On Jul. 24, 2026, a team led by LIAN Jiazhang at Zhejiang University’s College of Chemical and Biological Engineering, in collaboration with researchers from the University of New Brunswick (Canada) and Westlake University (China), have uncovered a previously unknown molecular mechanism that dramatically improves microbial production of vinblastine precursors. Their work increased the production of catharanthine — one of vinblastine’s two immediate precursors — to 164.9 milligrams per liter in engineered yeast, nearly 1,000 times higher than previously reported. Their findings were published online in Science on July 16.

Over the past decade, scientists have increasingly turned to microorganisms such as baker’s yeast as miniature chemical factories. By rewriting their genetic programs, researchers can persuade these microbes to produce pharmaceuticals that would otherwise have to be extracted from plants or synthesized through lengthy chemical processes. Compared with conventional production methods, microbial fermentation offers the promise of safer, more sustainable and scalable manufacturing.

LIAN Jiazhang’s group has pursued that vision for several years. In 2022, the team successfully reconstructed in yeast the approximately 30-step biosynthetic pathway leading to vinblastine precursors, a milestone that demonstrated the feasibility of producing the compound without relying on the plant itself. Yet one critical challenge remained. Despite the complete pathway being present, production stalled at only micrograms per liter, orders of magnitude below what would be required for industrial manufacturing.

The breakthrough emerged from an international collaboration.LIAN Jiazhang’s group maintained a long-standing dialogue with QU Yang’s laboratory at the University of New Brunswick, whose research focuses on plant biochemistry. During discussions about previous experiments, the two teams revisited an intriguing observation from virus-induced gene silencing studies. Whenever a gene known as CAD2 was switched off, vinblastine production collapsed to roughly one-tenth of its normal level.The result was bewildering because CAD2 had generally been regarded as a gene associated with lignin biosynthesis, the pathway responsible for producing a major structural component of plant cell walls.

Another clue soon emerged.CAD2 sits immediately beside the gene encoding geissoschizine synthase in the plant genome and is co-expressed with several genes known to participate in vinblastine biosynthesis. The stronger a plant tissue’s capacity to produce vinblastine, the higher the expression of CAD2. The researchers soon realized that they had most likely identified the long-sought missing component.To investigate its function, they joined forces with WANG Yajie’s team at Westlake University, combining expertise in synthetic biology, plant biochemistry and protein engineering.

The collaboration quickly paid off.When CAD2 was introduced into the engineered yeast strain, production of vinblastine precursors increased dramatically. Further biochemical and structural studies confirmed that the protein encoded by CAD2 played a completely unexpected role. Rather than acting as another enzyme in the pathway, it functioned as a molecular scaffold that physically organized the biosynthetic machinery. The researchers named the protein VinBLAST, short for Vinca alkaloid Biosynthesis Localizing and Activating Scaffold Tether.

VinBLAST works like a molecular bridge. One end binds SGD inside the nucleus, while the other binds GS. By physically bringing the two enzymes together within the same cellular compartment, it enables the unstable intermediate to be transferred directly from one active site to the next before it can degrade. Instead of diffusing through the cell and being lost, the molecule is efficiently channeled through the pathway. But VinBLAST performs another function as well. Using molecular dynamics simulations together with biochemical experiments, the researchers found that VinBLAST also remodels the substrate access tunnel of GS after binding to the enzyme. This subtle structural change dramatically enhances catalytic efficiency, increasing GS activity by approximately 24-fold.

The combination of these two effects — preventing loss of an unstable intermediate while simultaneously accelerating its conversion — proved transformative. Engineered baker’s yeast expressing VinBLAST produced 164.9 milligrams of catharanthine per liter, nearly 1,000-fold higher than previous microbial production systems and, in terms of this key intermediate, and achieving a biosynthetic efficiency that rivals — or even exceeds — that of the plant itself.

The team is collaborating with industrial partners to further scale up microbial production of vinblastine precursors and related alkaloids. If successful, the technology could provide a more reliable and economical manufacturing route than plant extraction while offering a general framework for producing a broad range of complex natural products.