Biosynthesis of β-Lactones: Origin of the Oxygen Atoms and Mechanism of β-Lactone Ring Formation

Abstract

<p>p.p1 {margin: 0.0px 0.0px 0.0px 0.0px; font: 11.0px Times; color: #454545} p.p2 {margin: 0.0px 0.0px 0.0px 0.0px; font: 11.0px Times; color: #2c2c2c} span.s1 {font: 9.0px Helvetica; color: #2c2c2c} span.s2 {font: 9.0px Helvetica; color: #5f5e5f} span.s3 {color: #2c2c2c} span.s4 {color: #5f5e5f} span.s5 {font: 8.5px Helvetica; color: #2c2c2c} span.s6 {color: #454545} span.s7 {font: 8.5px Helvetica} span.s8 {font: 8.5px Helvetica; color: #5f5e5f} span.s9 {color: #747474} span.s10 {color: #0a0a0a}</p> <p>β-Lactones are natural products containing a four-membered lactone ring and are</p> <p>potent inhibitors of various types of enzymes. The mechanism of β-Lactone ring formation</p> <p>was examined in vivo in order to identify the genes and proteins that effect cyclization.</p> <p>Incorporation experiments into ebelactone A, a polyketide-derived β-Lactone from</p> <p>Streptomyces ahuraviensis, were conducted. Doubly labelled sodium [1-</p> <p>¹³C,¹⁸0₂]propionate prepared from labelled cyanide and water was fed to the cultures of</p> <p>the organism to give labelled ebelactone A. ¹⁸0-induced isotopic shifts were observed for</p> <p>all oxygenated carbon atoms of the molecule indicating that these oxygen atoms are all</p> <p>derived from propionate. This result is consistent with formation of the β-Lactone ring by</p> <p>nucleophilic attack of the C-3 hydroxyl group of a polyketide precursor onto the C-l</p> <p>carbonyl carbon, and excludes other putative mechanisms for ring formation. Ebelactone</p> <p>A was chemically converted to its N-acetylcysteamine derivative (SNAC). Labelling</p> <p>experiments to test for conversion of this SNAC derivative to ebelactone A in vivo</p> <p>showed only a background chemical cyclization reaction.</p>