V. Poggetti

A novel quercetin 2,3-dioxygenase was engineered to reshape its substrate-binding cavity and redirect its specificity toward artificial flavonols. One variant with a larger substrate-binding cavity exhibited 20- to 1750-fold higher activity toward bulky flavonols with phenyl-based substitutions at position C-8. In contrast, a variant with a smaller substrate-binding cavity showed 15-fold higher activity toward the smaller flavonol 3,7-dihydroxyflavone.

ABSTRACT

A novel quercetin 2,3-dioxygenase from Penicillium chrysogenum, following biochemical characterization, served as the starting point for reshaping the substrate-binding cavity to alter its substrate specificity. Using a rational engineering strategy supported by computational predictive tools, we achieved high activity toward specific artificial flavonols. In all generated variants, amino acids were replaced with residues that naturally occur at the selected positions in homologous enzymes. Two variants with enlarged substrate-binding cavities exhibited improved activity toward bulkier substrates. In particular, the Y55F-F134L-M143L variant showed 20- to 1750-fold higher activity toward flavonol compounds with phenyl-based substitutions at position C-8. Conversely, one variant with a smaller substrate-binding cavity showed 15-fold higher activity toward the smaller flavonol 3,7-dihydroxyflavone. The procedure described here has implications for engineering metalloenzymes to alter their substrate specificity toward novel compounds.

This work presents a convergent, stereodivergent total synthesis of glabridin. A lipase-mediated DKR, combined with protecting-group engineering and fragment coupling, enables access to both enantiomers in short sequences and offers a general blueprint for the synthesis of isoflavan and related polyphenolic natural products.

ABSTRACT

Herein, we describe a modular, stereodivergent chemoenzymatic strategy for the enantioselective total synthesis of the natural products (+)- and (–)-glabridin. A lipase-catalyzed dynamic kinetic resolution establishes the key benzylic stereocenter, while a carefully engineered protecting-group manifold preserves stereochemical integrity during fragment coupling and cyclization. From inexpensive, commercially available resorcinol-derived building blocks, the sequences deliver (–)-glabridin in 10 steps with 14% overall yield and (+)-glabridin in 12 steps with 7% overall yield. This convergent platform provides practical access to both enantiomers of glabridin and offers a general blueprint for the stereocontrolled synthesis of structurally related polyphenolic natural products.

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

Thioxanthone is a highly versatile and effective organocatalyst for photochemical applications, with its low-toxicity, metal-free structure driving growing interest in sustainable photocatalysis. Building on our previous 2021 review, this update covers advances from 2021–2025 in thioxanthone-based synthetic organic photochemistry – excluding polymerization and is organized by reaction type to highlight its expanding versatility.

Abstract

Thioxanthone (TX) and its derivatives are standout, heavy-atom-free triplet photosensitizers, due to their high triplet energy, long-lived triplet states, and ability to work synergistically with metal catalysts. These features render them highly useful in photochemical processes. A previous 2021 review covered TX's photophysical properties and photochemical applications. This review constitutes an update and highlights the growing number of studies since then, demonstrating TX's versatility in synthetic organic photochemistry. The content covers the literature during the period 2021–2025 and is organized by reaction type excluding applications in polymerization reactions.

p-Benzoyl-l-phenylalanine (pBzF) integrates genetic code expansion with benzophenone photochemistry to enable proximity-based labeling, programmable biocatalysis, and biosafe microbial engineering, all from a single, site-specifically encoded amino acid.

ABSTRACT

p-Benzoyl-l-phenylalanine (pBzF) is a widely used noncanonical amino acid (ncAA) that expands the chemical repertoire of proteins. Its benzophenone (BP) chromophore undergoes near-quantitative intersystem crossing (ISC) to a triplet state, furnishing a highly efficient, site-addressable photoreactive handle. Beyond photochemistry, the bulky, hydrophobic side chain introduces distinct steric and electronic effects that enable new reactivity in protein active sites. Genetic incorporation of pBzF in vivo, including directed evolution, has unlocked applications ranging from site-specific photo-crosslinking for interaction mapping to engineering antibody fragments, sharpening monoclonal antibody (mAb) epitope recognition, and creating protein-based photocatalysts. pBzF has also proved powerful for mechanistic studies by stabilizing short-lived intermediates. More recently, pBzF-containing proteins have been leveraged in light-driven transformations, including [2+2] photocycloadditions, deracemizations, and dehalogenations, and in the construction of artificial photosynthetic systems. This review critically discusses these advances and establishes pBzF as a versatile photochemical and structural motif for building proteins with non-natural, light-responsive, and catalytically competent functions.