Spatial control of enzyme orientation at the lipid droplet interface enables regio- and chemoselective metabolic flux.

Reprogramming yeast lipid droplet interfaces with LD-anchoring motifs enables cytosol-facing versus LD inner-facing enzyme orientation, boosting prodeoxyviolacein biosynthesis 1300% to 46.25 mg/L.

• Why it matters: Spatially defined immobilization of multienzyme cascades is hard in dynamic intracellular environments, limiting intermediate channeling and metabolic-flux control.
• What they did: Guided by molecular dynamics simulations, the team designed LD-anchoring motifs to orient enzymes at the yeast LD monolayer interface and reorganized a trienzyme PDV cascade across the cytosol–LD boundary.
• The result: The oriented, interface-localized cascade substantially improved PDV production by 1300%, reaching 46.25 mg/L, enabling regio- and chemoselective conversion of hydrophilic substrates to hydrophobic products.

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