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Different behaviors of cyclic dipeptide prenyltransferases toward the tripeptide derivative ardeemin fumiquinazoline and its enantiomer

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Abstract

In nature, cyclic dipeptide prenyltransferases catalyze regioselective Friedel-Crafts alkylations of tryptophan-containing cyclic dipeptides. This enzyme class, belonging to the dimethylallyl tryptophan synthase superfamily, is known to be flexible toward aromatic prenyl acceptors, while mostly retaining its typical regioselectivity. Ardeemin fumiquinazoline (FQ) (1), a tryptophan-containing cyclic tripeptide derivative, is assembled in Aspergillus fischeri by the non-ribosomal peptide synthetase ArdA and modified by the prenyltransferase ArdB, leading to the pharmaceutically active hexacyclic ardeemin. Therefore, 1 and its enantiomer ent-ardeemin FQ (2) constitute potential substrates for aromatic prenyltransferases. In this study, we investigated the acceptance of both enantiomers by two cyclic dipeptide C2-prenyltransferases BrePT and FtmPT1 and three C3-prenyltransferases CdpNPT, CdpC3PT, and AnaPT. LC-MS analysis of the incubation mixtures and NMR analysis of the isolated products revealed that the stereochemistry at C11 and C14 in 1 and 2 has a strong influence on their acceptance by these enzymes and the regioselectivity of the prenylation reactions. 1 was very well accepted by BrePT, FtmPT1, and CdpNPT, with C2- or C3-prenylated derivatives as predominant products, which fills the prenylation gaps by tryptophan prenyltransferases reported in a previous study. 2 was a poor substrate for all the enzymes and converted with low regioselectivity and mainly prenylated at C6 and C7 of the indole moiety.

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Acknowledgments

We thank Lena Ludwig-Radtke for the synthesis of DMAPP and Rixa Kraut and Stefan Newel for taking MS and NMR spectra, respectively.

Funding

The Bruker micrOTOF QIII mass spectrometer was financially supported in part by a grant from the Deutsche Forschungsgemeinschaft (INST 160/620-1 to S.-M. L.).

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  1. Peter Mai and Lindsay Coby contributed equally to this work.

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  1. Institut für Pharmazeutische Biologie und Biotechnologie, Philipps-Universität Marburg, Robert-Koch-Str. 4, 35037, Marburg, Germany

    Shu-Ming Li

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  1. Peter Mai
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  2. Lindsay Coby
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Correspondence to Shu-Ming Li.

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Mai, P., Coby, L. & Li, SM. Different behaviors of cyclic dipeptide prenyltransferases toward the tripeptide derivative ardeemin fumiquinazoline and its enantiomer. Appl Microbiol Biotechnol 103, 3773–3781 (2019). https://doi.org/10.1007/s00253-019-09723-0

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