A Bacterial Sulfotransferase Catalyzes an Unusual Di-Sulfation in Natural Products Biosynthesis.

Abstract

Sulfation is a widely used strategy in nature to modify the solubility, polarity, and biological activities of molecules. The enzymes catalyzing sulfation, sulfotransferases (STs), are typically highly specific to a single sulfation site in a molecule. Herein, the identification and characterization of sulfated adipostatins is reported and reveals a novel sulfotransferase, AdpST, which is responsible for di-sulfation at two sites of adipostatins. The initial bioinformatic analysis in search of adipostatin analogs from Streptomyces davaonensis DSM101723 identifies adpST and a 3'-phosphoadenosine-5'-phosphosulfate (PAPS) biosynthetic cassette, which are co-clustered with the adipostatin-encoding type III polyketide synthase. Mono- and di-sulfated adipostatin analogs are discovered in the extracts of S. davaonensis DSM101723, whereas di-sulfated bacterial natural products has not been reported. Using a series of in vivo and in vitro experiments, it is confirmed that AdpST is solely responsible for both mono- and di-sulfation of adipostatins, a catalytic activity which has not been identified in bacterial PAPS-dependent STs to date. It is further demonstrated that the dedicated PAPS biosynthetic cassette improves di-sulfation capacity. Lastly, it is determined that AdpST shares similarity with a small group of uncharacterized STs, suggesting the presence of additional unique bacterial STs in nature, and that AdpST is phylogenetically distant from many characterized STs.