Microbial synthesis of stereoirregular poly(3-hydroxybutyrate)

Poly(3-hydroxybutyrate) (PHB) is the most extensively studied polyhydroxyalkanoate and has long been promoted as a sustainable alternative to petrochemical polymers due to its excellent biocompatibility and biodegradability. Despite decades of research, PHB has not achieved broad commercial adoption, in part because its ( R )-isotactic microstructure leads to undesirable material properties such as high crystallinity and poor processability. This stereoregularity is widely assumed to be a consequence of the strict stereoselectivity of PHA synthases. Here, we provide the first evidence that challenges this long-standing assumption. In a proof-of-concept study, we demonstrate that stereoirregular PHB containing 6.84% ± 0.04% ( S )-3 hydroxybutyrate with a m dyad fraction of 11.8% ± 0.7% can be produced in fed-batch fermentation at a productivity of (58 ± 9) mg L −1 h −1 . Importantly, the material properties of the resulting stereoirregular PHB align with improvements predicted from chemically synthesized PHB. Notably, the melting temperature reduced from 179.3°C ± 0.7°C to 154.3°C ± 1.1°C, which was accompanied by decreased molar mass decomposition during processing, suggesting improved recyclability of the stereoirregular polymer. These findings overturn key assumptions about PHA synthase stereoselectivity and open the door to microbial production of PHB with tunable material properties.