Peroxisome Engineering for Overproduction of Sesquiterpenoid α‑Santalene in Ogataea polymorpha

ABSTRACT

Santalene is the core aromatic component of natural sandalwood essential oil and the key precursor of santalol, which is a high‐value sesquiterpenoid with unique woody aroma and bioactivities. Microbial production emerges as a promising alternative supply route other than inefficient plant extraction. Herein, we systematically engineer a peroxisomal factory for α‐santalene overproduction in Ogataea polymorpha by optimizing mevalonate pathway in peroxisomes and enhancing the supply of reducing power NADPH and precursor acetyl‐CoA. The engineered strain produced 556.2 mg/L and 3.4 g/L α‐santalene in shake flask batch and fed‐batch fermentations, respectively. This work suggests O. polymorpha is a promising host for peroxisome engineering and offers a sustainable bio‐manufacturing route for santalol derivatives.