Understanding the Iterative Polyketide Synthase Involved in Fungal Strobilurin Biosynthesis

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Strobilurins are fungal metabolites which are produced by an unusual interative polyketide synthase (iPKS) which creates an unprecedented E,Z,E triene. Understanding the function and programming of iPKS is important because these enzymes could be reprogrammed to make sustainable compound synthesis platforms in future. The strobilurin iPKS presents a perplexing problem: how does a single dehydratase enzyme provide a different geometry of olefin in each beta-processing cycle? In addition, the system also specifies a very unusual benzoate starter unit. The strobilurin iPKS should provide very useful information about how to engineer other iPKS to have different starter units and different olefin geometries. The project will involve the expression and production of individual catalytic domains of the strobilurin iPKS and synthesis of small-molecule substrates. This will allow in vitro assays to be developed which will facilitate the study of the selectivity and mechanisms of the acy transferase and dehydratase catalytic domains. The Strobilurin iPKS also contains very unusual C-terminal catalytic domains, including an 'extra' C-methyltransferase, a fragment of a thiolesterase and a domain of unknown function. We will also study how these domains interact with and process chemical intermediates during the biosynthesis of the strobilurin polyketide.