Importance of asparagine-381 and arginine-487 for substrate recognition in CYP4Z1.

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ID: 95323
2020
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Abstract
The human cytochrome P450 enzyme CYP4Z1 remains an understudied enzyme despite its association with poor prognosis and overexpression in breast cancer. Hence, CYP4Z1 has previously been suggested as an anti-breast cancer target. In the present study we employed extended mutation analysis to increase our understanding of the substrate binding mode of this enzyme. In a combined in vitro and in silico approach we show for the first time that residue Arg487 plays an important role in substrate recognition and binding of CYP4Z1. Using a large array of recombinant CYP4Z1 mutants we show that, apart from Asn381, all other postulated binding residues only play an auxiliary role in substrate recognition and binding. Different substrate interaction motifs were identified via dynamic pharmacophores (dynophores) and their impact on catalytically competent substrate binding was classified. These new insights on the substrate recognition and binding mode represent an important step towards the rational design of CYP4Z1 prodrugs and guide further investigations into the so far poorly understood physiological role of CYP4Z1.
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du2020importancebiochemical Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Du, Wei;Machalz, David;Yan, Qi;Sorensen, Erik J;Wolber, Gerhard;Bureik, Matthias;
Journal biochemical pharmacology
Year 2020
DOI
S0006-2952(20)30071-X
URL
Keywords
Breast cancer molecular modeling substrate recognition cyp4z1 mutational studies

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