Indirubin is naturally synthesized by medicinal plants such as Isatis tinctoria L. (Woad) as a byproduct during the formation of indigo. Indirubin is also a constituent of the Chinese herbal medicine "Qing-Dai," used to treatchronic myelocytic leukemia. Moreover, it shows antiproliferative and antitumor effects against various chronic diseases by acting as a competitive inhibitor of ATP of cyclin-dependent kinases (CDKs) and targets cell cycle regulation, glycogen metabolism, and STAT signaling. But its low yield from medicinal plants coupled with its very low aqueous solubility, poor absorption, and low cellular activity limits its pharmaceutical application. We demonstrated that coexpressing a novel cytochrome P450 from Isatis tinctoria L. with a reductase, enzyme from Arabidopsis thaliana plants inE. coli enables the production of water-soluble indirubin derivatives at a titer of 254±49.07 mg/L and yield of 0.62 mg compounds/g tryptophan. The compounds can be easily extracted from the cells using water and centrifugation. The chemical structures of the compounds were uncovered using comprehensive analytical techniques. The compounds inhibit the growth of pathogenic strain Salmonella and cause cell cycle arrest of HeLa cells. In summary, we develop an efficient, sustainable, and green system for in vivo synthesis of pharmaceutically applicable indirubin derivatives.

Production of bioactive water-soluble indirubin derivative using novel plant P450

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