ArticleThe Journal of biological chemistry2016
Mechanism of 17α,20-Lyase and New Hydroxylation Reactions of Human Cytochrome P450 17A1: 18O LABELING AND OXYGEN SURROGATE EVIDENCE FOR A ROLE OF A PERFERRYL OXYGEN.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 33 papers.
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33 citing papers in PubMed, 66 citations in OpenAlex.
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- Updates on Mechanisms of Cytochrome P450 Catalysis of Complex Steroid Oxidations.International journal of molecular sciences · 2024Review
- Oxygen-18 Labeling Reveals a Mixed Fe-O Mechanism in the Last Step of Cytochrome P450 51 Sterol 14α-Demethylation.Angewandte Chemie (International ed. in English) · 2024Article
- Oxygen-18 Labeling Defines a Ferric Peroxide (Compound 0) Mechanism in the Oxidative Deformylation of Aldehydes by Cytochrome P450 2B4.ACS catalysis · 2024Article
- Allosteric modulation of cytochrome P450 enzymes by the NADPH cytochrome P450 reductase FMN-containing domain.The Journal of biological chemistry · 2023Article
- Engineering C-C Bond Cleavage Activity into a P450 Monooxygenase Enzyme.Journal of the American Chemical Society · 2023Article
- Steroid 17α-hydroxylase/17, 20-lyase (cytochrome P450 17A1).Methods in enzymology · 2023Article
- Crosstalk between ferroptosis and steroid hormone signaling in gynecologic cancers.Frontiers in molecular biosciences · 2023Review
- Importance of Asparagine 202 in Manipulating Active Site Structure and Substrate Preference for Human CYP17A1.Biochemistry · 2022Article
- Oviducal gland transcriptomics ofPeerJ · 2022Article
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- Mechanism of the Clinically Relevant E305G Mutation in Human P450 CYP17A1.Biochemistry · 2021Article
- Effects of fluorine substitution on substrate conversion by cytochromes P450 17A1 and 21A2.Organic & biomolecular chemistry · 2021Article
- Steroidogenic cytochrome P450 17A1 structure and function.Molecular and cellular endocrinology · 2021Review
- P450 CYP17A1 Variant with a Disordered Proton Shuttle Assembly Retains Peroxo-Mediated Lyase Efficiency.Chemistry (Weinheim an der Bergstrasse, Germany) · 2020Article
- A requirement for an active proton delivery network supports a compound I-mediated C-C bond cleavage in CYP51 catalysis.The Journal of biological chemistry · 2020Article
- Multistep Binding of the Non-Steroidal Inhibitors Orteronel and Seviteronel to Human Cytochrome P450 17A1 and Relevance to Inhibition of Enzyme Activity.Journal of medicinal chemistry · 2020Article
Corrections and comments
- Erratum issued
Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Cytochrome P450 (P450) reactions can involve C-C bond cleavage, and several of these are critical in steroid and sterol biosynthesis. The mechanisms of P450s 11A1, 17A1, 19A1, and 51A1 have been controversial, in the context of the role of ferric peroxide (FeO2 (-)) versus perferryl (FeO(3+), compound I) chemistry. We reinvestigated the 17α-hydroxyprogesterone and 17α-hydroxypregnenolone 17α,20-lyase reactions of human P450 17A1 and found incorporation of one (18)O atom (from (18)O2) into acetic acid, consonant with proposals for a ferric peroxide mechanism (Akhtar, M., Lee-Robichaud, P., Akhtar, M. E., and Wright, J. N. (1997) J. Steroid Biochem. Mol. Biol. 61, 127-132; Akhtar, M., Wright, J. N., and Lee-Robichaud, P. (2011) J. Steroid Biochem. Mol. Biol. 125, 2-12). However, the reactions were supported by iodosylbenzene (a precursor of the FeO(3+) species) but not by H2O2 We propose three mechanisms that can involve the FeO(3+) entity and that explain the (18)O label in the acetic acid, two involving the intermediacy of an acetyl radical and one a steroid 17,20-dioxetane. P450 17A1 was found to perform 16-hydroxylation reactions on its 17α-hydroxylated products to yield 16,17α-dihydroxypregnenolone and progesterone, suggesting the presence of an active perferryloxo active species of P450 17A1 when its lyase substrate is bound. The 6β-hydroxylation of 16α,17α-dihydroxyprogesterone and the oxidation of both 16α,17α-dihydroxyprogesterone and 16α,17α-dihydroxypregnenolone to 16-hydroxy lyase products were also observed. We provide evidence for the contribution of a compound I mechanism, although contribution of a ferric peroxide pathway in the 17α,20-lyase reaction cannot be excluded.
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