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TitleStructural basis for the biosynthesis of lovastatin.
Journal, issue, pagesNat Commun, Vol. 12, Issue 1, Page 867, Year 2021
Publish dateFeb 8, 2021
AuthorsJialiang Wang / Jingdan Liang / Lu Chen / Wei Zhang / Liangliang Kong / Chao Peng / Chen Su / Yi Tang / Zixin Deng / Zhijun Wang /
PubMed AbstractStatins 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), ...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.
External linksNat Commun / PubMed:33558520 / PubMed Central
MethodsEM (single particle)
Resolution2.91 - 3.6 Å
Structure data

30434

7cpx

EMDB-30434, PDB-7cpx:
Lovastatin nonaketide synthase
Method: EM (single particle) / Resolution: 2.91 Å

30435

7cpy

EMDB-30435, PDB-7cpy:
Lovastatin nonaketide synthase with LovC
Method: EM (single particle) / Resolution: 3.6 Å

Chemicals

ChemComp-NAP:
NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE

Source
  • aspergillus terreus (mold)
KeywordsBIOSYNTHETIC PROTEIN / polyketide synthase

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