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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.
Details
; Machalz, David 2 ; Wolber Gerhard 2 ; Sorensen, Erik J 3 ; Bureik Matthias 1
1 Tianjin University, School of Pharmaceutical Science and Technology, Health Sciences Platform, Tianjin, China (GRID:grid.33763.32) (ISNI:0000 0004 1761 2484)
2 Freie Universität Berlin, Pharmaceutical and Medicinal Chemistry (Computer-Aided Drug Design), Institute of Pharmacy, Berlin, Germany (GRID:grid.14095.39) (ISNI:0000 0000 9116 4836)
3 Tianjin University, School of Pharmaceutical Science and Technology, Health Sciences Platform, Tianjin, China (GRID:grid.33763.32) (ISNI:0000 0004 1761 2484); Princeton University, Department of Chemistry, Princeton, USA (GRID:grid.16750.35) (ISNI:0000 0001 2097 5006)