Reengineering Zingiber zerumbet: Recent Advances in Zerumbone Biosynthesis and Synthetic Biology
DOI:
https://doi.org/10.22452/stem.vol7no1.1Keywords:
Zerumbone, Ginger, Synthetic Biology, Metabolic Engineering, Bioactive CompoundAbstract
Zingiber zerumbet is a medicinal plant known for producing zerumbone, a sesquiterpenoid with reported anticancer, anti-inflammatory, antimicrobial and antioxidant activities. Growing interest in zerumbone has increased the need for sustainable production methods, as conventional extraction from plant material is limited by low and inconsistent yields, long growth periods, and the need for large cultivation areas. Recent advances in synthetic biology have provided new opportunities for microbial production of zerumbone through metabolic engineering. This review summarizes current knowledge on zerumbone biosynthesis, focusing on the identification and functional characterization of the key enzymes ZSS1, CYP71BA1 and ZSD1. The successful reconstruction of the zerumbone biosynthetic pathway in engineered Saccharomyces cerevisiae is discussed, together with strategies used to enhance precursor supply and improve pathway efficiency. Lessons from the microbial production of other valuable sesquiterpenoids, including artemisinin, nootkatone, and patchoulol, are also examined to identify engineering approaches applicable to zerumbone. Finally, future perspectives involving protein engineering, CRISPR-based metabolic engineering, artificial intelligence-assisted enzyme design, and sustainable biomanufacturing are highlighted. Together, these approaches suggest that continued optimization of precursor supply, CYP71BA1 activity, and metabolic pathway balance will be essential for translating microbial zerumbone production into a commercially viable process.
References
Alwakil, N. H., Mohamad Annuar, M. S. and Jalil, M. (2022). Synergistic effects of plant growth regulators and elicitors on α-humulene and zerumbone production in Zingiber zerumbet Smith adventitious root cultures. Molecules, 27(15), 4744. https://doi.org/10.3390/molecules27154744.
Li, C., Li, J., Wang, G. and Li, X. (2016). Heterologous biosynthesis of artemisinic acid in Saccharomyces cerevisiae. Journal of applied microbiology, 120(6), 1466-1478. https://doi.org/10.1111/jam.13044.
Li, W., Cui, L., Mai, J., Shi, T.-Q., Lin, L., Zhang, Z.-G., Ledesma-Amaro, R., Dong, W. and Ji, X.-J. (2022). Advances in metabolic engineering paving the way for the efficient biosynthesis of terpenes in yeasts. Journal of Agricultural and Food Chemistry, 70(30), 9246-9261. https://doi.org/10.1021/acs.jafc.2c03917.
Meng, X., Liu, H., Xu, W., Zhang, W., Wang, Z. and Liu, W. (2020). Metabolic engineering Saccharomyces cerevisiae for de novo production of the sesquiterpenoid (+)-nootkatone. Microbial cell factories, 19(1), 21. https://doi.org/10.1186/s12934-020-1295-6.
Okamoto, S., Yu, F., Harada, H., Okajima, T., Hattan, J. i., Misawa, N. and Utsumi, R. (2011). A short‐chain dehydrogenase involved in terpene metabolism from Zingiber zerumbet. The FEBS journal, 278(16), 2892-2900. https://doi.org/10.1111/j.1742-4658.2011.08211.x.
Ro, D.-K., Paradise, E. M., Ouellet, M., Fisher, K. J., Newman, K. L., Ndungu, J. M., Ho, K. A., Eachus, R. A., Ham, T. S. and Kirby, J. (2006). Production of the antimalarial drug precursor artemisinic acid in engineered yeast. Nature, 440(7086), 940-943. https://doi.org/10.1038/nature04640.
Yang, Y., Lin, P., Du, G., Chen, J., Peng, Z. and Zhang, J. (2026). Engineered Microbial Production of Sesquiterpenoids: Recent Advances and Prospects. ACS Synthetic Biology. https://doi.org/10.1021/acssynbio.6c00144.
Yu, F., Okamoto, S., Harada, H., Yamasaki, K., Misawa, N. and Utsumi, R. (2011). Zingiber zerumbet CYP71BA1 catalyzes the conversion of α-humulene to 8-hydroxy-α-humulene in zerumbone biosynthesis. Cellular and molecular life sciences, 68(6), 1033-1040. https://doi.org/10.1007/s00018-010-0506-4.
Yu, F., Okamto, S., Nakasone, K., Adachi, K., Matsuda, S., Harada, H., Misawa, N. and Utsumi, R. (2008). Molecular cloning and functional characterization of α-humulene synthase, a possible key enzyme of zerumbone biosynthesis in shampoo ginger (Zingiber zerumbet Smith). Planta, 227(6), 1291-1299. https://doi.org/10.1007/s00425-008-0700-x.
Zhang, C., Liu, J., Zhao, F., Lu, C., Zhao, G.-R. and Lu, W. (2018). Production of sesquiterpenoid zerumbone from metabolic engineered Saccharomyces cerevisiae. Metabolic engineering, 49, 28-35. https://doi.org/10.1016/j.ymben.2018.07.010.
Zhao, Y., Wu, Z., Li, J., Qi, Y., Zhang, X. and Shen, C. (2025). The key role of cytochrome P450s in the biosynthesis of plant derived natural products. Plant Physiology and Biochemistry, 222, 109695. https://doi.org/10.1016/j.plaphy.2025.109695.
