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Biochemical studies of purified anddissected fungal polyketidesynthase and nonribosomal peptide synthetase (PKS-NRPS) hybrid enzymesinvolved in biosynthesis of pseurotin and aspyridone indicate thatone α-methylation step during polyketide synthesis is a prerequisiteand a key checkpoint for chain transfer between PKS and NRPS modules.In the absence of the resulting γ-methyl feature, the completedpolyketide intermediate is offloaded as an α-pyrone insteadof being aminoacylated by the NRPS domain. These examples illustratethat precisely timed tailoring domain activities play critical rolesin the overall programming of the iterative PKS (and NRPS) functions. [ABSTRACT FROM AUTHOR]

A fungal C 4 -alkylated dihydroisocoumarin pathway was discovered and elucidated. This pathway includes the following (1) a nonreducing polyketide synthase and a P450 collaboratively synthesize hydroxylated C 3 -methylated isocoumarin 3 ; (2) a methyltransferase methylates 3 to 8 ; and (3) importantly, an esterase specifically catalyzes a ring reconstruction process of 8 to C 4 -alkylated dihydroisocoumarin 10 . Our discovery fills the gap in the enzymatic transformation process of natural C 4 -alkylated isocoumarin derivates.