Oral Presentation Royal Australian Chemical Institute National Congress 2026

Developing a Two-Enzyme Biocatalytic Platform for C1 Assimilation (138345)

Trishnamoni Gautom 1 , Bhubhud Thongrakon 1 , Paul Hudson 2 , Christian Schnepel 3
  1. KTH Royal Institute of Technology, Stockholm, STOCKHOLM, Sweden
  2. Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden
  3. Department of Chemistry, Durham University, Durham, United Kingdom

The development of efficient, non-natural C1 assimilation pathways is a key challenge in non-natural CO₂ fixation, as native carbon fixation routes are complex and poorly suited for in vitro deployment. Biocatalysis presents a sustainable route for CO₂ valorisation, enabled by enzyme engineering strategies that enhance catalytic efficiency and stability under industrial conditions[1], [2]. Here, we target the implementation of the formolase pathway, a short and energetically favourable route enabling biocatalytic conversion of CO₂-derived formate into carbohydrates via an enzymatic cascade. The work focuses on development and integration of two rate-limiting enzymatic steps. First, we aim to establish biocatalytic reduction of formate to formaldehyde by repurposing a carboxylic acid reductase (CAR) into a formic acid reductase (FAR). This is accomplished by screening a library of carboxylic acid reductases (CAR) with activity towards ammonium formate, applying both fluorescence and HPLC-based screening methods. [3] Extensive enzyme screening unveiled four CARs with moderate to high activity for formate. Our best FAR hits are being characterized further using protein crystallography and cryo-electron microscopy (cryo-EM) to understand substrate preferences and enable guided FAR engineering for improved total turnover and formaldehyde stability. Our efforts now concentrate on building a one-pot cascade by implementing the biocatalytic formose-type reaction using benzaldehyde lyase (BLS). variants. [4], [5] Active site remodelling of a thermostable BLS resulted in formolase (FLS) variants exhibiting altered substrate specificity from benzaldehyde to formaldehyde. The enzyme activity is verified using enzyme-coupled assays of the DHA product. Through integrated computational design and ML-guided mutagenesis we aim to improve C1–C1 bond formation rates. Ultimately, the optimized cascade establishes a foundation to build a scalable, biocatalytic platform for CO₂ upgrading, contributing to carbon circular economy.