Sustainable production of pharmaceutical drug precursors by engineered Corynebacterium glutamicum

Tyramine has become a compound of great interest to the pharmaceutical industry, not only due to its utility as a starting material for hydrogel production, but also as a precursor for a multitude of pharmaceutically relevant compounds. An important example of one of these compounds is N‑acetyltyramine, which has recently been found to be active against certain multi-drug resistant pathogens and is also a promising anticoagulant since it is inhibiting Factor Xa. However, the chemical synthesis of tyramine and its derivatives is associated with a lack of selectivity and the use of harsh conditions, which are environmentally unfavorable. Accordingly, we aimed to establish the biosynthesis of both tyramine and N‑acetyltyramine as a sustainable alternative.

Corynebacterium glutamicum represents an optimal host for this objective, as it is a well-established workhorse in the industrial amino acid production, with an output of millions of tons per year. Moreover, it has been engineered for the utilization of a range of monomeric carbon substrates, allowing for a flexible feedstock strategy ^[1]. Testing the overexpression of various aromatic‑l‑amino acid decarboxylases in the tyrosine overproducing strain AROM3, the highest tyramine titer of 1.9 g L^‑1 was achieved upon the overexpression of the tyrosine decarboxylase gene of Levilactobacillus brevis. Further engineering for an extended substrate spectrum allowed for a tyramine production on the alternative carbon sources xylose, ribose and glycerol. Moreover, the upscaling of tyramine production to a 1.5 L batch reactor was demonstrated to be stable ^[2]. In an effort to expand the tyramine synthesis pathway through the additional overexpression of acetyltransferase genes from diverse bacteria and insects, a de novo production of 2.5 g L^‑1 N‑acetyltyramine was achieved by overexpressing the acetyltransferase gene from Bombyx mori. Concluding, an efficient production of tyramine and N‑acetyltyramine from sustainable feedstocks was established, providing a scalable and eco-friendly alternative for chemical synthesis.

[1] Wendisch, V.F., Jorge, J.M.P., Pérez-García, F., Sgobba, E., 2016. Updates on industrial production of amino acids using Corynebacterium glutamicum. World J Microbiol Biotechnol 32, 105.

[2] Poethe, S. S., Junker, N., Meyer, F., & Wendisch, V. F., 2024. Sustainable production of the drug precursor tyramine by engineered Corynebacterium glutamicum. Appl Microbiol and Biotechnol, 108(1), 499.