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Metabolic engineering of Cupriavidus necator H16 for heterotrophic and autotrophic production of 3-hydroxypropionic acid

Salinas, Alejandro; McGregor, Callum; Irorere, Victor; Arenas-López, Christian; Bommareddy, Rajesh Reddy; Winzer, Klaus; Minton, Nigel P.; Kovács, Katalin


Alejandro Salinas

Callum McGregor

Victor Irorere

Christian Arenas-López

Rajesh Reddy Bommareddy

Professor of Applied Molecular Microbiology



3-Hydroxypropionate (3-HP) is a versatile compound for chemical synthesis and a potential building block for biodegradable polymers. Cupriavidus necator H16, a facultative chemolithoautotroph, is an attractive production chassis and has been extensively studied as a model organism for biopolymer production. Here, we engineered C. necator H16 for 3-HP biosynthesis from its central metabolism. Wild type C. necator H16 can use 3-HP as a carbon source, a highly undesirable trait for a 3-HP production chassis. However, deletion of its three (methyl-)malonate semialdehyde dehydrogenases (mmsA1, mmsA2 and mmsA3) resulted in a strain that cannot grow on 3-HP as the sole carbon source, and this strain was selected as our production host. A stepwise approach was used to construct pathways for 3-HP production via β-alanine. Two additional gene deletion targets were identified during the pathway construction process. Deletion of the 3-hydroxypropionate dehydrogenase, encoded by hpdH, prevented the re-consumption of the 3-HP produced by our engineered strains, while deletion of gdhA1, annotated as a glutamate dehydrogenase, prevented the utilization of aspartate as a carbon source, one of the key pathway intermediates. The final strain carrying these deletions was able to produce up to 8 mM 3-HP heterotrophically. Furthermore, an engineered strain was able to produce 0.5 mM 3-HP under autotrophic conditions, using CO2 as sole carbon source. These results form the basis for establishing C. necator H16 as an efficient platform for the production of 3-HP and 3-HP-containing polymers.


Salinas, A., McGregor, C., Irorere, V., Arenas-López, C., Bommareddy, R. R., Winzer, K., …Kovács, K. (2022). Metabolic engineering of Cupriavidus necator H16 for heterotrophic and autotrophic production of 3-hydroxypropionic acid. Metabolic Engineering, 74, 178-190.

Journal Article Type Article
Acceptance Date Oct 30, 2022
Online Publication Date Nov 3, 2022
Publication Date 2022-11
Deposit Date Nov 8, 2022
Publicly Available Date Nov 10, 2022
Journal Metabolic Engineering
Print ISSN 1096-7176
Electronic ISSN 1096-7184
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 74
Pages 178-190
Keywords Applied Microbiology and Biotechnology, Bioengineering, Biotechnology
Public URL
Publisher URL


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