Structural basis for the biosynthesis of lovastatin

Area of Science:

• Biochemistry
• Structural Biology
• Drug Discovery

Background:

• Statins are crucial cholesterol-lowering drugs.
• Lovastatin synthesis involves the lovastatin nonaketide synthase (LovB) and a trans-acting enoyl reductase (LovC).
• The structural basis for the iterative and permutative functions of the LovB-LovC megasynthase complex remained elusive.

Purpose of the Study:

• To determine the cryo-electron microscopy (cryo-EM) structures of the LovB-LovC complex and core LovB.
• To elucidate the structural basis for the catalytic mechanism of dihydromonacolin L (DML) synthesis.
• To provide insights for potential re-engineering of the megasynthase for novel statin generation.

Main Methods:

• Cryo-electron microscopy (cryo-EM) was used to resolve the structures.
• High-resolution structures of the LovB-LovC complex (3.60 Å) and core LovB (2.91 Å) were obtained.

Main Results:

• The domain organization of LovB was revealed as an X-shaped, face-to-face dimer with eight connected domains.
• The binding of LovC to the malonyl-acetyl transferase domain completes an L-shaped catalytic chamber comprising six active domains.
• Detailed structural insights into the megasynthase architecture and intermediate processing were provided.

Conclusions:

• The determined structures provide a mechanistic understanding of the LovB-LovC megasynthase.
• This structural information may facilitate the rational design and engineering of novel statin derivatives.
• The findings advance the field of polyketide biosynthesis and drug development.