Authors
Chang Li, Quanwei Yu, Fang Yue, Xizi Wang, Yazhou Zhao, Jianfeng Zhang, Wei Song, Zheyong Xue
Published in
Engineering in life sciences. Volume 26. Issue 8. Pages e008. Epub Aug 12, 2026.
Abstract
Cyclopamine, a typical isosteroidal alkaloid identified as a hedgehog pathway inhibitor, serves as a crucial molecular scaffold for the semi-synthesis of drugs treating nevoid basal cell carcinoma. Verazine is a key intermediate in the biosynthetic pathway of cyclopamine. In this study, we reconstructed the biosynthetic pathway of verazine in engineered Saccharomyces cerevisiae BY-SQ1, obtaining a strain that produced verazine with a yield of 265.38 μg/L. Furthermore, during a 1,000-ns classical MD trajectory, cholesterol retained a broadly consistent heme-facing pose within VcCYP90B27. The modeled pro-R C22 hydrogen remained closer to the heme Fe center on average than the pro-S hydrogen (4.01 vs 4.65 Å), revealing a persistent orientational bias in the bound ensemble. MM-GBSA and contact analyses further indicated that hydrophobic packing around the steroid scaffold and side chain may help maintain this asymmetric presentation. This research not only lays a foundation for the biosynthesis of cyclopamine and other steroidal alkaloids, but also provides a structural rationale for how cholesterol recognition by VcCYP90B27 may contribute to the observed 22R hydroxylation and identifies candidate residues for experimental evaluation.
PMID:
42781495
Bibliographic data and abstract were imported from PubMed on 25 Sep 2026.
Read full publication at:
Please sign in
to see all details.
Advertisement
Stats
- Recommendations n/a n/a positive of 0 vote(s)
- Views 8
- Comments 0