A methyltransferase molecular switch unlocks <i>para</i> -quinone methide generation and oligomerization

Quinone methides (QMs) are highly reactive intermediates with dual electrophilic/nucleophilic character, serving as versatile synthons in organic synthesis and biosynthesis. Their broader utility remains limited by their inherent instability and scarce practical generation methods. While biosynthetic <i>o</i>-QM formation from <i>ortho</i>-hydroxybenzyl alcohols is well-established, dedicated pathways to generate <i>p</i>-QMs that function as building blocks remain elusive. Here, we report a fungal biosynthetic pathway from <i>Mycocitrus zonatus</i> strain Mcr that generates a reactive 2,4-dihydroxybenzyl alcohol precursor. Crucially, a novel family of membrane-dependent methyltransferase (AcreE) acts as a "molecular switch" by masking the <i>ortho</i>-hydroxy group, encouraging <i>p</i>-QM formation and blocking conventional <i>o</i>-QM generation. This <i>p</i>-QM undergoes iterative intermolecular 1,6-conjugate additions, yielding oligomeric products. This study reveals a dedicated <i>p</i>-QM biosynthetic logic, not only demonstrating methylation as a strategy to control the fate of the reactive intermediate, but also providing novel machinery for accessing synthetically challenging <i>p</i>-QM intermediates.