Characterization of 2-Oxindole Forming Heme Enzyme MarE, Expanding the Functional Diversity of the Tryptophan Dioxygenase Superfamily

Journal of the American Chemical Society

5 years ago

Characterization of 2-Oxindole Forming Heme Enzyme MarE, Expanding the Functional Diversity of the Tryptophan Dioxygenase Superfamily

Yi Zou, Zixin Deng, Yuyang Zhang, Tingting Huang, Xiaozheng Wang, Yi Tang, Shuangjun Lin, Yingxia Lan, Nelson L. Brock

3-Substituted 2-oxindoles are important structural motifs found in many biologically active natural products and pharmaceutical lead compounds. Here, we report an enzymatic formation of the 3-substituted 2-oxindoles catalyzed by MarE in the maremycin biosynthetic pathway in Streptomyces sp. B9173. MarE is a homologue of Fe^II/heme-dependent tryptophan 2,3-dioxygenases (TDOs). Typical TDOs usually catalyze the insertion of two oxygen atoms from O₂ into an indole ring to generate N-formylkynurenine (NFK)-like products. In contrast, MarE catalyzes the insertion of a single oxygen atom from O₂ into an indole ring, to probably generate an epoxyindole intermediate that undergoes an unprecedented 2,3-hydride migration to form 2-oxindole structure. MarE shows substrate robustness to catalyze the conversion of a series of 3-substituted indoles into their corresponding 3-substituted 2-oxindoles. Although containing most key amino acid residues conserved in well-known TDO homologues, MarE falls into a separate new subgroup in the phylogenetic tree. The characterization of MarE and its homologue enriches the functional diversities of TDO superfamily and provides a new strategy for discovering novel natural products containing 3-substituted 2-oxindole pharmacophores by genome mining.

Publisher URL: http://dx.doi.org/10.1021/jacs.7b05517

DOI: 10.1021/jacs.7b05517