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| Title | Structural Insights into Three Bifunctional Sesterterpene Synthases and Product Profile Investigation by Domain Swapping and Active Site Mutation. |
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| Journal, issue, pages | J Am Chem Soc, Year 2026 |
| Publish date | Jan 23, 2026 |
 Authors | Zhenyu Lei / Ruiqing Lyu / Wenlong Song / Chenyu Zhang / Lin Bai / Donghui Yang / Ming Ma /  |
| PubMed Abstract | Terpene synthases (TSs) catalyze the formation of diverse hydrocarbon skeletons by using different linear polyisoprenyl diphosphates as the substrates, whose biosyntheses are catalyzed by ...Terpene synthases (TSs) catalyze the formation of diverse hydrocarbon skeletons by using different linear polyisoprenyl diphosphates as the substrates, whose biosyntheses are catalyzed by prenyltransferases (PTs). In nature, some TSs are bifunctional enzymes catalyzing both polyisoprenyl diphosphate formation and subsequent cyclization, containing a C-terminal PT domain and an N-terminal terpene cyclase (TC) domain. To date, several bifunctional PT-TC diterpene synthases and triterpene synthase have been structurally characterized, whereas there have been no structural insights reported for bifunctional PT-TC sesterterpene synthases (StTSs). We here report the cryo-EM structures of three full-length StTSs (EvAS, EvSS, and PbSS), revealing that EvAS and PbSS share a similar PT-driven hexamerization architecture, but EvSS possesses a PT-hexamer stacked helical hollow tubular architecture that has not been observed for other TSs. Domain swapping among the three StTSs shows that not only the production yields but also the major product types of TCs can be greatly affected by different noncovalently linked PTs. The atypical α-helical bundle crystal structure of the TC domain of EvAS was determined, revealing key secondary structures whose positions may affect the cyclization function. Systematic mutations on key residues in the active sites of the TC domains of EvAS and EvSS generated seven new compounds, expanding the structural diversity of sesterterpenes. These results uncover the new structural architecture of bifunctional TSs and expand our understanding of their substrate transfer and catalytic function, and benefit the rational engineering and design of collaborated PT and TC pairs in the generation of terpene molecules. |
 External links | J Am Chem Soc / PubMed:41575888 |
| Methods | EM (single particle) |
| Resolution | 3.04 - 3.3 Å |
| Structure data | EMDB-66378, PDB-9wyv: EMDB-66379, PDB-9wyx: EMDB-66380, PDB-9wz3: EMDB-66433, PDB-9x0f: |
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 Keywords | BIOSYNTHETIC PROTEIN / Astellifadiene synthase / Sesterbrasiliatriene synthase PbSS / EvSS / Stellatatriene synthase |
aspergillus stellatus (mold)