{"id":{"repo_id":"uiuc","oai_identifier":"oai:www.ideals.illinois.edu:2142/120504"},"canonical_url":"https://search.dev.ndltd.org/etd/uiuc/oai:www.ideals.illinois.edu:2142/120504","repository":{"repo_id":"uiuc","name":"University of Illinois - Urbana-Champaign","base_url":"https://www.ideals.illinois.edu/oai-pmh"},"display":{"title":"Stereochemical control in lanthipeptide biosynthesis","abstract":"Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2025-05-01","abstract_html":"Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2025-05-01","abstract_has_math":false,"creators":["Sarksian, Raymond"],"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 A","Hergenrother, Paul J","Chan, Jeff","Olshansky, Lisa"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2023,"date_issued":"2023-05","date_published":"2023-05","updated_at":"2026-07-22T22:24:57Z","subjects":["Natural Products","Lanthipeptide","Stereochemistry","Enzymatic Reactions"],"languages":["en","eng"],"rights":["Copyright 2023 Raymond Sarksian"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/2142/120504","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["van der Donk, Wilfred A","Hergenrother, Paul J","Chan, Jeff","Olshansky, Lisa"]},{"key":"dc:creator","label":"Author","values":["Sarksian, Raymond"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2023-05","2023-04-12"]},{"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":["Natural Products","Lanthipeptide","Stereochemistry","Enzymatic Reactions"]}]},{"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 2023 Raymond Sarksian"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://hdl.handle.net/2142/120504"]}]},{"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 2025-05-01","The student, Raymond Sarksian, accepted the attached license on 2023-04-04 at 17:20.","The student, Raymond Sarksian, submitted this Dissertation for approval on 2023-04-04 at 17:31.","This Dissertation was approved for publication on 2023-04-12 at 16:49.","DSpace SAF Submission Ingestion Package generated from Vireo submission #18919 on 2023-09-01 at 17:20:17","Lanthipeptides are polycyclic natural products that contain lanthionine (Lan) and/or methyllanthionine (MeLan) cross-links. These thioether macrocycles in lanthipeptides bestow upon these molecules their unique bioactivities and provide proteolytic stability. Despite the complex structure of lanthipeptides, these natural products are derived from simple ribosomally synthesized linear precursor peptides that contain all L-amino acids. The linear precursor peptides are extensively post-translationally modified through dehydration and cyclization reactions to generate stereochemically defined (Me)Lan residues. As with other natural products, the complex stereochemistry of lanthipeptides, particularly the stereochemical configuration of (Me)Lan residues, is critical for their biological activities. The research studies described herein focus on investigating lanthipeptide stereochemistry and how stereochemistry is controlled during the biosynthesis of lanthipeptides. In chapter 2, the morphogenetic lanthipeptide SapT was discovered to be the first lanthipeptide to contain D-allo-L-MeLan macrocycles. Critical to the discovery of the D-allo-L-MeLan diastereomer in SapT was developing synthetic and analytical methods to unambiguously determine MeLan stereochemistry. The unusual product stereochemistry in SapT prompted mechanistic studies in chapter 3 to determine how D-allo-L-MeLan cross-links were formed. Through structural characterization of a model biosynthetic intermediate, it was determined that SapT biosynthesis proceeds through (E)- rather than (Z)-dehydrobutyrine (Dhb) intermediates that have been observed previously for all characterized lanthipeptides. The glutamyl lyase (GL) in SapT biosynthesis was thus shown to catalyze stereoselective syn-elimination. In chapter 4, additional syn-GLs were bioinformatically identified in lanthipeptide biosynthetic gene clusters and one representative gene cluster termed coi was experimentally investigated. The coi gene cluster was determined to generate a polycyclic lanthipeptide termed mCoiA1 that contained three MeLan diastereomers, each at different locations within the peptide. One of the MeLan residues in mCoiA1 was determined to be a D-allo-L-MeLan residue. Therefore, the studies outlined in chapter 4 illustrated that D-allo-L-MeLan macrocycles are not limited to SapT, but are rather common in lanthipeptides and can be predicted based on the amino acid sequence of the GL. Finally, in chapter 5 experimental studies were aimed towards elucidating how lanthipeptide cyclases control and alter Lan product stereochemistry. The studies described in this thesis illustrate how stereochemistry is tightly regulated enzymatically in nature to produce stereochemically complex peptidic natural products and provide direction towards future investigations into lanthipeptides."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Stereochemical control in lanthipeptide biosynthesis"]}]}],"canonical_facts":{"dc:contributor":["van der Donk, Wilfred A","Hergenrother, Paul J","Chan, Jeff","Olshansky, Lisa"],"dc:creator":["Sarksian, Raymond"],"dc:date":["2023-05","2023-04-12"],"dc:description":["Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2025-05-01","The student, Raymond Sarksian, accepted the attached license on 2023-04-04 at 17:20.","The student, Raymond Sarksian, submitted this Dissertation for approval on 2023-04-04 at 17:31.","This Dissertation was approved for publication on 2023-04-12 at 16:49.","DSpace SAF Submission Ingestion Package generated from Vireo submission #18919 on 2023-09-01 at 17:20:17","Lanthipeptides are polycyclic natural products that contain lanthionine (Lan) and/or methyllanthionine (MeLan) cross-links. These thioether macrocycles in lanthipeptides bestow upon these molecules their unique bioactivities and provide proteolytic stability. Despite the complex structure of lanthipeptides, these natural products are derived from simple ribosomally synthesized linear precursor peptides that contain all L-amino acids. The linear precursor peptides are extensively post-translationally modified through dehydration and cyclization reactions to generate stereochemically defined (Me)Lan residues. As with other natural products, the complex stereochemistry of lanthipeptides, particularly the stereochemical configuration of (Me)Lan residues, is critical for their biological activities. The research studies described herein focus on investigating lanthipeptide stereochemistry and how stereochemistry is controlled during the biosynthesis of lanthipeptides. In chapter 2, the morphogenetic lanthipeptide SapT was discovered to be the first lanthipeptide to contain D-allo-L-MeLan macrocycles. Critical to the discovery of the D-allo-L-MeLan diastereomer in SapT was developing synthetic and analytical methods to unambiguously determine MeLan stereochemistry. The unusual product stereochemistry in SapT prompted mechanistic studies in chapter 3 to determine how D-allo-L-MeLan cross-links were formed. Through structural characterization of a model biosynthetic intermediate, it was determined that SapT biosynthesis proceeds through (E)- rather than (Z)-dehydrobutyrine (Dhb) intermediates that have been observed previously for all characterized lanthipeptides. The glutamyl lyase (GL) in SapT biosynthesis was thus shown to catalyze stereoselective syn-elimination. In chapter 4, additional syn-GLs were bioinformatically identified in lanthipeptide biosynthetic gene clusters and one representative gene cluster termed coi was experimentally investigated. The coi gene cluster was determined to generate a polycyclic lanthipeptide termed mCoiA1 that contained three MeLan diastereomers, each at different locations within the peptide. One of the MeLan residues in mCoiA1 was determined to be a D-allo-L-MeLan residue. Therefore, the studies outlined in chapter 4 illustrated that D-allo-L-MeLan macrocycles are not limited to SapT, but are rather common in lanthipeptides and can be predicted based on the amino acid sequence of the GL. Finally, in chapter 5 experimental studies were aimed towards elucidating how lanthipeptide cyclases control and alter Lan product stereochemistry. The studies described in this thesis illustrate how stereochemistry is tightly regulated enzymatically in nature to produce stereochemically complex peptidic natural products and provide direction towards future investigations into lanthipeptides."],"dc:format":["application/pdf"],"dc:identifier":["https://hdl.handle.net/2142/120504"],"dc:language":["en","eng"],"dc:rights":["Copyright 2023 Raymond Sarksian"],"dc:subject":["Natural Products","Lanthipeptide","Stereochemistry","Enzymatic Reactions"],"dc:title":["Stereochemical control in lanthipeptide biosynthesis"],"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":"2026-07-22T22:24:57Z"}