“…Mechanistic studies of purified 6‐MSAS using substrate/intermediate analogues and enzyme inhibitors,18 as well as enzyme mutagenesis,14a, 19 have led to two distinct biosynthetic proposals: in the first, DH‐catalyzed dehydration of a 3‐hydroxytriketide intermediate is followed by a further round of chain extension, trans to cis isomerization of a double bond, aromatization, and finally thioester hydrolysis (Scheme 1 a) 18c, 19a. In the second, a 3‐hydroxytriketide intermediate is directly extended to a 5‐hydroxytetraketide, which cyclizes, dehydrates, and aromatizes prior to final product release (Scheme 1 b) 18c, 19b. A recent study of the 6‐MSAS‐like enzyme ATX from Aspergillus terreus has supported this second route and provided evidence of involvement of a so‐called thioester hydrolase (THID) domain in product release 19b.…”