Biosynthetic studies on maleidride natural products

Student thesis: Doctoral ThesisDoctor of Philosophy (PhD)

Abstract

Maleidrides are a family of polyketide-derived fungal natural products assembled on a mediumsized alicyclic ring with one or two fused maleic anhydride moieties. This thesis describes biosynthetic studies on scytalidin 31, (a nonadride with a 9-membered ring), produced by the fungus Scytalidium album and establishes a biosynthetic link to the octadride zopfiellin 35, (with an 8-membered ring), produced by Diffractella curvata.

Following a general introduction to maleidrides in Chapter 1, biosynthetic studies on scytalidin
31 are described in Chapter 2. A combination of genome sequencing, gene knockout experiments and isotopic labelling studies established key steps in the biosynthesis of the nonadride framework. 6-Hydroxylation of deoxyscytalidin 78 to scytalidin 31 in S. album is catalysed by the α-ketoglutarate dependent dioxygenase Scy_L2. The hydrolase, Scy_R4, also plays an important role in this final transformation.

Chapter 3 focusses on the biosynthesis of zopfiellin 35. A combination of gene knockout experiments, isotopic labelling, feeding studies and in vitro assays revealed that the octadride core of zopfiellin 35 is formed via ring contraction of deoxyscytalidin 78. Following 5-hydroxylation of 78 to give 170, ring contraction to 36 occurs, catalysed by the multifunctional α-KG dependent dioxygenase, Zop_L9. The final step is side-chain hydroxylation.

Feeding studies to D. curvata ∆zop_PKS mutant were used to probe the mechanism of ring contraction. Feeding scytalidin 31 gave castaneiolide 182 and two novel ring cleaved products, alcohol 183 and acid 184. Their structures were elucidated by spectroscopic methods. Interestingly, feeding alkene 173 to this mutant gave castaneiolide 182 and alcohol 183.
Date of Award28 Sep 2021
Original languageEnglish
Awarding Institution
  • The University of Bristol
SupervisorAndy M Bailey (Supervisor) & Chris L Willis (Supervisor)

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