Research Projects

Developing synthetically valuable enzymatic reactions that do not naturally occur in biochemistry or traditional organic chemistry is a significant challenge in biocatalysis. Combining photochemistry with pyridoxal 5′-phosphate (PLP)-dependent biocatalysis offers a promising avenue for creating novel reaction methodologies. To address this challenge, we envision utilizing transaminases (TAs), a versatile class of PLP-dependent enzymes, to develop “new-to-nature” reactions. TAs efficiently catalyze reversible transamination of ketones to amines with high enantioselectivity under mild, environmentally friendly conditions. This makes them essential tools in sustainable organic synthesis, especially for producing chiral amines and amino acids, key building blocks in pharmaceuticals. The industrial relevance of TAs is exemplified by the biocatalytic synthesis of therapeutics such as Sitagliptin (Januvia®), demonstrating their potential for scalability and environmentally friendly manufacturing. Recently, efforts have extended enzyme catalysis beyond natural reactions through innovative photobiocatalytic techniques. PLP-dependent enzymes like tryptophan synthases and threonine aldolases have been re-engineered for photo-driven, enantioselective synthesis of noncanonical alpha-amino acids (ncAAs), achieving radical C–C functionalization of amino acids. However, these methods often depend on external photocatalysts and are limited to a small substrate scope, including glycine, D- and L-alanine, L-serine, and L-threonine. While transaminases can accept a broad array of alpha-amino acids, amines, and ketones, their potential for photo-biocatalysis remains largely unexplored. This gap presents an opportunity to expand enzyme-mediated radical chemistry within this class, independent of external photocatalysts and with broader substrate compatibility toward diverse amines. Building on recent advances in photo-biocatalysis and our expertise in electron donor-acceptor (EDA) complex-mediated photobiocatalytic beta-alkylation of enals, we propose to pioneer an enantioselective, photobiocatalytic gamma-C(sp3)-H functionalization of alpha-amino acids catalyzed by transaminases. Our approach involves in-situ formation of an EDA complex within the enzyme’s active site, activated by visible light. This strategy exploits the enzyme’s inherent stereoselectivity, eliminating external photocatalysts for a more sustainable and practical system. Applications will be extended through scale-up, enzyme immobilization for reusability, and integration with flow chemistry. The mechanism begins with enzymatic activation of a gamma-leaving group on the amino acid substrate—such as O-acetyl-L-homoserine (AHS) or homomethionine—forming an aldimine intermediate. This undergoes elimination to generate a reactive iminium ion. Simultaneously, the potassium salt of (S)-alpha-methyl phenyl acetic acid (S-MPA) interacts with the iminium ion, forming an ion pair. Under visible light, the iminium ion becomes excited, turning into a powerful oxidant. This triggers in-situ formation of an EDA complex between the excited iminium and S-MPA, enabling a single-electron transfer that generates a radical pair, leading to decarboxylation. The resulting chiral benzyl radicals then undergo stereocontrolled radical-radical recombination with a beta-enaminyl radical, producing gamma-functionalized amino acids with high enantioselectivity. Due to the rapid kinetics, the “memory of chirality” from S-MPA can be retained during product formation, which we will investigate in detail. This innovative approach combines enzymatic selectivity with photochemically driven radical chemistry, removing the need for external photocatalysts and expanding the scope of transaminase catalysis for non-natural transformations. Ultimately, this project aims to establish new pathways for the sustainable synthesis of ncAAs with high enantiopurity, with broad implications for pharmaceuticals and beyond.