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Structural basis for the biosynthesis of lovastatin

Author

Listed:
  • Jialiang Wang

    (Shanghai Jiao Tong University)

  • Jingdan Liang

    (Shanghai Jiao Tong University)

  • Lu Chen

    (Shanghai Jiao Tong University)

  • Wei Zhang

    (Shanghai Jiao Tong University)

  • Liangliang Kong

    (National Facility for Protein Science in Shanghai)

  • Chao Peng

    (National Facility for Protein Science in Shanghai)

  • Chen Su

    (National Facility for Protein Science in Shanghai)

  • Yi Tang

    (University of California)

  • Zixin Deng

    (Shanghai Jiao Tong University)

  • Zhijun Wang

    (Shanghai Jiao Tong University)

Abstract

Statins are effective cholesterol-lowering drugs. Lovastatin, one of the precursors of statins, is formed from dihydromonacolin L (DML), which is synthesized by lovastatin nonaketide synthase (LovB), with the assistance of a separate trans-acting enoyl reductase (LovC). A full DML synthesis comprises 8 polyketide synthetic cycles with about 35 steps. The assembling of the LovB–LovC complex, and the structural basis for the iterative and yet permutative functions of the megasynthase have remained a mystery. Here, we present the cryo-EM structures of the LovB–LovC complex at 3.60 Å and the core LovB at 2.91 Å resolution. The domain organization of LovB is an X-shaped face-to-face dimer containing eight connected domains. The binding of LovC laterally to the malonyl-acetyl transferase domain allows the completion of a L-shaped catalytic chamber consisting of six active domains. This architecture and the structural details of the megasynthase provide the basis for the processing of the intermediates by the individual catalytic domains. The detailed architectural model provides structural insights that may enable the re-engineering of the megasynthase for the generation of new statins.

Suggested Citation

  • Jialiang Wang & Jingdan Liang & Lu Chen & Wei Zhang & Liangliang Kong & Chao Peng & Chen Su & Yi Tang & Zixin Deng & Zhijun Wang, 2021. "Structural basis for the biosynthesis of lovastatin," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21174-8
    DOI: 10.1038/s41467-021-21174-8
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    Cited by:

    1. Jialiang Wang & Xiaojie Wang & Xixi Li & LiangLiang Kong & Zeqian Du & Dandan Li & Lixia Gou & Hao Wu & Wei Cao & Xiaozheng Wang & Shuangjun Lin & Ting Shi & Zixin Deng & Zhijun Wang & Jingdan Liang, 2023. "C–N bond formation by a polyketide synthase," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    2. Guifa Zhai & Yan Zhu & Guo Sun & Fan Zhou & Yangning Sun & Zhou Hong & Chuan Dong & Peter F. Leadlay & Kui Hong & Zixin Deng & Fuling Zhou & Yuhui Sun, 2023. "Insights into azalomycin F assembly-line contribute to evolution-guided polyketide synthase engineering and identification of intermodular recognition," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

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