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Title: The biosynthesis of polyether antibiotics
Author: Harvey, B. M.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2006
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This research aimed to delineate the final stages of polyether biosynthesis, using the monensin pathway as a model system. The metabolites produced by mutants in which the gene encoding the putative epoxidase MonCI (monCI) along with the proposed isomerase genes monBII and monBII (BHΔCIBIBII) were disrupted were found to be (stereo)chemically identical to those produced by a strain deficient in monCI only (ABΔCI), suggesting that MonBI and MonBII do not play a role in double bond isomerisation. In agreement with this, site-directed mutagenesis of a residue in MonBI previously implicated in authentic double bond isomerase did not abolish the activity of MonBI. The type II thiesterases (TEs) MonAIX and MonAX were investigated as candidates for the enzyme that releases the polyketide chain. However, neither of the genes monAIX or monAX is essential for monensin biosynthesis and these TEs are proposed to act as conventional PKS-editing enzymes, and it is proposed here that this offloading step is catalysed by MonCII. In vitro assays of MonCII, previously assigned as the putative episode hydrolase, showed that it has thioesterase activity, in particular against a thioester derivative of monensin A, supporting previous proposals that oxidative cyclisation might occur while the substrate is enzyme bound. In collaboration with Dr. S.F. Haydock, the biosynthetic gene cluster for nigericn biosynthesis was sequenced from Streptomyces violaceoniger sp. DSM4137 and found to be similar to those of monensin and nanchangmycin.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available