Published online: 29 April 2026; doi:10.1038/s41929-026-01532-9

Stereoselective radical C–C couplings remain a major challenge. Now photometallobiocatalytic cross-coupling of organotrifluoroborates and α-diazoesters is achieved with high enantio- and diastereoselectivity via an outer-sphere radical mechanism mediated by engineered cytochrome c and eosin B.

The de novo design of enzymes remains a central challenge, requiring consideration of catalytic mechanism and optimization across biochemical and biophysical criteria. To capture these criteria, we draw on principles from evolutionary biology. Here, we present dEVA (design by EVolutionary Algorithm), a multi-objective design framework for structure-based protein design. We apply dEVA to the zero-shot, de novo design of metalloenzymes by optimizing for the coordination sphere of catalytic metals. We fully characterize one of these designs: a bi-zinc metalloenzyme exhibiting promiscuous hydrolytic activity towards both phosphomonoesters and phosphodiesters. This design achieves a catalytic efficiency (kcat/KM) of up to 1500 M-1s-1 and a rate enhancement ((kcat/KM)/kw) of up to 3 x 1013, comparable to characterized natural phosphatases. dEVA offers a general and modular strategy for the programmable design of protein function without dependence on natural templates, predefined motif, or evolutionary information.

Nature Reviews Chemistry, Published online: 20 April 2026; doi:10.1038/s41570-026-00819-6

This Review encompasses recent developments in photochemical, electrochemical and electrophotochemical C–N coupling reactions, focusing on metal-catalysed and metal-free methodologies under diverse activation conditions. It highlights sustainable and versatile synthetic strategies for C–N bond formation.

The genetic incorporation of noncanonical amino acids (ncAAs) into proteins represents an effective approach to endow enzymes with novel functions. Here, we highlight the novel concept of integration of ncAAs biosynthesis and incorporation firmly into the realm of enzyme design, establishing an efficient strategy for creating artificial enzymes with in situ biosynthesized ncAAs featuring non-natural catalytic activity.

Artificial enzymes engineered by site-specific incorporation of catalytically active noncanonical amino acids (ncAAs) into protein scaffolds represent a rapidly advancing class of biocatalysts, particularly for chemical transformations lacking natural enzymatic counterparts. Integrating biosynthesis and genetic incorporation of ncAAs has rapidly expanded the toolkit for enzyme design and catalysis. This review surveys engineered metabolic routes and precursor feeding strategies that supply diverse ncAAs in vivo, and contrasts cell-free and cellular approaches for their production. We examine advances in orthogonal translation systems and site-specific incorporation that enable installation of catalytic, redox, and spectroscopic functionalities, and highlight applications where ncAA-bearing proteins catalyze new-to-nature reactions, and improve selectivity for directed evolution. Recent work on in-cell biosynthesis of ncAAs coupled to on-demand incorporation is discussed for its potential to streamline workflows and enable enzyme design and catalysis in one-pot. Finally, we identify remaining challenges and outline opportunities for coupling metabolic engineering and protein engineering to create next-generation artificial enzymes.