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Unique Structural Features Relate to Evolutionary Adaptation of Cytochrome P450 in the Abyssal Zone

Tatiana Y. Hargrove, David Lamb Orcid Logo, Zdzislaw Wawrzak, George Minasov, Jared V. Goldstone, Steven Kelly, John J. Stegeman, Galina I. Lepesheva Orcid Logo

International Journal of Molecular Sciences, Volume: 26, Issue: 12, Start page: 5689

Swansea University Authors: David Lamb Orcid Logo, Steven Kelly

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DOI (Published version): 10.3390/ijms26125689

Abstract

Cytochromes P450 (CYPs) form one of the largest enzyme superfamilies, with similar structural folds yet biological functions varying from synthesis of physiologically essential compounds to metabolism of myriad xenobiotics. Sterol 14α-demethylases (CYP51s) represent a very special P450 family, regar...

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Published in: International Journal of Molecular Sciences
ISSN: 1422-0067
Published: MDPI AG 2025
Online Access: Check full text

URI: https://cronfa.swan.ac.uk/Record/cronfa69797
Abstract: Cytochromes P450 (CYPs) form one of the largest enzyme superfamilies, with similar structural folds yet biological functions varying from synthesis of physiologically essential compounds to metabolism of myriad xenobiotics. Sterol 14α-demethylases (CYP51s) represent a very special P450 family, regarded as a possible evolutionary progenitor for all currently existing P450s. In metazoans CYP51 is critical for the biosynthesis of sterols including cholesterol. Here we determined the crystal structures of ligand-free CYP51s from the abyssal fish Coryphaenoides armatus and human-. Comparative sequence–structure–function analysis revealed specific structural elements that imply elevated conformational flexibility, uncovering a molecular basis for faster catalytic rates, lower substrate selectivity, and intrinsic resistance to inhibition. In addition, the C. armatus structure displayed a large-scale repositioning of structural segments that, in vivo, are immersed in the endoplasmic reticulum membrane and border the substrate entrance (the FG arm, >20 Å, and the β4 hairpin, >15 Å). The structural distinction of C. armatus CYP51, which is the first structurally characterized deep sea P450, suggests stronger involvement of the membrane environment in regulation of the enzyme function. We interpret this as a co-adaptation of the membrane protein structure with membrane lipid composition during evolutionary incursion to life in the deep sea.
Keywords: cytochrome P450; sterol 14α-demethylase (CYP51); crystal structure; structure–function; conformational flexibility; biological membranes; evolutionary adaptation
College: Faculty of Medicine, Health and Life Sciences
Funders: This research was funded by the National Institutes of Health Grant R35 GM151876 (G.I.L.). Vanderbilt University is a member institution of the Life Sciences Collaborative Access Team at Sector 21 of the Advanced Photon Source (Argonne, IL, USA). Use of the Advanced Photon Source at Argonne National Laboratory was supported by the United States Department of Energy, Office of Science, Office of Basic Energy Sciences, under contract DE-AC02-06CH11357.
Issue: 12
Start Page: 5689

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