Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.570574
Title: Structure-activity relationship and biosynthesis of the methylenomycin furans
Author: Malet, Nicolas
Awarding Body: University of Warwick
Current Institution: University of Warwick
Date of Award: 2012
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Abstract:
Today, more than 70 % of clinically-used antibiotics are produced by Streptomyces species. However, it is estimated that only 1 % of secondary metabolites produced by these bacteria have been discovered to date. Chemical communication in bacteria is defined as producing and responding to signalling molecules, which govern physiological processes, including antibiotic production and morphological differentiation. By understanding the signalling mechanisms of such molecules, new bioactive metabolites, of value to society, can be discovered. Examples of well characterized signalling molecules include acylhomoserine lactones (AHLs) and γ-butyrolactones (GBLs). A recently-discovered novel class of signalling molecules, 2-alkyl-4-hydroxymethylfuran-3- carboxylic acids (AHFCAs), which induce methylenomycin antibiotic biosynthesis in S. coelicolor is being studied in our group. We have investigated the structure-activity relationship of AHFCAs with respect to induction of methylenomycin production. The methodology of Davis et al. has been applied and extended to synthesise a range of AHFCA analogues with different alkyl chains, as well as modifications to the hydroxymethyl and carboxyl groups and the heterocycle (Figure 2). The ability of the resulting library of compounds to induce methylenomycin production was investigated. Structural features that are important for the biological activity of the AHFCAS were identified. Surprisingly, several analogues had very similar biological activity to the natural products. In 2007, a biosynthetic pathway to γ-butyrolactones was proposed and AfsA was shown to be a key enzyme in this process. mmfL encodes an AfsA-like protein, which is hypothesised to catalyse the formation of a butenolide intermediate in methylenomycin furan biosynthesis. mmfH and mmfP encode a flavin-dependent monooxygenase and a phophatase, respectively. Here, we report biochemical characterisation of the MmfL, MmfP and MmfH enzymes as well as attemps to reconstitute the methylenomycin furan biosynthetic pathway in vitro.
Supervisor: Not available Sponsor: Warwick Collaborative Postgraduate Research Scholarship
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.570574  DOI: Not available
Keywords: QD Chemistry
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