2026-09-18T23:01:12Z https://www.ideals.illinois.edu/oai-pmh

oai:www.ideals.illinois.edu:2142/129669 2026-02-05 col_2142_5131 col_2142_14789 com_2142_5130 com_2142_14788 com_2142_8903

application/pdf en text Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2027-05-01 The student, Yue Yu, accepted the attached license on 2025-03-14 at 10:28. The student, Yue Yu, submitted this Dissertation for approval on 2025-03-14 at 12:05. This Dissertation was approved for publication on 2025-03-24 at 11:23. DSpace SAF Submission Ingestion Package generated from Vireo submission #21677 on 2025-10-19 at 19:52:29 Genome mining for natural product biosynthesis: Amino acids, nonribosomal peptides, and ribosomal peptides with posttranslational modifications Yu, Yue 2025-03-24 van der Donk, Wilfred van der Donk, Wilfred Zhao, Huimin Nair, Satish Mehta, Angad natural product biosynthesis enzymes eng Natural products, secondary metabolites produced by microbial species, have served as privileged drug scaffolds in human medicine. Their complex structures are biosynthesized by enzymes encoded in the microbial genome, often referred to as biosynthetic gene clusters (BGCs). Despite the importance of natural products, many biosynthetic pathways of known natural products and related enzymatic mechanisms remain poorly understood. In addition, advances in genome sequencing have revealed numerous orphan BGCs, where either the structure of the natural product or the function of encoded enzymes cannot be reliably predicted. These unresolved questions in natural product biosynthesis motivated my research to explore genome mining for discovering biosynthetic pathways with novel biosynthetic logic and enzymatic mechanisms. In Chapter 1, I introduce the biosynthetic machinery responsible for three classes of natural products: nonribosomal peptides (NRPs), ribosomally synthesized and post-translationally modified peptides (RiPPs), and single amino acid-derived natural products, termed pearlins. Chapter 2 describes a carrier peptide-mediated biosynthesis of the pearlin 3-thiahomoleucine and the reconstitution of a cobalamin-dependent radical S-adenosylmethionine enzyme that catalyzes C-isopropylation. Chapter 3 details the discovery of the nonribosomal peptide threopeptin and the biochemical study of a novel peptide extension machinery. Chapter 4 demonstrates how genome mining of enzymes annotated as ‘domain of unknown function’ led to the discovery of new post-translational modifications in peptide natural products. Overall, these studies revealed unexpected enzyme functions and novel biosynthetic strategies, providing new insights into natural product biosynthesis and new opportunities for future bioengineering applications in drug development. 2025-05 Thesis https://hdl.handle.net/2142/129669 Copyright 2025 Yue Yu Chemistry Chemistry University of Illinois Urbana-Champaign Ph.D. Dissertation