Degree Type

Thesis

Degree Name

Master of Science (MS)

Department

Chemistry

Supervisor

P.H.M. Harrison

Language

English

Abstract

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β-Lactones are natural products containing a four-membered lactone ring and are

potent inhibitors of various types of enzymes. The mechanism of β-Lactone ring formation

was examined in vivo in order to identify the genes and proteins that effect cyclization.

Incorporation experiments into ebelactone A, a polyketide-derived β-Lactone from

Streptomyces ahuraviensis, were conducted. Doubly labelled sodium [1-

¹³C,¹⁸0₂]propionate prepared from labelled cyanide and water was fed to the cultures of

the organism to give labelled ebelactone A. ¹⁸0-induced isotopic shifts were observed for

all oxygenated carbon atoms of the molecule indicating that these oxygen atoms are all

derived from propionate. This result is consistent with formation of the β-Lactone ring by

nucleophilic attack of the C-3 hydroxyl group of a polyketide precursor onto the C-l

carbonyl carbon, and excludes other putative mechanisms for ring formation. Ebelactone

A was chemically converted to its N-acetylcysteamine derivative (SNAC). Labelling

experiments to test for conversion of this SNAC derivative to ebelactone A in vivo

showed only a background chemical cyclization reaction.

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