# An Integrated Engineering Approach to Intensify the Biocatalytic Metaraminol Synthesis

## TL;DR

This paper improves the enzymatic synthesis of metaraminol by addressing side-product formation and optimizing enzyme use for higher yields.

## Contribution

The study introduces a novel approach combining enzyme optimization and continuous extraction to achieve near-complete metaraminol synthesis.

## Key findings

- Side-product formation, including cofactor adducts, limits enzymatic metaraminol synthesis.
- Using purified amine transaminase at tenfold concentration and continuous extraction achieved >99% yield.
- l-alanine was successfully integrated as an amine donor alternative to isopropylamine.

## Abstract

Metaraminol is a chiral amino alcohol and plays an important role as a precursor molecule and active pharmaceutical ingredient in industry. Its enzymatic synthesis has been developed in recent years and can serve as an alternative to conventional synthesis routes that use toxic, fossil‐based resources. Although the enzymatic two‐step reaction toward metaraminol has been intensively investigated in the past, full conversion has never been reached in the amine transaminase‐catalyzed step. In this study, we focus on identifying and overcoming the hurdles of the transamination step to reach higher metaraminol yields. Photometric and LC‐MS analyses revealed side‐product formation as a major drawback for the enzymatic metaraminol synthesis. Besides the oxidation of (R)‐3‐OH‐PAC as well as its imine formation with isopropylamine, we demonstrate for the first time the adduct formation of the cofactor pyridoxal‐5’‐phosphate with metaraminol. Only by changing the amine transaminase formulation to purified enzyme and increasing the concentration by tenfold, >99% product yield with a metaraminol concentration of 75 mM was reached. Further, we successfully integrated the amine donor l‐alanine by applying a continuous product extraction system as an alternative to isopropylamine. We believe that our findings and optimization strategies can also serve as a blueprint for other amine‐based syntheses.

The amine transaminase‐catalyzed amination of (R)‐3‐hydroxyphenylacetylcarbinol toward metaraminol involves severe side‐product formation, hampering high product titers. The application of a continuous extraction system together with an increased amine transaminase concentration and optimal enzyme formulation enhanced the overall metaraminol yield.© 2026 WILEY‐VCH GmbH