Jul 26, 2021
Research image
The team demonstrates the synergy of MicroED and synthetic biology in natural product discovery, technologies that together will ultimately accelerate the speed of new drug discovery.
 
In the paper, they report the use of microcrystal electron diffraction (MicroED), an emerging cryogenic electron microscopy (CryoEM) method, in combination with genome mining, to accelerate natural product (NP) discovery and structural elucidation. 
 
The team’s paper titled “Prospecting for natural products by genome mining and microcrystal electron diffraction” was published in the July 26, 2021 issue of Nature Chemical Biology.
 
Senior authors Professors Yi Tang and Hosea Nelson, and first authors graduate student Lee Joon Kim and research scientist Dr. Masao Ohashi.
Senior authors Professors Yi Tang and Hosea Nelson, and first authors graduate student Lee Joon Kim and research scientist Dr. Masao Ohashi.
 
The lead author is 4th year graduate student Lee Joon Kim of the Nelson group and research scientist Masao Ohashi from the Tang group. Co-authors are former Tang group postdoc Dr. Zhuan Zhang and visiting scientist Dan Tan; former Nelson group postdoc Dr. Matthew Asay, now a Senior Research Scientist at Universal Display Corporation; senior staff scientist Duilio Cascio; Professor José A. Rodriguez; and senior authors Professors Yi Tang and Hosea M. Nelson
 
Natural products are structurally complex molecules produced by living organisms such as bacteria, fungi and plants.  These molecules include erythromycin, paclitaxel (Taxol), etc. and are frontline pharmaceuticals for preventing and treating many human diseases. Because of their low abundance in nature, isolation and structural characterization are bottlenecks for their continued discovery.  In this work, the researchers synergized two new approaches to tackle this bottleneck and accelerate the discovery. The Tang lab used synthetic biology approaches to mine enzymes from fungi that can produce new compounds, as well as compounds that are “orphaned” due to unavailability of the original reported organism. The Nelson lab used the new MicroED approach to rapidly solve three-dimensional structures of the new molecules. These molecules, due to their structural features and low abundance, are difficult to fully analyze using current methods such as NMR and X-ray diffraction. The team’s work showed MicroED can rapidly reveal and confirm structures of natural products. When combined together, the synthetic biology and MicroED techniques will enable rapid discovery of new natural products, which will accelerate drug discovery.  
 
The next step: In future research, the authors hope to increase the throughput and generality of this approach  to dramatically accelerate the discovery of new compounds from natural sources. They envision MicroED and synthetic biology as synergistic tools that will together become a staple in the drug discovery pipeline.
 
For further information contact Professor Yi Tang, yitang@g.ucla.edu and Professor Hosea Nelson, hosea@chem.ucla.edu.