Artificial Lanthanide Enzymes for Selective Photocatalysis: 'Enlightening' Metalloenzyme Design and Evolution

Introduction

Enzymes are efficient and selective biocatalysts. They are in high demand in the chemical and pharmaceutical industry, as they facilitate more sustainable production processes. However, it remains challenging to develop novel enzymes that catalyze reactions beyond nature's synthetic repertoire.

Proposed Approach

To tackle this problem, I propose a fundamentally new approach that merges metal-dependent chemical photocatalysis with enzyme engineering. Photoexcitation is a powerful catalytic tool. It enables alternative modes of substrate activation by generating radical intermediates.

Challenges in Synthetic Chemistry

Controlling these reactive species to confer regio- and stereoselectivity, however, is a major challenge in synthetic chemistry. The key idea of this proposal is thus to perform photocatalytic reactions inside the chiral environment of artificial metalloproteins, which can be optimized efficiently by directed evolution.

Recent Developments

My group recently established the formation of lanthanide-protein complexes from highly stable, computationally designed protein scaffolds. Based on this work, we now aim to engineer a photoenzymatic platform for synthetically valuable chemistry.

Main Goals

The main goal is to implement and optimize lanthanide photocatalysis in these proteins to facilitate:

1. Stereoselective C-H activation
2. C-C bond forming reactions

Moreover, a fundamental mechanistic understanding of how such new photocatalytic function emerges in proteins will be crucial for enzyme engineering.

Proposed Strategy

To that end, I propose a strategy that mimics natural evolution in a two-step process:

1. Starting from libraries of naive small proteins, a high-throughput screen will first identify lanthanide binders.
2. These binders are then exposed to a selection system that couples the survival of a bacterial host to an enzymatic detoxification reaction.

Expected Outcomes

PhotoLanZyme will yield a new class of sustainable and stereoselective photobiocatalysts. The approach is transferable to other photoredox-active metals, emphasizing its broad potential for synthetic applications.