Insight by proxy – investigating the evolutionary history of beauvericin biosynthesis through ketoisovalerate reductase accessory gene

Study of core fungal biosynthetic genes is frequently complicated due to multi-modular structure and tangled history of key synthase families. In this case, relatively simpler accessory genes responsible for early parts of biosynthetic process (e.g. substrate synthesis) can provide additional insight as proxies sharing common history after recruitment into the biosynthetic cluster. We have investigated the origins of key accessory enzyme in beauvericin (cyclic oligodepsipeptide) biosynthesis – ketoisovalerate reductase (KIVR) – from its emergence in a subfamily of NADP-dependent reductases involved in alternate pyrimidine biosynthetic route, throughout its role as provider of hydroxyisovaleric acid metabolite, until its strong genetic linkage as part of cyclic oligodepsipeptide beauvericin cluster.

Our studies pinpoint the recruitment of ketoisovalerate reductase to a common hypocrealean ancestor and its spread via postulated duplications and horizontal gene transfer throughout key genera in Cordycipitaceae and Nectriaceae. The existence of beauvericin cluster within divergent complexes of phytopathogenic Fusaria is shown to be paraphyletic, with independent acquisition of cluster by species in F. oxysporum and F. tricinctum complexes. The remarkable mechanistic conservation of reductase structural template point to the crucial role of regulatory rewiring of KIVR during its emergence as key substrate (D-Hiv) provider for beauvericin biosynthetic process. Prospects for use of KIVR as a marker of toxigenicity, as well as possibility of KIVR complementation in low producing strains of pathogenic/biocontrol Hypocreales are discussed as well.

Keywords: cyclodepsipeptides, beauvericin, bassianolide, Hypocreales

Research supported by Polish National Science Centre OPUS 8 grant: NCN 2014/15/B/NZ9/01544.