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Cited by 1Enzyme Structure and FunctionProtein Structure and DynamicsLipid Membrane Structure and Behavior

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

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Hargrove, Tatiana Y., Lamb, David C., Wawrzak, Zdzislaw, Minasov, George, Goldstone, Jared V., Kelly, Steven L., Stegeman, John J., Lepesheva, Galina I.·2025·International Journal of Molecular Sciences
DOI 10.3390/ijms26125689PMC PMC12192976

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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.

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Metadata

Authors
Hargrove, T. Y., Lamb, D. C., Wawrzak, Z., Minasov, G., Goldstone, J. V., Kelly, S. L., Stegeman, J. J., & Lepesheva, G. I.
Affiliations
  • Vanderbilt University (US)
  • Northwestern University (US)
  • Swansea University (GB)
ORCID
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2025-06-13
Volume
26
Issue
12
Pages
5689
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms26125689
PMC
PMC12192976
OpenAlex
W4411278792
Cited by
1
References
3
Citations by year
2025: 1
FWCI
0.21
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
Funders
  • National Institutes of Health (R35 GM151876, DE-AC02-06CH11357)
  • United States Department of Energy, Office of Science, Office of Basic Energy Sciences (R35 GM151876, DE-AC02-06CH11357)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
Keywords
cytochrome P450, CYP51, sterol 14α-demethylase, Coryphaenoides armatus, abyssal fish, deep-sea adaptation, crystal structure, conformational flexibility, substrate specificity, membrane environment, endoplasmic reticulum, membrane lipid composition, sterol biosynthesis, cholesterol biosynthesis, adaptive evolution

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