Architecture of the polyketide synthase module: surprises from electron cryo-microscopy

• The first structures of a polyketide synthase module were solved by cryo-EM.
• The module structure is strikingly different than its fatty acid synthase homolog.
• Structures illustrate the dynamics of the module during its catalytic cycle.
• The carrier protein domain localizes optimally for the next reaction of its cargo.

Modular polyketide synthases (PKS) produce a vast array of bioactive molecules that are the basis of many highly valued pharmaceuticals. The biosynthesis of these compounds is based on ordered assembly lines of multi-domain modules, each extending and modifying a specific chain-elongation intermediate before transfer to the next module for further processing. The first 3D structures of a full polyketide synthase module in different functional states were obtained recently by electron cryo-microscopy. The unexpected module architecture revealed a striking evolutionary divergence of the polyketide synthase compared to its metazoan fatty acid synthase homolog, as well as remarkable conformational rearrangements dependent on its biochemical state during the full catalytic cycle. The design and dynamics of the module are highly optimized for both catalysis and fidelity in the construction of complex, biologically active natural products.