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dc.contributor.advisorNaismith, James
dc.contributor.advisorKilian, Petr
dc.contributor.authorGe, Ying
dc.coverage.spatialxv, 165, [39] p.en_US
dc.date.accessioned2019-10-21T13:56:16Z
dc.date.available2019-10-21T13:56:16Z
dc.date.issued2019-06-26
dc.identifier.urihttp://hdl.handle.net/10023/18723
dc.description.abstractRibosomally synthesized and post-translationally modified peptides (RiPPs) are a burgeoning family of natural products with desirable bioactivities. The cyanobactin class of RiPPs have demonstrated anticancer, anti-microbial activities and more, and have therefore attracted research attentions. Cyanobactins are synthesised as a precursor peptide (PatE homologues) containing recognition sequences and core peptides (sequences that become the final products), the latter of which undergo various modifications including heterocyclization, prenylation, oxidation and macrocyclization. The posttranslational modification enzymes (PTMEs) utilised to modify the cyanobactin precursor have demonstrated magnificent versatilities that are potentially exploitable for the creation of libraries of natural and unnatural compounds. The structure and function of each of these enzymes are reviewed in Chapter 1, along with the current application of the cyanobactin biosynthetic pathway. Chapter 2 describes my work on creating and characterising modified heterocyclases. The leader peptide was appended to heterocyclases that produce both thiazolines and (methyl)oxazolines. The modified catalysts are not only capable of utilising leaderless peptides, but also have higher yields than the native enzyme. The next chapter investigates the reaction order of heterocyclase enzymes. The leader peptide was found to be partially responsible for the reaction order. In Chapter 4 the same investigation was applied to the oxidase, which aromatises and stabilises the heterocycles. The oxidase reaction was determined to be independent of the leader. Chapter 5 delves into the phosphate chemistry of the heterocyclase, which uses ATP/Mg²⁺ via a kinase mechanism, but subsequently catalyses additional reactions that yield AMP and PPᵢ. Finally, Chapter 6 describes the structural characterisation of Psychrobacter arcticus ATP phosphoribosyltransferase (ATPPRT), which is the first dedicated enzyme in histidine biosynthesis, and provides a key regulatory point for this pathway.en
dc.description.sponsorship"The work is supported by ERC grant NCB-TNT (339367)." -- Acknowledgementsen
dc.language.isoenen_US
dc.publisherUniversity of St Andrews
dc.relationMelo Czekster , C , Ge , Y & Naismith , J H 2016 , ' Mechanisms of cyanobactin biosynthesis ' , Current Opinion in Chemical Biology , vol. 35 , pp. 80-88 . https://doi.org/10.1016/j.cbpa.2016.08.029 (http://hdl.handle.net/10023/11669)en
dc.relationStroek , R , Ge , Y , Talbot , P D , Glok , M K , Bernas , K E , Thomson , C M , Gould , E R , Alphey , M S , Liu , H , Florence , G J , Naismith , J H & da Silva , R G 2017 , ' Kinetics and structure of a cold-adapted hetero-octameric ATP phosphoribosyltransferase ' , Biochemistry , vol. 56 , no. 5 , pp. 793-803 . https://doi.org/10.1021/acs.biochem.6b01138 (http://hdl.handle.net/10023/12496)en
dc.relationAlphey , M S , Fisher , G , Ge , Y , Gould , E R , Guerreiro Machado , T F , Liu , H , Florence , G J , Naismith , J H & da Silva , R G 2018 , ' Catalytic and anticatalytic snapshots of a short-form ATP phosphoribosyltransferase ' , ACS Catalysis , vol. 8 , no. 6 , pp. 5601-5610 . https://doi.org/10.1021/acscatal.8b00867 (http://hdl.handle.net/10023/17684)en
dc.relationGao , S , Ge , Y , Bent , A F , Schwarz-Linek , U & Naismith , J H 2018 , ' Oxidation of the cyanobactin precursor peptide is independent of the leader peptide and operates in a defined order ' , Biochemistry , vol. 57 , no. 41 , pp. 5996-6002 . https://doi.org/10.1021/acs.biochem.8b00835 ( http://hdl.handle.net/10023/18467)en
dc.relation.urihttp://hdl.handle.net/10023/11669
dc.relation.urihttp://hdl.handle.net/10023/12496
dc.relation.urihttp://hdl.handle.net/10023/17684
dc.relation.urihttp://hdl.handle.net/10023/18467
dc.subject.lccQP601.G4
dc.titleStructural and chemical investigation of three biosynthetic enzymesen_US
dc.typeThesisen_US
dc.contributor.sponsorEuropean Research Council (ERC)en_US
dc.type.qualificationlevelDoctoralen_US
dc.type.qualificationnamePhD Doctor of Philosophyen_US
dc.publisher.institutionThe University of St Andrewsen_US
dc.identifier.doihttps://doi.org/10.17630/10023-18723


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