{"id":{"repo_id":"uiuc","oai_identifier":"oai:www.ideals.illinois.edu:2142/26343"},"canonical_url":"https://search.dev.ndltd.org/etd/uiuc/oai:www.ideals.illinois.edu:2142/26343","repository":{"repo_id":"uiuc","name":"University of Illinois - Urbana-Champaign","base_url":"https://www.ideals.illinois.edu/oai-pmh"},"display":{"title":"Toward the synthesis and evaluation of novel N-acylated FR-900098 analogs","abstract":"Malaria represents one of the most significant threats to global health today, with half of the world’s population currently at risk. Although there exist several antimalarial drugs to treat the disease, many of them have been used and over-used for decades, leading to widespread resistance in the causative Plasmodium parasite. As a result, new antimalarials are needed not only to replace the old, but also to supplement each other in novel combination therapies. Two such candidates are fosmidomycin and its N-acetyl analog FR-900098, Streptomycete natural products first identified in the 1980s. These compounds were later found to be potent inhibitors of 1-deoxy-D-xylulose 5-phosphate reductoisomerase, a necessary enzyme in Plasmodium for isoprenoid biosynthesis via the non-mevalonate pathway, which does not exist in humans. Although FR-900098 was determined to be about twice as potent as fosmidomycin, it is important to note that, as a Streptomycete secondary metabolite, it is by no means optimized as a human antimalarial drug. In the work presented here, we have studied and characterized the N-acetyltransferase FrbF from the FR-900098 biosynthetic pathway, which was recently completely reconstituted in E. coli. This enzyme is responsible for transfer of the acetyl group from acetyl-CoA to the phosphonate substrate, representing the penultimate step in FR-900098 synthesis. By exploiting the substrate specificity of FrbF, we can synthesize novel derivatives of FR-900098 with alternate N-acyl functionalities both in vivo and in vitro, such as the N-propionyl analog FR-900098P, which was found to be even more potent than its parent compound. We have also heterologously expressed and characterized the target enzyme from P. falciparum, which serves as a tool to evaluate the effectiveness of novel antimalarial compounds. Finally, we have developed a screening method for the directed evolution of FrbF to identify mutants with altered substrate specificity.","abstract_html":"Malaria represents one of the most significant threats to global health today, with half of the world’s population currently at risk. Although there exist several antimalarial drugs to treat the disease, many of them have been used and over-used for decades, leading to widespread resistance in the causative Plasmodium parasite. As a result, new antimalarials are needed not only to replace the old, but also to supplement each other in novel combination therapies. Two such candidates are fosmidomycin and its N-acetyl analog FR-900098, Streptomycete natural products first identified in the 1980s. These compounds were later found to be potent inhibitors of 1-deoxy-D-xylulose 5-phosphate reductoisomerase, a necessary enzyme in Plasmodium for isoprenoid biosynthesis via the non-mevalonate pathway, which does not exist in humans. Although FR-900098 was determined to be about twice as potent as fosmidomycin, it is important to note that, as a Streptomycete secondary metabolite, it is by no means optimized as a human antimalarial drug. In the work presented here, we have studied and characterized the N-acetyltransferase FrbF from the FR-900098 biosynthetic pathway, which was recently completely reconstituted in E. coli. This enzyme is responsible for transfer of the acetyl group from acetyl-CoA to the phosphonate substrate, representing the penultimate step in FR-900098 synthesis. By exploiting the substrate specificity of FrbF, we can synthesize novel derivatives of FR-900098 with alternate N-acyl functionalities both in vivo and in vitro, such as the N-propionyl analog FR-900098P, which was found to be even more potent than its parent compound. We have also heterologously expressed and characterized the target enzyme from P. falciparum, which serves as a tool to evaluate the effectiveness of novel antimalarial compounds. Finally, we have developed a screening method for the directed evolution of FrbF to identify mutants with altered substrate specificity.","abstract_has_math":false,"creators":["Cobb, Ryan E."],"institution":"University of Illinois at Urbana-Champaign","degree_name":"M.S.","degree_level":"Thesis","degree_discipline":"Chemical Engineering","degree_department":null,"school":null,"contributors":["Zhao, Huimin"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2011,"date_issued":"2011-08-26T15:24:12Z","date_published":"2011-08-26T15:24:12Z","updated_at":"2026-07-22T22:25:26Z","subjects":["deoxyxylulose-5-phosphate reductoisomerase (Dxr)","FR-900098","antimalarials","N-acetyltransferase","FrbF"],"languages":["en"],"rights":["© 2011 Ryan Ellis Cobb"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/2142/26343","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Zhao, Huimin"]},{"key":"dc:creator","label":"Author","values":["Cobb, Ryan E."]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2011-08-26T15:24:12Z","2013-08-27T10:00:24Z","2011-08"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Chemical Engineering"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Thesis"]},{"key":"thesis:degree_name","label":"Degree Name","values":["M.S."]},{"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":["deoxyxylulose-5-phosphate reductoisomerase (Dxr)","FR-900098","antimalarials","N-acetyltransferase","FrbF"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en"]},{"key":"dc:rights","label":"Dc Rights","values":["© 2011 Ryan Ellis Cobb"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["http://hdl.handle.net/2142/26343"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Malaria represents one of the most significant threats to global health today, with half of the world’s population currently at risk. 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In the work presented here, we have studied and characterized the N-acetyltransferase FrbF from the FR-900098 biosynthetic pathway, which was recently completely reconstituted in E. coli. This enzyme is responsible for transfer of the acetyl group from acetyl-CoA to the phosphonate substrate, representing the penultimate step in FR-900098 synthesis. By exploiting the substrate specificity of FrbF, we can synthesize novel derivatives of FR-900098 with alternate N-acyl functionalities both in vivo and in vitro, such as the N-propionyl analog FR-900098P, which was found to be even more potent than its parent compound. We have also heterologously expressed and characterized the target enzyme from P. falciparum, which serves as a tool to evaluate the effectiveness of novel antimalarial compounds. 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In the work presented here, we have studied and characterized the N-acetyltransferase FrbF from the FR-900098 biosynthetic pathway, which was recently completely reconstituted in E. coli. This enzyme is responsible for transfer of the acetyl group from acetyl-CoA to the phosphonate substrate, representing the penultimate step in FR-900098 synthesis. By exploiting the substrate specificity of FrbF, we can synthesize novel derivatives of FR-900098 with alternate N-acyl functionalities both in vivo and in vitro, such as the N-propionyl analog FR-900098P, which was found to be even more potent than its parent compound. We have also heterologously expressed and characterized the target enzyme from P. falciparum, which serves as a tool to evaluate the effectiveness of novel antimalarial compounds. 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