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Cited by 24Pharmacogenetics and Drug MetabolismMetal-Catalyzed Oxygenation MechanismsSteroid Chemistry and Biochemistry

New insights into the role of cytochrome P450 reductase (POR) in microsomal redox biology

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Porter, Todd D.·2012·Acta Pharmaceutica Sinica B
DOI 10.1016/j.apsb.2012.02.002
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Abstract

Cytochrome P450 reductase (POR) is an essential electron transfer protein located on the endoplasmic reticulum of most cell types, and has long been appreciated for its role in cytochrome P450-mediated drug metabolism. Additional roles and electron acceptors for POR have been described, but it is largely with the recent availability of POR-null tissues that these supplemental roles for POR have been able to be explored. These studies have confirmed POR as the principal redox partner for the microsomal P450s responsible for drug and xenobiotic metabolism as well as cholesterol and bile acid synthesis, and for heme oxygenase, which catalyzes the initial step in the breakdown of heme. Surprisingly, these studies have revealed that squalene monooxygenase, an enzyme essential to cholesterol synthesis, has a second unknown redox partner in addition to POR, and that 7-dehydrocholesterol reductase, previously proposed to require POR as an electron donor, functions fully independently of POR. These studies have also helped define the role of cytochrome b5 in P450 catalysis, and raise the question as to the extent to which POR contributes to b5-dependent redox pathways.

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  • A dominant nonsense mutation in squalene epoxidase (Sqle) was found in an unbiased forward genetic suppressor screen in Mecp2 null mice.

    “Curiously, a dominant nonsense mutation was found in squalene epoxidase (Sqle), a monooxygenase and rate-limiting cholesterol biosynthesis enzyme, which requires an electron donor from mitochondria for its function [157].”

    From Rett syndrome: a neurological disorder with metabolic components (2018) · cites this paper as [157]

    Section 2.2 (page unavailable) identifies squalene monooxygenase as an enzyme in sterol synthesis that requires an electron-transfer partner. It does not report a dominant nonsense mutation, a forward genetic suppressor screen, or findings in Mecp2-null mice. Its discussion of POR and a second microsomal reductase also does not support the citing sentence’s claim that the electron donor comes from mitochondria. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Sqle is a monooxygenase and rate-limiting cholesterol biosynthesis enzyme that requires an electron donor from mitochondria for its function.

    “Curiously, a dominant nonsense mutation was found in squalene epoxidase (Sqle), a monooxygenase and rate-limiting cholesterol biosynthesis enzyme, which requires an electron donor from mitochondria for its function [157].”

    From Rett syndrome: a neurological disorder with metabolic components (2018) · cites this paper as [157]

    Section 2.2 identifies Sqle as squalene monooxygenase, an enzyme in sterol synthesis that requires an electron-transfer partner. It describes POR and a second, unidentified microsomal reductase—not an electron donor from mitochondria—and does not call Sqle rate-limiting. Page numbers are unavailable in our copy. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

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Cites

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Research works printed but not linked: 31

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Cited by

Sorted by citations

Authors
Porter, T. D.
Affiliations
University of Kentucky (US)
Corresponding author
Porter, Todd D.
Venue
Acta Pharmaceutica Sinica B
Publisher
Elsevier BV
Published
2012-04
Volume
2
Issue
2
Pages
102-106
ISSN
2211-3835 (ISSN-L)
DOI
10.1016/j.apsb.2012.02.002
OpenAlex
W2016648157
Cited by
24
References
2
Citations by year
2024: 1 · 2023: 2 · 2022: 3 · 2021: 5 · 2020: 2 · 2019: 2 · 2018: 5 · 2016: 1 · 2015: 2 · 2012: 1
FWCI
1.09
Type
journal article
Language
en
Open access
Licence
Locations
  • Acta Pharmaceutica Sinica B (publishedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
  • Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Steroid Chemistry and Biochemistry
Keywords
NADPH-cytochrome P450 reductase, POR, electron transfer, cytochrome P450, drug metabolism, xenobiotic metabolism, cholesterol biosynthesis, bile acid synthesis, heme oxygenase, squalene monooxygenase, DHCR7, cytochrome b5

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