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Exploring the Chemical Space of Proluciferins as Probe Substrates for Human Cytochrome P450 Enzymes

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Abstract

We report the synthesis of 21 new proluciferin compounds that bear a small aliphatic ether group connected to the 6’ hydroxy function of firefly luciferin and either contain an acid or methyl ester function at the dihydrothiazole ring. Each of these compounds was found to be a substrate for some members of the human CYP1 and CYP3 families; a total of 92 new enzyme–substrate pairs were identified. In a screen of the whole human P450 complement (CYPome) with three selected proluciferin acid substrates, another 13 enzyme–substrate pairs were detected, which involve enzymes belonging to the CYP2, CYP4, CYP7, CYP21, and CYP27 families. All in all, we identified new probe substrates for members of seven out of 18 human CYP families.

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Authors and Affiliations

  1. School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, 300072, China

    Jie Zhao, Xue Zhang, Yueyin Wang, Huimin Huang, Shishir Sharma, Sangeeta Shrestha Sharma, Erik J. Sorensen & Matthias Bureik

  2. Pharmaceutical and Medicinal Chemistry (Computer-Aided Drug Design), Institute of Pharmacy, Freie Universität Berlin, 14195, Berlin, Germany

    Clemens Alexander Wolf, Sijie Liu & Gerhard Wolber

  3. Department of Chemistry, Princeton University, Princeton, NJ, 08544, USA

    Erik J. Sorensen

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  1. Jie Zhao
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Contributions

GW, EJS, and MB conceived and designed the research and supervised the project. JZ, XZ, YW, HH, SS, and SSS carried out the in vitro experiments. CAW and SL carried out the in silico experiments. JZ, XZ, CAW, and SL performed data processing and formal analyses in consultation with all other authors. JZ, CAW, SL, GW, and MB wrote the draft manuscript. All authors have edited and agreed to the published version of the manuscript.

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Correspondence to Matthias Bureik.

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Jie Zhao and Xue Zhang contributed equally to this article.

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Zhao, J., Zhang, X., Wang, Y. et al. Exploring the Chemical Space of Proluciferins as Probe Substrates for Human Cytochrome P450 Enzymes. Appl Biochem Biotechnol 195, 1042–1058 (2023). https://doi.org/10.1007/s12010-022-04184-0

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