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Structural modeling of cytochrome P450 51 from a deep-sea fish points to a novel structural feature in other CYP51s

Jared V. Goldstone, David Lamb Orcid Logo, Steven Kelly Orcid Logo, Galina I. Lepesheva, John J. Stegeman

Journal of Inorganic Biochemistry, Volume: 245, Start page: 112241

Swansea University Authors: David Lamb Orcid Logo, Steven Kelly Orcid Logo

  • Accepted Manuscript under embargo until: 28th April 2024

Abstract

Cytochromes P450 enzymes involved in the metabolism of endogenous and xenobiotic substrates, provide an excellent model system to study how membrane proteins with unique functions have catalytically adapted through evolution. Molecular adaptation of deep-sea proteins to high hydrostatic pressure rem...

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Published in: Journal of Inorganic Biochemistry
ISSN: 0162-0134
Published: Elsevier BV 2023
Online Access: Check full text

URI: https://cronfa.swan.ac.uk/Record/cronfa63599
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Abstract: Cytochromes P450 enzymes involved in the metabolism of endogenous and xenobiotic substrates, provide an excellent model system to study how membrane proteins with unique functions have catalytically adapted through evolution. Molecular adaptation of deep-sea proteins to high hydrostatic pressure remains poorly understood. Herein, we have characterized recombinant cytochrome P450 sterol 14-demethylase (CYP51), an essential enzyme of cholesterol biosynthesis, from an abyssal fish species, Coryphaenoides armatus. C. armatus CYP51 was heterologously expressed in Escherichia coli following N-terminal truncation and purified to homogeneity. Recombinant C. armatus CYP51 bound its sterol substrate lanosterol giving a Type I binding spectra (KD 15 μM) and catalyzed lanosterol 14-demethylation turnover at 5.8 nmol/min/nmol P450. C. armatus CYP51 also bound the azole antifungals ketoconazole (KD 0.12 μM ) and propiconazole (KD 0.54 μM) as determined by Type II absorbance spectra. Comparison of C. armatus CYP51 primary sequence and modeled structures with other CYP51s identified amino acid substitutions that may confer an ability to function under pressures of the deep sea and revealed heretofore undescribed internal cavities in human and other non-deep sea CYP51s. The functional significance of these cavities is not known.
Keywords: Adaptation; CYP51; Cytochrome P450; Deep sea; Fish; Pressure.
College: Faculty of Medicine, Health and Life Sciences
Funders: Support for this research was provided by the Woods Hole Center for Oceans and Human Health (the U.S. Oceans and Human Health Program (NIH grant P01ES028938 and National Science Foundation grant OCE-1840381) (J.J.S.), the Ocean Vision 2030 Fund and its generous donors through the Woods Hole Oceanographic Institution (J.V.G.), the Vertebrate Genome Nomenclature Committee NIH U24HG003345 (J.V.G.). Funding at Swansea University was supported by the European Regional Development Fund/ Welsh European Funding Office via the BEACON project (S.L.K.) and a UK-US Fulbright Scholarship (D.C.L.). Funding at Vanderbilt University was supported by NIH grant R01 GM067871 (G.I.L.).
Start Page: 112241