PhD defence H. (Hangyu) Zhou

Exploring and enhancing the catalytic promiscuity of 2-deoxy-D-ribose-5-phosphate aldolase

It took nature billions of years to evolve the many enzymes that catalyze numerous diverse reactions. In turn, enzymes can now be tailored to catalyze non-natural reactions and accommodate a wide variety of structurally diverse substrates, through advances in protein engineering.

The well-known aldolase DERA (2-deoxy-D-ribose-5-phosphate Aldolase), which utilizes a catalytic lysine residue, naturally catalyzes the reversible aldol addition between acetaldehyde and D-glyceraldehyde-3-phosphate. Inspired by advances in aminocatalysis, we redesigned DERA to catalyze a range of synthetically valuable reactions beyond its native aldol activity, including cofactor-independent anti- and syn-selective epoxidation, asymmetric conjugate cyanation and stereospecific radical coupling via photodecarboxylation.

By bridging aminocatalysis and biocatalysis, and extending DERA’s reactivity into the realms of asymmetric iminium catalysis and photocatalysis, our work paves the way for engineering this class I aldolase to catalyze other mechanistically related and synthetically useful reactions, redefining the functional limits of natural enzymes.

Supervisors:prof. dr. G.J. (Gerrit) Poelarends, dr. F.J. (Frank) Dekker