Citation: Jianing Liu, Qian Zhang, Cong Su, Songyang Sui, Changkang Li, Ridao Chen, Dawei Chen, Jimei Liu, Jungui Dai, Kebo Xie. Identification of a BBE-like enzyme involved in the biosynthesis of pyranocoumarins and its catalytic mechanism in the pyran ring formation[J]. Chinese Chemical Letters, ;2026, 37(10): 112531. doi: 10.1016/j.cclet.2026.112531 shu

Identification of a BBE-like enzyme involved in the biosynthesis of pyranocoumarins and its catalytic mechanism in the pyran ring formation

State Key Laboratory of Bioactive Substance and Function of Natural Medicines, NHC Key Laboratory of Biosynthesis of Natural Products, CAMS Key Laboratory of Enzyme and Biocatalysis of Natural Drugs, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China

keboxie@imm.ac.cn

Received Date: 6 November 2025
Revised Date: 12 February 2026
Accepted Date: 13 February 2026
Available Online: 13 February 2026

Figures(7)

Pyranocoumarins are a characteristic class of pyranophenolic compounds predominantly found in plants of the Moraceae, Umbelliferae, and Rutaceae families. These pyranophenolics not only exhibit diverse physiological activities, but also have a wide range of pharmacological activities such as anti-cancer, anti-spasmatic, and anticoagulant. However, the biosynthetic mechanism of pyranocoumarins, especially the formation mechanism of the pyran core in the final step, remains unclear. It was hypothesized the pyran core is formed by dehydration of decursinol after oxidation and cyclization of demethylsuberosin. Here we characterized a berberine bridge enzyme (BBE)-like enzyme namely FcBBElike4 from Ficus carica. FcBBElike4 could catalyze direct cyclization of 6- and 8-isoprenyl coumarins into corresponding pyranocoumarins, which functionally characterized as an oxidocyclase (OC). This finding elucidated the final step in the biosynthetic pathway for pyranocoumarins. The catalytic mechanism of FcBBElike4 was investigated and a general key active site of aspartic acid residue determining the cyclization activity of BBE-like enzymes was identified. Diverse BBE-like enzymes with diene synthesis activities were mined and further engineered into rare OCs with high catalytic activity and broad substrate spectra. What is more, an enzymatic approach to synthesize pyranophenolics was constructed based on engineered OCs and applied in the synthesis of drug molecules. This study not only elucidates the key biosynthetic steps of pyranocoumarins but also offers insights into engineering common BBE-like enzymes into rare and useful OCs.
- Pyranocoumarins,
- Biosynthesis,
- BBE-like enzymes,
- Oxidocyclase,
- Benzopyran,
- Function switch
1. [1]
  M.T. Khandy, A.K. Sofronova, T.Y. Gorpenchenko, et al., Plants 11 (2022) 3135. doi: 10.3390/plants11223135
2. [2]
  J.C. Amaral, M.M. da Silva, M.F.G.F. da Silva, et al., J. Nat. Prod. 83 (2020) 1409–1415. doi: 10.1021/acs.jnatprod.9b00607
3. [3]
  C.M.S. Junior, S.M.C. Silva, E.M. Sales, et al., Fitoterapia 168 (2023) 105489. doi: 10.1016/j.fitote.2023.105489
4. [4]
  Y.S. Zou, Y.X. Teng, J. Li, et al., Green Chem. Eng. 5 (2024) 150–154. doi: 10.1016/j.gce.2023.04.003
5. [5]
  D. Chaudhary, P. Bedi, S. Santra, et al., Lett. Org. Chem. 19 (2022) 362–387. doi: 10.2174/1570178618666210202152452
6. [6]
  C.R. Su, S.F. Yeh, C.M. Liu, et al., Bioorg. Med. Chem. 17 (2009) 6137–6143. doi: 10.1016/j.bmc.2008.12.007
7. [7]
  R.J. Shi, S.Z. Liu, Y. Zhao, et al., Fitoterapia 178 (2024) 106181. doi: 10.1016/j.fitote.2024.106181
8. [8]
  J. Zhang, W.F. Zhu, J. Xu, et al., J. Ethnopharmacol. 214 (2018) 37–46. doi: 10.1016/j.jep.2017.11.016
9. [9]
  B. Burlando, M. Clericuzio, L. Cornara, J. Mini-Rev. Med. Chem. 17 (2017) 108–121.
10. [10]
  K. Zhou, S. Yang, S.M. Li, Nat. Prod. Rep. 38 (2021) 2236–2260. doi: 10.1039/d0np00083c
11. [11]
  T.C. McKee, R.W. Fuller, C.D. Covington, et al., J. Nat. Prod. 59 (1996) 754–758. doi: 10.1021/np9603784
12. [12]
  N.C. Veitch, Nat. Prod. Rep. 24 (2007) 417–464. doi: 10.1039/b511238a
13. [13]
  M.S. Baliga, A.R. Shivashankara, R. Haniadka, et al., Food Res. Int. 44 (2011) 1800–1811. doi: 10.1016/j.foodres.2011.02.035
14. [14]
  M.Y. Tian, Y.N. Wang, A.Q. Lu, et al., Phytochem. Anal. 33 (2022) 644–653. doi: 10.1002/pca.3117
15. [15]
  E.H. Hakim, S.A. Achmad, L.D. Juliawaty, et al., J. Nat. Med. 60 (2006) 161–184. doi: 10.1007/s11418-006-0048-0
16. [16]
  E.W.C. Chan, S.K. Wong, J. Tangah, et al., J. Integr. Med. 18 (2020) 189–195. doi: 10.1016/j.joim.2020.02.006
17. [17]
  T. Fujimoto, Y. Hano, T. Nomura, Planta Med. 50 (1984) 218–221. doi: 10.1055/s-2007-969682
18. [18]
  L.A. Sorbera, P. Leeson, J. Castaner, Drugs Future 24 (1999) 235–245. doi: 10.1358/dof.1999.024.03.474035
19. [19]
  S.M. Kang, S. Seo, E.J. Song, et al., Cells 12 (2023) 1232. doi: 10.3390/cells12091232
20. [20]
  B. Malawska, Curr. Top. Med. Chem. 5 (2005) 69–85. doi: 10.2174/1568026053386944
21. [21]
  T. Mizumura, K. Nithipatikom, G.J. Gross, Circulation 92 (1995) 1236–1245. doi: 10.1161/01.CIR.92.5.1236
22. [22]
  F. Karamat, A. Olry, R. Munakata, et al., Plant J. 77 (2014) 627–638. doi: 10.1111/tpj.12409
23. [23]
  Y.C. Zhao, Y.D. He, L.L. Han, et al., Acta Pharm. Sin. B 14 (2024) 869–880. doi: 10.1016/j.apsb.2023.10.016
24. [24]
  X.C. Huang, H. Tang, X. Wei, et al., Nat. Commun. 15 (2024) 6864. doi: 10.1038/s41467-024-51285-x
25. [25]
  H.B. Gómez-Robledo, F. Cruz-Sosa, A. Bernabé-Antonio, et al., BMC Plant. Biol. 16 (2016) 177. doi: 10.1186/s12870-016-0862-9
26. [26]
  T. Gülck, B.L. Møller, Trends. Plant Sci. 25 (2020) 985–1004. doi: 10.1016/j.tplants.2020.05.005
27. [27]
  M. Iijima, R. Munakata, H. Takahashi, et al., Plant Physiol. 174 (2017) 2213–2230. doi: 10.1104/pp.17.00586
28. [28]
  Q. Ding, N.X. Guo, L. Gao, et al., Nat. Commun. 15 (2024) 2492. doi: 10.1038/s41467-024-46845-0
29. [29]
  Y. Shoyama, T. Tamada, K. Kurihara, et al., J. Mol. Biol. 423 (2012) 96–105. doi: 10.1016/j.jmb.2012.06.030
30. [30]
  B. Daniel, B. Konrad, M. Toplak, et al., Arch. Biochem. Biophys. 632 (2017) 88–103. doi: 10.1016/j.abb.2017.06.023
31. [31]
  L. Gao, C. Su, X.X. Du, et al., Nat. Chem. 12 (2020) 620–628. doi: 10.1038/s41557-020-0467-7
32. [32]
  M. Bano, K.P. Barot, S.V. Jain, et al., Med. Chem. Res. 24 (2015) 3008–3020. doi: 10.1007/s00044-015-1344-6
33. [33]
  R.F. Fatykhov, I.A. Khalymbadzha, O.N. Chupakhin, et al., Synthesis 51 (2019) 3617–3624. doi: 10.1055/s-0039-1690104
34. [34]
  K.C. Nicolaou, J.A. Pfefferkorn, A.J. Roecker, et al., J. Am. Chem. Soc. 122 (2000) 9939–9953. doi: 10.1021/ja002033k
35. [35]
  D. Yi, T. Bayer, C.P.S. Badenhorst, et al., Chem. Soc. Rev. 50 (2021) 8003–8049. doi: 10.1039/d0cs01575j
36. [36]
  E.L. Bell, W. Finnigan, S.P. France, et al., Nat. Rev. Methods Primers 1 (2021) 46.
37. [37]
  K.B. Xie, Q. Zhang, F. Ye, et al., Chin. Chem. Lett. 35 (2024) 109028. doi: 10.1016/j.cclet.2023.109028
38. [38]
  Y. Li, Y.N. Wang, Y.G. Luo, et al., Chin. Chem. Lett. 35 (2024) 109576.
39. [39]
  J.J. Zhou, Z.L. Wang, M. Zhang, et al., Chin. Chem. Lett. 36 (2025) 110805. doi: 10.1016/j.cclet.2024.110805
40. [40]
  J.M. Liu, Z.F. Wang, J. Wu, et al., Chin. Chem. Lett. 34 (2023) 108363. doi: 10.1016/j.cclet.2023.108363
41. [41]
  Y.Y. Liu, X.N. Li, S.Y. Sui, et al., Acta Pharm. Sin. B 13 (2023) 1771–1785.
42. [42]
  R.D. Chen, B.Q. Gao, X. Liu, et al., Nat. Chem. Biol. 13 (2017) 226–234. doi: 10.1038/nchembio.2263
43. [43]
  T. Wang, J.S. Zou, K.B. Wang, et al., Angew. Chem. Int. Ed. 64 (2025) e202419092.
44. [44]
  S.Q. Zhang, K.B. Wang, Y.N. Liu, et al., ACS Catal. 14 (2024) 17598–17608. doi: 10.1021/acscatal.4c05811
45. [45]
  X. Liu, L. Sheng, M.M. Zhao, et al., Drug Metab. Pharmacokinet. 30 (2015) 89–96. doi: 10.2495/CUEE140111
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