Molecular basis for enzymatic control of enantiodivergent Diels-Alder reactions in spirotetronate biosynthesis

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Chemical synthesis of complex molecules with applications in medicine, animal health and agriculture is often inefficient and cumbersome, with problems including poor overall product yields, difficulties with scale-up and heavy reliance on non-renewable resources. Harnessing natural product biosynthetic enzymes is a promising strategy for more sustainable, scalable and efficient production of complex molecules. However, a detailed molecular understanding of the catalytic mechanisms of such enzymes is required to achieve this. This project aims to develop a better understanding of how Diels-Alderase enzymes that catalyse key [4+2] cycloaddition reactions in the biosynthesis of spirotetronate natural products control the stereochemistry of their products. A highly interdisciplinary approach combining synthesis of substrates and substrate analogues with enzymology, analytical chemistry, structural biology, site-directed mutagenesis and docking simulations will be employed . The outcomes of this work will underpin future efforts to exploit enzymes that catalyse complexity-generating transformations, such as Diels-Alder [4+2] cycloadditions, for more sustainable production of structurally complex molecules.