Diketopiperazines (DKPs) offer many clinical applications. Nocardioazine A is an anticancer diketopiperazine natural product isolated by Capon and co-workers from a marine actinomycete. This molecule exhibited anticancer properties by inhibiting P-glycoprotein to reverse the drug resistance that handicaps the efficacy of many anticancer therapies. Previous work from the Lane and Viswanathan groups showed that in E. coli expressing genes from the hypothesized nocardioazine A pathway, NozA catalyzed the reaction to produce the nocardioazine intermediate, cyclo(L-Trp-L-Trp), from L-Tryptophan (L-Trp). Thus, we are testing the hypothesis that these enzymes may accept unnatural amino acids to yield cyclo(L-Trp-L-Trp) analogs. To test this, the E. coli cells expressing NozA were fed unnatural amino acids, then analyzed with liquid chromatography-mass spectrometry (LC-MS) to evaluate the production of DKP molecules containing the unnatural amino acids. The LC-MS data supported that NozA was able to incorporate unnatural amino acids, including halogenated and methylated Trp analogs, to yield novel DKPs.

Biosynthesis of diketopiperazine natural products from unnatural amino acids

255th National Meeting (2018)

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