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Alkynes found in natural products are typically assembled by metal-dependent enzymes. The enzyme BesB instead forms a terminal alkyne-containing amino acid using pyridoxal phosphate as a cofactor. Here, the authors use structural and mechanistic investigations to identify the key features of BesB that allow it to carry out its fascinating chemistry.

A haem protein that serves as a dual-function catalyst capable of inserting a carbene into a N–H bond to form α-amino lactones has been reported. The enzyme catalyses both carbene transfer and the subsequent proton transfer in a single active site. This transformation can proceed at the gram scale with high efficiency and enantioselective control.

The scope of Lewis acid catalysis mediated by enzymes is low compared with the range of reactions it drives in organic synthesis. Now the substitution of the iron centre with copper, and the subsequent directed evolution, enabled a non-haem iron hydroxylase to efficiently catalyse asymmetric abiotic Conia-ene cyclizations.

Despite the existence of many N–N-containing natural metabolites, little is known about the enzymatic mechanisms of N–N bond formation. Now, a catalytically relevant X-ray crystal structure of an N–N-bond-forming enzyme, PipS, is reported and detailed insights into its catalytic mechanism are provided.

Decarboxylative azidation is a valuable transformation in organic chemistry, but a biocatalytic equivalent remained elusive. Now merging photoredox with metalloenzymatic catalysis enables the enantioselective decarboxylative radical azidation and thiocyanation of N-hydroxyphthalimide esters.

Methods for enzymatic C–F bond formation are rare. Now an enzymatic method for enantioselective C(sp³)–F bond formation is reported, through reprogramming non-haem iron enzyme (S)-2-hydroxypropylphosphonate epoxidase. Mechanistic studies reveal that the process proceeds through an iron-mediated radical fluorine transfer process.

Catabolizing lignin-derived aromatic compounds requires an aryl-O-demethylation step. Here the authors present the structures of GcoA and GcoB, a cytochrome P450-reductase pair that catalyzes aryl-O-demethylations and show that GcoA displays broad substrate specificity, which is of interest for biotechnology applications.

Biocatalytic methods for the synthesis of chiral cyclohexenones bearing quaternary stereocentres through oxidation and reduction reactions are reported. Mechanistic studies reveal the role of active-site residues in the oxidation process and inform the development of the enzymatic reduction reaction.

Aldolases have been a mainstay in synthesis, but their scope has been limited to activated electrophiles. Now carbon–carbon bond formation with ketone electrophiles is enabled by transaldolases, which form a strong nucleophile that is resistant to protonation. This chemistry enables convergent synthesis of non-canonical amino acids bearing tertiary alcohol side chains.

The direct regioselective oxidation of internal alkenes to ketones poses an important synthetic challenge. Now, directed evolution of a cytochrome P450 enzyme affords a ketone synthase that can efficiently oxidize internal arylalkenes directly to ketones with high chemo- and regioselectivity.

The use of biocatalysis to support early-stage drug discovery campaigns remains largely untapped. Here, engineered biocatalysts enable the synthesis of sp³-rich polycyclic compounds through an intramolecular cyclopropanation of benzothiophenes, affording a class of complex scaffolds potentially useful for fragment-based drug discovery campaigns.

Enzymes are capable of controlling the reactivity and selectivity of catalytic mechanisms involving highly reactive intermediates. Now, flavine mononucleotide-dependent ene-reductases have been repurposed as photobiocatalysts for generating and taming unstable N-centred radicals, enabling their application in asymmetric radical C–N couplings.

Insights on the mechanistic differences between artificial metalloenzymes (ArMs) with non-native metal centres and the free cofactor or natural enzymes are scarce. Now, a detailed mechanistic analysis of a cyclopropanation reaction catalysed by such an ArM is provided, revealing intriguing differences to the natural system.

Connecting conformational dynamics and epistasis has so far been limited to a few proteins and a single fitness trait. Here, the authors provide evidence of positive epistasis on multiple catalytic traits in the evolution and dynamics of engineered cytochrome P450 monooxygenase, offering insights for in silico protein design.

Mixtures of various size fullerenes are available as a component of fullerene soot, but isolating pure fullerenes is a challenging task. Here, the authors use a porphyrin-based supramolecular cage that encapsulates fullerenes with high selectivity and releases C₆₀by a simple washing technique.

The structure of a Stig cyclase, HpiC1, reveals how it catalyzes Cope rearrangement and 6-exo-trig cyclization, including how it controls the position of electrophilic aromatic substation that distinguishes hapalindole from fischerindole alkaloids.

Discovery and characterization of two Brønsted acid enzymes from quinolone alkaloid biosynthesis provides new biocatalytic approaches for the challenging but synthetically useful cationic rearrangement of epoxides.