Braca

Expanding the genetic code to enable the selective and specific incorporation of non-canonical monomers (ncMs), beyond -L amino acids with variant sidechains, is a key outstanding challenge. Here we discover orthogonal aminoacyl-tRNA synthetases that selectively and specifically acylate their cognate orthogonal tRNA in vivo with eleven new ncMs spanning five different chemical classes: ,-disubstituted-amino acids, malonic acids, carboxylic acids, {beta}2-amino acids and N-cyclic amino acids. We demonstrate that co-translational incorporation of ,-disubstituted-amino acids, {beta}2-amino acids, {beta}3-amino acids and N-cyclic amino acids is strongly dependent on the codons either side of the codon used to direct ncM incorporation, with several ncMs incorporated at less than 1% of sequence contexts. We evolve orthogonal tRNAs that enable the incorporation of previously unincorporated ncMs, enable the incorporation of ncMs at >95% of sequence contexts and, increase the incorporation efficiency at challenging sequence contexts up to 40-fold. We demonstrate the encoded cellular synthesis of proteins and macrocycles containing ncMs and, explicitly demonstrate that our evolved tRNAs provide direct access to a wider range of genetically encoded macrocyclic sequences containing ncMs. Our results provide a foundation for composing, discovering and manufacturing proteins and peptides with functions augmented by ncMs.

An integrated electroenzymatic platform synergizes engineered thiamine diphosphate (ThDP)-dependent radical biocatalysis with mediated electrochemical oxidation, achieving the highly enantioselective desymmetrization of dialdehydes to access silicon-stereogenic carboxylic acids. Harnessing electricity to access enzyme-bound radical intermediates unlocks a new-to-nature biocatalytic route to non-racemic silicon-stereogenic compounds.

ABSTRACT

Chiral silicon-stereogenic organosilanes are finding increasingly widespread applications in pharmaceutical science and biomedical materials. However, the enzymatic construction of silicon chiral centers remains underdeveloped. Here, we report the integration of thiamine diphosphate (ThDP)-dependent radical biocatalysis and mediated electrochemical oxidation to unlock non-natural enzymatic oxidative desymmetrization, enabling the highly enantioselective synthesis of silicon stereocenters. Using symmetric silane dialdehydes as substrates, variants of benzaldehyde lyase from Pseudomonas fluorescens (PfBAL) together with ferrocene methanol (FcMeOH) as a redox mediator facilitate selective oxidation. This method features a broad substrate scope, producing a range of enantioenriched silicon-containing carboxylic acids with excellent enantioselectivity (22 examples, up to >99.5% ee). Mechanistic investigations confirm substrate binding, explain the origin of enantioselectivity, and validate the mediated electron transfer pathway. This study expands the enzyme reactivity repertoire by merging electrochemical synthesis with biocatalysis, establishing an effective biocatalytic strategy for constructing silicon chirality.

Nature Chemistry, Published online: 13 April 2026; doi:10.1038/s41557-026-02116-7

Hydrophobicity plays an important role in protein function, but tuning hydrophobicity with canonical amino acids is chemically limited. Now through the genetic incorporation of bulky, highly hydrophobic non-canonical amino acids, their utility in enzyme engineering by enhancing the function of a copper-dependent laccase through hydrophobic tuning has been demonstrated.

Nature Synthesis, Published online: 07 April 2026; doi:10.1038/s44160-026-01017-4

This Review explores biophotoelectrocatalysis, a biohybrid strategy that couples photo(electro)catalysts with enzymes and cells to drive selective chemical synthesis using sunlight. Recent advances, mechanistic insights and emerging applications—from photoenzymes to waste-to-value biorefineries—highlight the potential of biophotoelectrocatalysis for sustainable solar-to-chemical manufacturing.

Nature Catalysis, Published online: 02 April 2026; doi:10.1038/s41929-026-01515-w

Radical C(sp3)–C(sp3) bond formation with stereocontrol is challenging. Now, photoredox catalysis and repurposed thiamine-dependent enzymes are combined to couple cinnamyl aldehydes with benzylic radicals, yielding enantioenriched carboxylic acids bearing one or even two stereocentres.

Nature Catalysis, Published online: 27 March 2026; doi:10.1038/s41929-026-01511-0

Metalloenzymes serve as staple biocatalysts for a broad range of reactions, offering exquisite selectivity and wide-ranging applicability when paired with versatile metals such as nickel. The mechanism behind sulfonamide formation catalysed by a recently discovered Ni-dependent enzyme has now been revealed, opening tractable avenues to biocatalyst-mediated expansion of the sulfonamide chemical space.

Nature Chemistry, Published online: 18 March 2026; doi:10.1038/s41557-026-02085-x

We developed a strategy to repurpose rare codons in mammalian cells, enabling the simultaneous incorporation of up to five distinct noncanonical amino acids into a single protein. By avoiding previous limitations in genetic code expansion using stop codons, this rare codon recoding facilitated advanced protein engineering applications.

Nature Synthesis, Published online: 24 March 2026; doi:10.1038/s44160-026-01043-2

Redesigning non-haem iron enzymes to incorporate a nickel centre enables ligand-to-metal charge transfer-driven photoenzymatic C(sp²)–S cross-coupling.

We report a photoenzymatic hydroalkylation that enables streamlined, stereocontrolled access to aryl glutarimide precursors relevant to targeted protein degradation. Engineered flavin-dependent “ene”-reductases provide broad scope and high enantioselectivity through a distinct electron transfer–enantioselective proton transfer pathway.

ABSTRACT

We describe a photoenzymatic hydroalkylation reaction that enables the efficient and stereocontrolled synthesis of aryl glutarimide precursors—chemically and configurationally robust entry points to bioactive agents for targeted protein degradation. Screening of flavin-dependent “ene”-reductases identified GluER HA _rac , a G. oxydans variant, as an efficient and substrate-tolerant catalyst, granting access to >30 (hetero)aryl glutarimide precursors. A directed evolution campaign then furnished a hexamutant, GluER HA _ent , that delivers the products in up to 93:7 enantiomeric ratio. Mechanistic experiments revealed a pathway that departs from the hydrogen atom transfer mechanism previously established for related systems, proceeding instead via radical–polar crossover followed by enantioselective proton transfer from an active-site tyrosine residue. Collectively, these studies establish a biocatalytic platform for advancing the synthesis and diversification of glutarimide-containing degraders.

Nature, Published online: 17 March 2026; doi:10.1038/d41586-026-00787-3

The database of 200 million protein-structure predictions now includes homodimers, adding new biological relevance.

Despite intense interest, the mechanism of iron-catalyzed aryl–aryl cross-coupling remains poorly understood. Combining Mössbauer spectroscopy, kinetics analysis, and DFT computations these studies reveal a novel Fe(I)/Fe(II)/Fe(III) catalytic for aryl–aryl cross-coupling mediated by an Fe(II) PC_NHCP Pincer complex. These findings close a key knowledge gap and offer design principles for sustainable iron-mediated cross-coupling.

ABSTRACT

The widespread use of precious metal catalysts in C–C bond-forming reactions is increasingly challenged by concerns over toxicity, cost, and limited availability. As a sustainable alternative, iron offers distinct advantages in cross-coupling chemistry, but its broader application has been hindered by limited mechanistic understanding. Here, we report a mechanistically driven investigation of aryl–aryl Kumada cross-coupling catalyzed by our previously reported iron complex [(PC_NHCP)FeCl₂] (2). Through a combination of multinuclear NMR, ⁵⁷Fe Mössbauer spectroscopy, single-crystal X-ray diffraction, and reactivity studies, we identify and characterize key in situ formed intermediates, including mono- and bis-arylated iron species, along the catalytic pathway. While PCP-ligated Fe(II) complexes support two-electron chemistry, our findings uncover a distinct radical mechanism responsible for the efficient formation of the biaryl products. Furthermore, we demonstrate that small coordinating molecules, such as N₂, significantly influence the speciation and reactivity of the iron catalyst. These insights advance fundamental understanding of iron-mediated cross-coupling and provide new design principles for sustainable C(sp²)–C(sp²) bond construction.

Nature Chemistry, Published online: 13 March 2026; doi:10.1038/s41557-026-02084-y

The site-specific incorporation of noncanonical amino acids (ncAAs) has so far been limited to single-type ncAA incorporation in mammalian cells. Now, the repurposing of rare codons and engineering of mutually orthogonal aminoacyl-tRNA synthetase/tRNA pairs enable up to five distinct ncAAs in a single protein, which can be applied to study mammalian pathways of interest.