C–S bond formation reactions are widely distributed in the biosynthesis of biologically active molecules, and thus have received much attention over the past decades. Herein, we report intramolecular C–S bond formation by a P450 monooxygenase, TleB, which normally catalyzes a C−N bond formation in teleocidin biosynthesis. Based on the proposed reaction mechanism of TleB, a thiol‐substituted substrate analogue was synthesized and tested in the enzyme reaction, which afforded the unprecedented sulfur‐containing thio‐indolactam V, in addition to an unusual indole‐fused 6/5/8‐tricyclic product whose structure was determined by the crystalline sponge method. Interestingly, conformational analysis revealed that the SOFA conformation is stable in thio‐indolactam V, in sharp contrast to the major TWIST form in indolactam V, resulting in differences in their biological activities.
Teleocidins are potent protein kinase C activators, and possess a unique indole‐fused nine‐membered lactam structure. Teleocidin biosynthesis starts from the formation of a dipeptide by non‐ribosomal peptide synthetase (NRPS), followed by oxidative C−N bond formation by a cytochrome P450 oxidase, reverse‐prenylation by a prenyltransferase, and methylation‐initiated terpene cyclization by a C‐methyltransferase. This minireview focuses on recent research progress toward the elucidation of the molecular basis for the remarkable P450‐catalyzed intramolecular C−N bond‐forming reaction, which is challenging in synthetic chemistry, to generate the indolactam scaffold. In addition, precursor‐directed biosynthesis with the promiscuous P450 enzymes led to the formation of a series of unnatural and novel molecular scaffolds, including a sulfur‐substituted indolactam with a different conformation from that of indolactam V.
C–S bond formation reactions are widely distributed in the biosynthesis of biologically active molecules, and thus have received much attention over the past decades. Herein, we report intramolecular C–S bond formation by a P450 monooxygenase, TleB, which normally catalyzes a C−N bond formation in teleocidin biosynthesis. Based on the proposed reaction mechanism of TleB, a thiol‐substituted substrate analogue was synthesized and tested in the enzyme reaction, which afforded the unprecedented sulfur‐containing thio‐indolactam V, in addition to an unusual indole‐fused 6/5/8‐tricyclic product whose structure was determined by the crystalline sponge method. Interestingly, conformational analysis revealed that the SOFA conformation is stable in thio‐indolactam V, in sharp contrast to the major TWIST form in indolactam V, resulting in differences in their biological activities.
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