Accelerating the discovery of alkyl halide-derived natural products using halide depletion

Abstract

Even in the genomic era, microbial natural product discovery workflows can be laborious and limited in their ability to target molecules with specific structural features. Here we leverage an understanding of biosynthesis to develop a workflow that targets the discovery of alkyl halide-derived natural products by depleting halide anions, a key biosynthetic substrate for enzymatic halogenation, from microbial growth media. By comparing the metabolomes of bacterial cultures grown in halide-replete and deficient media, we rapidly discovered the nostochlorosides, the products of an orphan halogenase-encoding gene cluster from Nostoc punctiforme ATCC 29133. We further found that these products, a family of unusual chlorinated glycolipids featuring the rare sugar gulose, are polymerized via an unprecedented enzymatic etherification reaction. Together, our results highlight the power of leveraging an understanding of biosynthetic logic to streamline natural product discovery.

Chemo-enzymatic total synthesis: current approaches toward the integration of chemical and enzymatic transformations

“…In the field of chemo-enzymatic total synthesis utilizing polyketide synthase (PKS)-related macrocyclization enzymes, Xiang and co-workers recently reported the total synthesis of cylindrocyclophanes [ 64 ]. The cyanobacterial non-canonical enzyme CylK, discovered and characterized by Balskus and co-workers [ 65 – 67 ], facilitated an intramolecular Friedel–Crafts-type homo-dimerization and led to the efficient construction of the 22-membered paracyclophane scaffold. Of several sophisticated chemo-enzymatic strategies, this review highlights the total syntheses of tylactone ( 4 ) and juvenimicins ( Scheme 7 and Scheme 8 ) [ 68 ].…”