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ChEM-H scientists highlight promise of molecular assembly lines

Chaitan Khosla
Jul 1 2014

Stanford ChEM-H scientists propose a new hypothesis for how bacterial assembly lines produce an important class of drugs, potentially helping scientists generate novel drugs including new types of antibiotics.

By Kelly Zalocusky

Snapshot

Some of the most effective treatments for human disease--including blockbuster antibacterial, anti-cancer, and anti-hypertension drugs—are compounds called polyketides made by bacteria. Scientists are just beginning to understand how enzymatic assembly lines called polyketide synthases produce these exceptionally intricate molecules. In their recent Perspective in the journal  Biochemistry, Chaitan Khosla, director of Stanford ChEM-H, and Daniel Herschlag, professor of biochemistry, explained the current state of knowledge regarding the operating principles of these assembly lines. They also put forth a radically new hypothesis for how a polyketide molecule moves along its enzymatic assembly line during the fabrication process. If this hypothesis proves correct, it could allow scientists to engineer an unimaginable range of novel, antibiotic-like compounds. 

Why does this matter?

As the genomes of more and more bacteria are sequenced, scientists continue to uncover previously unknown polyketide assembly lines. These new assembly lines may be responsible for manufacturing our next blockbuster anti-hypertensive agent, life-saving antibiotic, or anti-cancer compound. Understanding the polyketide assembly lines will allow scientists to search efficiently for new naturally occurring drugs.

Furthermore, understanding these assembly lines will allow scientists to engineer bacteria to synthesize any imaginable polyketide. Co-opting nature's own assembly lines may allow for more rapid responses to antibiotic resistance or for manufacturing drugs with fewer side effects.

What is it?

To make such a spectacular range of structurally complex antibiotics, polyketide assembly lines solve two important biochemical problems. First, they are very good at constructing molecules with defined three-dimensional structures. A polyketide molecule with 10 shape-inducing carbon atoms can assume as many as 1024  (210) theoretically possible shapes with the same chemical formula, but the assembly line always manufactures exactly one of those possible shapes. This property is very important for their activity as drugs.

Second, the polyketide product is built from start to finish by transporting it along the assembly line in just one direction. Each stop on the enzymatic assembly line is like a robot in an automobile factory--adding one additional piece to the molecule, twisting it into the correct configuration, and passing the product onto the next tiny molecular robot.

The challenge in understanding the polyketide assembly line is that the molecular robots are too small and too dynamic to see, even with our most powerful microscopes. State-of-the-art X-ray instruments, such as those recently installed at the SLAC National Accelerator Laboratory, may soon be able to unravel this problem. When that happens, the hypothesis put forward by Khosla, Herschlag, and their collaborators could be a critical chapter in the operating manual required interpret such atomic-scale images.