Indolotryptolines are bisindole natural products isolated from microbial and eDNA sources. Here, we report the sequence of transformations that convert an indolocarbazole to the indolotryptoline cladoniamide through reconstruction of the four-enzyme cascade in E. coli. This cascade involves, first, conversion of an indolocarbozole to a C4c-C7a cis diol by ClaX1; second, N-methylation by ClaM1; third, rearrangement to the indolotryptoline scaffold by ClaX2; and fourth, installation of an O-methyl group by ClaM3. We furthermore elucidate the origins of minor cladoniamides D-G as the products of nonenzymatic, base-catalyzed opening of the succinimide ring of cladonimiades A-B. Overall, this work reveals the precarious pathway indolocarbazole-derived metabolites must traverse as they are converted into indolotryptoline products and highlights the importance of nonenzymatic chemistry in generating bisindole diversity.