arrow_circle_up

We develop strategies that enable enzymes to catalyze reactions that are currently unknown in nature.

We are working to establish visible light irradiation as a general strategy for unlocking new catalytic functions from enzymes. Using the redox formalisms commonly used by synthetic chemists, we can design valuable chemical reactions that nature has never envisioned that solve long standing challenges in chemical synthesis.

Discovering versatile biocatalysis that can be used to accelerate the synthesis of drugs and agrochemicals.

Based in the Frick Chemistry Laboratory at Princeton University, the Hyster lab integrates the fields of organic synthesis, organometallic chemistry, chemical biology, and protein engineering to develop new biocatalytic reactions that solve longstanding selectivity challenges and expand how enzymes can be used to achieve sustainable chemical synthesis.

arrow_circle_left arrow_circle_right
●○○

Using photoenzymatic catalysis to unlock new synthetic reactions.

Our approach provides access to enantioselective transformations involving radicals that are currently unmatched by organocatalysts and transition metal catalysts.

arrow_circle_left arrow_circle_right
○●○

Harnessing enzymes for streamlined organic synthesis.

We use the retrosynthetic disconnections available to enzymes to accelerate the synthesis of molecules with medicinal and biological relevance.

arrow_circle_left arrow_circle_right
○○●

Building artificial enzymes with emergent functions.

We are merging enzymes with transition metal complexes to develop biohydrids with functions that are unrealized by either the enzyme or metal alone.

Recent publications.

  • Engineering a photoenzyme to use red light

    Jose M. Carceller, Bhumika Jayee, Claire G. Page, Daniel G. Oblinsky, Gustavo Mondragón-Solórzano, Nithin Chintala, Jingzhe Cao, Zayed Alassad, Zheyu Zhang, Nathaniel White, Danny J. Diaz, Andrew D. Ellington, Gregory D. Scholes, Sijia S. Dong, Todd K. Hyster

    Chem 2025, 11, 1-11.

    Publication Abstract

    Photoenzymatic reactions involving flavin-dependent “ene”-reductases (EREDs) rely on protein-templated charge transfer (CT) complexes between the cofactor and substrate for radical initiation. These complexes typically absorb in the blue region of the electromagnetic spectrum. Here, we engineered an ERED to form CT complexes that absorb red light. Mechanistic studies indicate that red-light activity is due to the growth of a red-absorbing shoulder off the previously identified cyan absorption feature. Molecular dynamics simulations, docking, and excited-state calculations suggest that the cyan feature involves a π→π∗ transition on flavin, whereas the red-light absorption is a π→π∗ transition between flavin and the substrate. Differences in the electronic transition are due to changes in the substrate-binding conformation and allosteric tuning of the electronic structure of the cofactor-substrate complex. Microenvironment tuning of the CT complex for red-light activity is observed with other engineered photoenzymatic reactions, highlighting this effect’s generality.

  • Emergence of a distinct mechanism of C–N bond formation in photoenzymes

    Felix C. Raps, Ariadna Rivas-Souchet, Chey M. Jones, Todd K. Hyster

    Nature 2024.

    Publication Abstract

    C–N bond formation is integral to modern chemical synthesis due to the ubiquity of nitrogen heterocycles in small-molecule pharmaceuticals and agrochemicals. Alkene hydroamination with unactivated alkenes is an atom economical strategy for constructing these bonds. However, these reactions are challenging to render asymmetric when preparing fully substituted carbon stereocenters. Here, we report a photoenzymatic alkene hydroamination to prepare 2,2-disubstituted pyrrolidines by a Baeyer-Villiger Monooxygenase. Five rounds of protein engineering afforded a mutant, providing excellent product yield and stereoselectivity. Unlike related photochemical hydroaminations, which rely on the oxidation of the amine or alkene for C–N bond formation, this work exploits a through-space interaction of a reductively generated benzylic radical and the nitrogen lone pair. This antibonding interaction lowers the oxidation potential of the radical, enabling electron transfer to the flavin cofactor. Experiments indicate that the enzyme microenvironment is essential in enabling a novel C–N bond formation mechanism with no parallel in small molecule catalysis. Molecular dynamics simulations were performed to investigate the substrate in the enzyme active site which further support this hypothesis. This work is a rare example of an emerging mechanism in non-natural biocatalysis, where an enzyme has access to a mechanism that its individual components do not. Our study showcases the potential of enhancing emergent mechanisms using protein engineering to provide unique mechanistic solutions to unanswered challenges in chemical synthesis.

  • Synergistic Photoenzymatic Catalysis Enables Synthesis of a-Tertiary Amino Acids Using Threonine Aldolases

    Yao Ouyang, Claire Page, Catherine Bliodeau, Todd K. Hyster

    J. Am. Chem. Soc. 2024, 146, 20, 13754–13759.

    Publication Abstract

    a-Tertiary amino acids are essential components of drugs and agrochemicals, yet traditional syntheses are step-intensive and provide access to a limited range of structures with varying levels of enantioselectivity. Here, we report the α-alkylation of unprotected alanine and glycine by pyridinium salts using pyridoxal (PLP)-dependent threonine aldolases with a Rose Bengal photoredox catalyst. The strategy efficiently prepares various a-tertiary amino acids in a single chemical step as a single enantiomer. UV-vis spectroscopy studies reveal a ternary interaction between the pyridinium salt, protein, and photocatalyst, which we hypothesize is responsible for localizing radical formation to the protein active site. This method highlights the opportunity for combining photoredox catalysts with enzymes to reveal new catalytic functions for known enzymes.

Hyster Lab Group Photo

Our team.

The Hyster Lab is led by Principal Investigator, Todd Hyster. Our research team comprises a group of exceptional post-doctoral associates and fellows, graduate students, and undergraduates.

Hyster Lab logo avatar bulb cap Hyster Lab logo avatar filament Hyster Lab logo avatar arrows