Biosynthesis of Tetramate Derivatives in <i>Penicillium crustosum</i> Reveals the Involvement of <i>ortho</i>-Quinone Methide in Crosstalk of Multiple Pathways

Genome mining and gene deletion experiments in <i>Penicillium crustosum</i> proved the involvement of the PKS-NRPS PemA and the <i>trans</i>-enoyl reductase PemB in the formation of three enantiomeric clavatol-containing tetramate pairs. Overexpression of a transcription factor significantly improved the product yields. Feeding experiments provided evidence for their formation via 1,4-Michael addition of hydroxyclavatol to two tetramates from the Pem pathway. This study provides another example of the involvement of reactive intermediates in multiple biosynthetic pathways.