Alpiniamide A is a linear polyketide produced by Streptomyces endophytic bacteria. Despite its relatively simple chemical structure suggestive of a linear assembly line biosynthetic construction involving a hybrid polyketide synthase-nonribosomal peptide synthetase enzymatic protein machine, we report an unexpected nonlinear synthesis of this bacterial natural product. Using a combination of genomics, heterologous expression, mutagenesis, isotope-labeling, and chain terminator experiments, we propose that alpiniamide A is assembled in two halves and then ligated into the mature molecule. We show that each polyketide half is constructed using orthogonal biosynthetic strategies, employing either cis-or trans-acyl transferase mechanisms, thus prompting an alternative proposal for the operation of this PKS- NRPS.

ACS Chem. Biol. 2020, 15, 1067−1077

Nonlinear biosynthesis of Alpiniamide: a hybrid cis/trans-AT PKS-NRPS pathway

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