{"id":{"repo_id":"uiuc","oai_identifier":"oai:www.ideals.illinois.edu:2142/127491"},"canonical_url":"https://search.dev.ndltd.org/etd/uiuc/oai:www.ideals.illinois.edu:2142/127491","repository":{"repo_id":"uiuc","name":"University of Illinois - Urbana-Champaign","base_url":"https://www.ideals.illinois.edu/oai-pmh"},"display":{"title":"Post-translational modifications as a route to new chemistry, useful enzymes, and unexpected mechanisms","abstract":"Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2026-12-01","abstract_html":"Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2026-12-01","abstract_has_math":false,"creators":["Nguyen, Dinh Thanh"],"institution":"University of Illinois at Urbana-Champaign","degree_name":"Ph.D.","degree_level":"Dissertation","degree_discipline":"Chemistry","degree_department":null,"school":null,"contributors":["van der Donk, Wilfred Adrianus","Mitchell, Douglas Alan","Nair, Satish K","Chan, Jefferson Kar Fai"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2024,"date_issued":"2024-12-05","date_published":"2024-12-05","updated_at":"2026-07-22T22:25:04Z","subjects":["Enzymes","Natural Products"],"languages":["en","eng"],"rights":["Copyright 2024 Dinh Nguyen"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/2142/127491","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["van der Donk, Wilfred Adrianus","Mitchell, Douglas Alan","Nair, Satish K","Chan, Jefferson Kar Fai"]},{"key":"dc:creator","label":"Author","values":["Nguyen, Dinh Thanh"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2024-12-05","2024-12"]},{"key":"dc:type","label":"Dc Type","values":["text","Thesis"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Chemistry"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Dissertation"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Ph.D."]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["University of Illinois at Urbana-Champaign"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Enzymes","Natural Products"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en","eng"]},{"key":"dc:rights","label":"Dc Rights","values":["Copyright 2024 Dinh Nguyen"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://hdl.handle.net/2142/127491"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2026-12-01","The student, Dinh Nguyen, accepted the attached license on 2024-12-03 at 18:54.","The student, Dinh Nguyen, submitted this Dissertation for approval on 2024-12-03 at 19:25.","This Dissertation was approved for publication on 2024-12-05 at 12:55.","DSpace SAF Submission Ingestion Package generated from Vireo submission #21488 on 2025-03-28 at 14:55:37","Advances in directed evolution, which tailored enzymes to catalyze reactions on the substrate(s) of interest, facilitated the development of biocatalytic routes toward therapeutics. Additionally, enzymes catalyze remarkable transformations to construct privileged scaffolds that benefit drug discovery campaigns. The mentioned drug discovery and development efforts often rely on available reported enzymatic transformations, underscoring the need to discover new enzyme chemistry and enzymes with broad substrate tolerance. A common challenge in this pursuit is identifying the correct substrate(s) of uncharacterized enzymes of interest. This obstacle can be circumvented when exploring enzymes involved in ribosomally-synthesized and post-translationally modified peptides (RiPPs), as their substrates are genomically encoded peptides. In Chapter 1, I review advances in mining genomes for novel RiPP enzymes and briefly describe how they influence my thesis research. In Chapter 2, I describe the discovery of aminopyruvatides, a novel class of cyclic RiPPs biosynthesized by three distinct metalloenzymes. This work highlights a novel enzyme catalyzing the unprecedented conversion of C-terminal aspartate to aminopyruvate and the detailed structural characterization with multiple state-of-the-art techniques, including microcrystal electron diffraction. Chapter 3 describes how the substrate information and the genomic context guided me to discover that the [4+2] cyclase in Micromonospora rosaria is a substrate-tolerant enzyme, producing 14- to 68-membered pyridine-based cyclic peptides with diverse sequences. In Chapter 4, I investigate the substrate recognition mechanism of a tRNA-dependent enzyme previously discovered in the van der Donk lab through genome mining. This investigation revealed the role of a cryptic coiled-coil domain in recognizing the anticodon of tRNAs. Collectively, I demonstrate that uncharacterized RiPP pathways are a rich reservoir of novel chemistry, useful enzymes, and unexpected mechanisms."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Post-translational modifications as a route to new chemistry, useful enzymes, and unexpected mechanisms"]}]}],"canonical_facts":{"dc:contributor":["van der Donk, Wilfred Adrianus","Mitchell, Douglas Alan","Nair, Satish K","Chan, Jefferson Kar Fai"],"dc:creator":["Nguyen, Dinh Thanh"],"dc:date":["2024-12-05","2024-12"],"dc:description":["Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2026-12-01","The student, Dinh Nguyen, accepted the attached license on 2024-12-03 at 18:54.","The student, Dinh Nguyen, submitted this Dissertation for approval on 2024-12-03 at 19:25.","This Dissertation was approved for publication on 2024-12-05 at 12:55.","DSpace SAF Submission Ingestion Package generated from Vireo submission #21488 on 2025-03-28 at 14:55:37","Advances in directed evolution, which tailored enzymes to catalyze reactions on the substrate(s) of interest, facilitated the development of biocatalytic routes toward therapeutics. Additionally, enzymes catalyze remarkable transformations to construct privileged scaffolds that benefit drug discovery campaigns. The mentioned drug discovery and development efforts often rely on available reported enzymatic transformations, underscoring the need to discover new enzyme chemistry and enzymes with broad substrate tolerance. A common challenge in this pursuit is identifying the correct substrate(s) of uncharacterized enzymes of interest. This obstacle can be circumvented when exploring enzymes involved in ribosomally-synthesized and post-translationally modified peptides (RiPPs), as their substrates are genomically encoded peptides. In Chapter 1, I review advances in mining genomes for novel RiPP enzymes and briefly describe how they influence my thesis research. In Chapter 2, I describe the discovery of aminopyruvatides, a novel class of cyclic RiPPs biosynthesized by three distinct metalloenzymes. This work highlights a novel enzyme catalyzing the unprecedented conversion of C-terminal aspartate to aminopyruvate and the detailed structural characterization with multiple state-of-the-art techniques, including microcrystal electron diffraction. Chapter 3 describes how the substrate information and the genomic context guided me to discover that the [4+2] cyclase in Micromonospora rosaria is a substrate-tolerant enzyme, producing 14- to 68-membered pyridine-based cyclic peptides with diverse sequences. In Chapter 4, I investigate the substrate recognition mechanism of a tRNA-dependent enzyme previously discovered in the van der Donk lab through genome mining. This investigation revealed the role of a cryptic coiled-coil domain in recognizing the anticodon of tRNAs. Collectively, I demonstrate that uncharacterized RiPP pathways are a rich reservoir of novel chemistry, useful enzymes, and unexpected mechanisms."],"dc:format":["application/pdf"],"dc:identifier":["https://hdl.handle.net/2142/127491"],"dc:language":["en","eng"],"dc:rights":["Copyright 2024 Dinh Nguyen"],"dc:subject":["Enzymes","Natural Products"],"dc:title":["Post-translational modifications as a route to new chemistry, useful enzymes, and unexpected mechanisms"],"dc:type":["text","Thesis"],"thesis:degree_discipline":["Chemistry"],"thesis:degree_level":["Dissertation"],"thesis:degree_name":["Ph.D."],"thesis:institution_name":["University of Illinois at Urbana-Champaign"]},"updated_at":"2026-07-22T22:25:04Z"}