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New Proluciferin Substrates for Human CYP4 Family Enzymes

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Abstract

We report the synthesis of seven new proluciferins for convenient activity determination of enzymes belonging to the cytochrome P450 (CYP) 4 family. Biotransformation of these probe substrates was monitored using each of the twelve human CYP4 family members, and eight were found to act at least on one of them. For all substrates, activity of CYP4Z1 was always highest, while that of CYP4F8 was always second highest. Site of metabolism (SOM) predictions involving SMARTCyp and docking experiments helped to rationalize the observed activity trends linked to substrate accessibility and reactivity. We further report the first homology model of CYP4F8 including suggested substrate recognition residues in a catalytically competent conformation accessed by replica exchange solute tempering (REST) simulations.

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Authors and Affiliations

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

    Jingyao Liu, Erik J. Sorensen & Matthias Bureik

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

    David Machalz & Gerhard Wolber

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

    Erik J. Sorensen

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  1. Jingyao Liu
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  2. David Machalz
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Correspondence to Erik J. Sorensen or Matthias Bureik.

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Liu, J., Machalz, D., Wolber, G. et al. New Proluciferin Substrates for Human CYP4 Family Enzymes. Appl Biochem Biotechnol 193, 218–237 (2021). https://doi.org/10.1007/s12010-020-03388-6

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