Biosynthesis of Indolocarbazole and Goadsporin, Two Different Heterocyclic Antibiotics Produced by Actinomycetes

Abstract

The biosynthesis of staurosporine, rebeccamycin, and goadsporin, which are produced by actinomycetes and contain characteristic heterocyclic rings, was characterized by genetic methods. Staurosporine and rebeccamycin contain an indolocarbazole ring synthesized from two molecules of tryptophan, with indolepyruvic acid imine and chromopyrrolic acid as biosynthetic intermediates. A tetrameric hemoprotein synthesizes chromopyrrolic acid, and cytochrome P450 peroxidase catalyzes the intramolecular C-C coupling and decarboxylation of chromopyrrolic acid to form the indolocarbazole core. Goadsporin is a thiopeptide containing thiazole and oxazole heterocyclic rings. The structural gene godA is ribosomally translated to a goadsporin precursor peptide, and oxazole, methyloxazole, and thiazole rings are derived from serine, threonine, and cystein through post-translational modifications. On the basis of these knowledges, a wide variety of indolocarbazole and goadsporin analogs through the rational gene recombination and disruption of these biosynthetic genes were successfully produced.

YcaO-Dependent Posttranslational Amide Activation: Biosynthesis, Structure, and Function

“…204, 205 Putative membrane-associated proteases (GodB and GodC) cleave the modified precursor peptide (GodA), and an N-acetyltransferase (GodH) modifies the newly formed N-terminus. 206, 207 Transcription of the goadsporin BGC is controlled by GodR, an activator, 208 whose overexpression results in increased production of goadsporin, although the best titers were achieved through heterologous expression in S. lividans and co-culturing with Tsukamurella pulmonis . 208, 209 In order to prevent inhibition of its own growth, the BGC encodes the immunity protein GodI (see below).…”

“…However, GodI is insensitive to goadsporin and presumably replaces the inhibited subunit, allowing normal SRP function. 207 The observations that goadsporin induces secondary metabolism but at higher concentrations is growth inhibitory raises questions about what its “true” function may be in vivo. Goadsporin serves as a reminder that not all natural compounds that inhibit the growth of various microorganisms were necessary intended for niche competition.…”

A novel detergent-stable solvent-tolerant serine thiol alkaline protease from Streptomyces koyangensis TN650

“…While proteases from bacteria have been extensively purified and characterized, little attention has been paid to actinomycetes. They are, a Gram-positive mycelium-forming bacterial group that exhibits a complex developmental cycle, able to degrade macromolecules in the soil, being particularly efficient in the breakdown of proteins [9,10]. The ability of these bacteria to produce large amounts of enzymes, as proteases with varied substrate specificities, offers another highly valued property.…”

Advances in Chromobacterium violaceum and properties of violacein-Its main secondary metabolite: A review

“…Finally, we can cite the coordinated action of two oxygenases, also flavin-dependent, designated VioC and VioD. VioD is able to hydroxylate PVA at the 5-position of the indole ring to yield proviolacein, and VioC can oxidize the other indole ring at the 2-position to generate the oxindole and finally to produce violacein (Jiang et al, 2010;Kamaeva et al, 2014;Onaka, 2009). Commonly, the 1,2-shift of the indole nucleus on the left side of the violacein structure ( Fig.…”