Structural and Functional Interrogation of the Abyssomicin C Biosynthetic Pathway

Student thesis: Doctoral ThesisDoctor of Philosophy (PhD)

Abstract

Natural product biosynthetic pathways produce a plethora of biologically active compounds, including antibiotics. These secondary metabolites are produced by a number of enzyme families found within bacteria, fungi and plants. These enzymes can be large, multidomain, complexes harbouring an intricate series of precisely controlled structural and functional interactions. Once their chemical products are liberated, a wide variety of tailoring enzymes perform complex and often understudied chemical reactions to create the final, active, biomolecule. This study aims to further our understanding of these processes through the characterisation of a number of enzymes within the abyssomicin C biosynthetic pathway. Type I polyketide synthases act in a concerted manner to create a linear chain, which is functionalised before cyclisation by the bona fide natural Diels-Alderase, AbyU, eventually leading to the potent antibiotic, abyssomicin C. A structural characterisation of the modular polyketide synthase AbyB3 via X-ray crystallography and cryo-EM methods aims to reconcile existing models for polyketide synthase architecture and mechanism, whilst an in-depth mechanistic characterisation of AbyU represents the first of its kind with respect to these deceptively complex catalysts.
Date of Award29 Sep 2020
Original languageEnglish
Awarding Institution
  • The University of Bristol
SupervisorPaul R Race (Supervisor) & Chris L Willis (Supervisor)

Keywords

  • Biosynthesis
  • Polyketides
  • Diels-Alderase
  • Polyketide Synthase
  • Crystallography
  • Cryo-electron Microscopy
  • Kinetics

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