Title: Discovery and Characterization of Natural Product Biosynthetic Pathways

Abstract: Peptide natural products (PNPs) are compounds that contain multiple amide bonds connecting amino acid or carboxylic acid building blocks.  Many PNPs display potent biological activities.  The largest families of PNPs are classified as nonribosomal peptides (NRPs) and ribosomally synthesized and posttranslationally modified peptides (RiPPs). These compounds are synthesized via nonribosomal peptide synthetases (NRPSs) and RiPPs-associated enzymes, respectively.   In the first part of the talk, I will present the discovery of a new class of Copper-dependent oxidative modification enzyme involved in fungal RiPP biosynthesis.  This new family of enzymes, previously annotated as DUF3328 enzymes, has a completely novel fold and uses two copper metals at the active site to catalyze a variety of reactions in RiPPs maturation, including oxidative crosslinking, desaturation and halogenation  
In addition to these two canonical families of PNPs, an additional group of PNPs that is not derived from either of these pathways has garnered interests in recent years.  These PNPs are short peptides or pseudopeptides that have useful bioactivities.  In the second part of talk, I will present recent progress in our lab to discover the biosynthetic pathway of such PNPs from fungi using enzymes such as ATP-grasp enzymes and amide-bond synthetases as leads.  Using the well-known cysteine protease inhibitor E-64 as an example, we demonstrate how these standalone enzymes can form PNPs in fungi.  The biosynthetic enzymes are shown to be highly robust and promiscuous, which enabled the generation of thousands of analogs and one-pot biocatalytic preparation of clinically relevant, synthetic analogs.  Using these enzymes as beacons for genome mining, many biosynthetic gene clusters can be identified and characterized, leading to the discovery of new PNPs containing diverse building blocks. 

Brief Biography: Yi Tang received his undergraduate degree in Chemical Engineering and Material Science from Penn State University.  He received his Ph.D. in Chemical Engineering from California Institute of Technology under the guidance of Prof. David A. Tirrell.  After NIH postdoctoral training in Chemical Biology from Prof. Chaitan Khosla at Stanford University, he started his independent career at University of California Los Angeles in 2004.  He is currently the Ralph M. Parsons Foundation Chair in Department of Chemical and Biomolecular Engineering at UCLA, and holds joint appointments in the Department of Chemistry and Biochemistry; and Department of Bioengineering.  His awards include the ACS Arthur C. Cope Scholar Award (2012), the EPA Presidential Green Chemistry Challenge Award (2012), NIH DP1 Director Pioneer Award (2012), the ACS Eli Lilly Award in Biological Chemistry (2014), the Society of Industrial Microbiology and Biotechnology Charles Thom Award (2019) and the Marvin Johnson Award from American Chemical Society (2025).  He has coauthored over 250 papers, as well as several books with the late Prof. Christopher Walsh, including “Natural Product Biosynthesis, Chemical Logic and Enzymatic Machinery” of which 2nd edition is now available. 

See more of Dr. Tang's research on his website: https://sites.google.com/site/yitanglab/hom