Malet, Nicolas (2012) Structure-activity relationship and biosynthesis of the methylenomycin furans. PhD thesis, University of Warwick.

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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.

Item Type:	Thesis or Dissertation (PhD)
Subjects:	Q Science > QD Chemistry
Library of Congress Subject Headings (LCSH):	Furans -- Synthesis, Structure-activity relationships (Biochemistry), Furans -- Structure-activity relationships
Official Date:	June 2012
Dates:	Date Event June 2012 Submitted
Institution:	University of Warwick
Theses Department:	Department of Chemistry
Thesis Type:	PhD
Publication Status:	Unpublished
Supervisor(s)/Advisor:	Challis, Gregory L.
Sponsors:	Warwick Collaborative Postgraduate Research Scholarship
Extent:	xliii, 284 leaves : illustrations.
Language:	eng

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