A methyltransferase molecular switch unlocks para-quinone methide generation and oligomerization

Abstract

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 o-QM formation from ortho-hydroxybenzyl alcohols is well-established, dedicated pathways to generate p-QMs that function as building blocks remain elusive. Here, we report a fungal biosynthetic pathway from Mycocitrus zonatus 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 ortho-hydroxy group, encouraging p-QM formation and blocking conventional o-QM generation. This p-QM undergoes iterative intermolecular 1,6-conjugate additions, yielding oligomeric products. This study reveals a dedicated p-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 p-QM intermediates.