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Structural context of NADPH-cytochrome P450 reductase mutations that alter cytochrome P450 1A2 substrate regioselectivity

2026-06Artigo científico Acesso aberto
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dc.contributor.authorBurris-Hiday, Sarah D.
dc.contributor.authorEsteves, Francisco
dc.contributor.authorKranendonk, Michel
dc.contributor.authorScott, Emily E.
dc.contributor.institutionComprehensive Health Research Centre (CHRC) - pólo NMS
dc.contributor.institutionNOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)
dc.contributor.pblASPET - American Society for Pharmacology and Experimental Therapeutics
dc.date.accessioned2026-06-22T14:56:01Z
dc.date.available2026-06-22T14:56:01Z
dc.date.issued2026-06
dc.descriptionPublisher Copyright: © 2026 The Author(s). Published by Elsevier Inc. on behalf of American Society for Pharmacology and Experimental Therapeutics. This is an open access article under the CC BY-NC-ND license. http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.description.abstractNADPH-cytochrome P450 (P450) reductase serves as the obligate redox partner for the majority of human P450 enzymes, those responsible for both drug metabolism and homeostasis. NADPH-derived electrons are accepted by the reductase FAD-containing domain and then transferred to its flavin mononucleotide–containing domain (FMND). This domain directly binds P450 enzymes, providing electrons essential for P450 catalysis. Reductase mutations, and specifically those of its FMND, have been widely studied and variously affect P450 function. Most intriguing, previous studies identified 5 specific FMND single amino acid mutations that alter the regioselectivity of CYP1A2 caffeine metabolism. The studies herein further show that these same mutations also alter CYP1A2 methoxyresorufin O-demethylation, mostly in the same direction and scale. To provide experimental information about these FMND mutants, their X-ray crystal structures were determined (1.1–1.5 Å resolution). Although only subtle changes in FMND structure were observed, they were not confined to the local vicinity of the mutation. Changes were instead primarily in the loops binding the flavin cofactor, shifting the backbone of these loops farther from or closer to the flavin cofactor. The extent of loop shifting varies depending on the mutation but indicates that only subtle changes in these loops are required to affect the P450 interaction enough to transmit structural changes to the P450 active site. Significance Statement: Experimental structural information is lacking for the interaction between human cytochrome P450 (P450) enzymes and their reductase, but some reductase mutations alter P450 catalytic regioselectivity, suggesting that the protein/protein interaction alters substrate orientation in the distant P450 active site. The current work establishes that such mutations yield only small changes in the structure of the reductase flavin mononucleotide–containing domain, suggesting that small changes in the interaction nonetheless significantly influence P450 active site catalysis.en
dc.description.versionpublishersversion
dc.description.versionpublished
dc.format.extent5188890
dc.identifier.doi10.1016/j.dmd.2026.100300
dc.identifier.issn0090-9556
dc.identifier.otherPURE: 163157559
dc.identifier.otherPURE UUID: c5f76a31-ec73-40a6-a29d-a135a47a21b6
dc.identifier.otherScopus: 105038233350
dc.identifier.otherPubMed: 42105715
dc.identifier.urihttp://hdl.handle.net/10362/204022
dc.identifier.urlhttps://www.scopus.com/pages/publications/105038233350
dc.language.isoeng
dc.peerreviewedyes
dc.subjectAllostery
dc.subjectCYP1A2
dc.subjectCytochrome P450
dc.subjectNADPH-cytochrome P450 reductase
dc.subjectProtein-protein interaction
dc.subjectX-ray crystallography
dc.subjectPharmacology
dc.subjectPharmaceutical Science
dc.titleStructural context of NADPH-cytochrome P450 reductase mutations that alter cytochrome P450 1A2 substrate regioselectivityen
dc.typejournal article
degois.publication.issue6
degois.publication.titleDrug Metabolism And Disposition
degois.publication.volume54
dspace.entity.typePublication
rcaap.rightsopenAccess

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