Prospecting for natural products by genome mining and microcrystal electron diffraction

Lee Joon Kim; Masao Ohashi; Zhuan Zhang; Dan Tan; Matthew Asay; Duilio Cascio; José A Rodriguez; Yi Tang; Hosea M Nelson

doi:10.1038/s41589-021-00834-2

Prospecting for natural products by genome mining and microcrystal electron diffraction

Nat Chem Biol. 2021 Aug;17(8):872-877. doi: 10.1038/s41589-021-00834-2. Epub 2021 Jul 26.

Authors

Lee Joon Kim^#¹, Masao Ohashi^#², Zhuan Zhang^#², Dan Tan², Matthew Asay¹, Duilio Cascio^{1

3}, José A Rodriguez^{1

3}, Yi Tang^{4

5}, Hosea M Nelson⁶

Affiliations

¹ Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA, USA.
² Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, CA, USA.
³ UCLA-DOE Institute for Genomics and Proteomics, University of California, Los Angeles, Los Angeles, CA, USA.
⁴ Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA, USA. yitang@g.ucla.edu.
⁵ Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, CA, USA. yitang@g.ucla.edu.
⁶ Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA, USA. hosea@chem.ucla.edu.

^# Contributed equally.

Abstract

More than 60% of pharmaceuticals are related to natural products (NPs), chemicals produced by living organisms. Despite this, the rate of NP discovery has slowed over the past few decades. In many cases the rate-limiting step in NP discovery is structural characterization. Here we report the use of microcrystal electron diffraction (MicroED), an emerging cryogenic electron microscopy (CryoEM) method, in combination with genome mining to accelerate NP discovery and structural elucidation. As proof of principle we rapidly determine the structure of a new 2-pyridone NP, Py-469, and revise the structure of fischerin, an NP isolated more than 25 years ago, with potent cytotoxicity but hitherto ambiguous structural assignment. This study serves as a powerful demonstration of the synergy of MicroED and synthetic biology in NP discovery, technologies that when taken together will ultimately accelerate the rate at which new drugs are discovered.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Biological Products / chemistry*
Cryoelectron Microscopy*
Models, Molecular
Molecular Conformation

Substances

Biological Products

Abstract

Publication types

MeSH terms

Substances

Grants and funding