Investigating Diels-Alderases for the Biocatalytic Synthesis of Abyssomicin 2 and Neoabyssomicin A

点击翻译按钮获取中文摘要

It is currently estimated that 700,000 people die from resistant bacterial infections each year. Polyketide-derived natural products isolated from microorganisms are a rich source of discovery for new antibacterial, antitumour and antifungal compounds. The identification of such molecules is of the utmost importance to combat the rise in antimicrobial resistance. The overall aim of this project is to fully understand how polyketides are assembled in nature to allow rational engineering of the biosynthetic pathway to access novel bioactive molecules efficiently and inexpensively in gram-scale quantities. Diels-Alder reactions are amongst the most powerful transformations in synthetic chemistry owing to their exquisite regio- and stereoselectivity, so new catalysts able to promote these reactions would have major value. Enzymes are attractive candidates for development as chiral catalysts owing to their inherently "green" nature. This project will focus on the bona fide natural Diels-Alderase, AbmU, which has been shown to catalyse the cyclisation of a linear substrate to form the spirotetronate core in the biosynthesis of abyssomicin 2 and neoabyssomicin A. The later tailoring steps of the biosynthetic pathway will be investigated by undertaking the first total synthesis of neoabyssomicin A. To enable the widespread use of AbmU as a biocatalyst, its substrate scope, catalytic efficiency and scalability will be explored using a combination of organic synthesis and synthetic biology.