Mechanistic studies on aromatase and related CC bond cleaving P-450 enzymes
Abstract
Some P-450 systems, notably aromatase and 14 alpha-demethylase catalyse not only the hydroxylate reaction but also the oxidation of an alcohol into a carbonyl compound as well as a C-C bond cleavage process. All these reactions occur at the same active site. A somewhat analogous situation is noted with 17 alpha-hydroxylase-17,20-lyase that participates in hydroxylation as well as C-C bond cleavage process. The C-C bond cleavage reactions catalysed by the above enzymes conform to the general equation: [formula: see text] It is argued that all three types of reaction catalyzed by these enzymes may be viewed as variations on a common theme. In P-450 dependent hydroxylation the initially formed FeIII-O-O. species is converted into FeIII-O-OH and the heterolysis of the oxygen-oxygen bond of the latter then gives the oxo-derivative for which a number of canonical structures are possible; for example FeV = O<==>(+.)FeIV = O<==>FeIV-O.. One of these, FeIV-O. behaves like an alkoxyl radical and participates in hydrogen abstraction from C-H bond to produce FeIV-OH and carbon radical. The latter is then quenched by the delivery of hydroxyl radical from FeIV-OH. The latter species may thus be regarded as a carrier of hydroxyl radical. We have proposed that the C-C bond cleavage reaction occurs through the participation of the FeIII-O-OH species that is trapped by the electrophilic property of the carbonyl compound giving a peroxide adduct that fragments to produce an acyl-carbon cleavage. Scientific developments leading up to this conclusion are considered. In the first author's views, "The study of mechanisms is not a scientific but a cultural activity. Mechanisms do not aim at an absolute truth but are intended to be a "running" commentary on the status of knowledge in a field. As the structural knowledge in a field advances Mechanisms evolve to take note of the new findings. Just as a constructive "running" commentary provides the stimulus for higher standards of performance, so Mechanisms call for better and firmer structural information from their practitioners".
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Aromatase catalyzes the rate-limiting final step in estrogen production, the hydroxylation of androstenedione to estrone and of T to E2.
“It catalyzes the rate-limiting final step in estrogen (E) production, the hydroxylation of androstenedione to estrone and of T to E 2 (Fig. 1).”
From A new era in ovulation induction (2006) · cites this paper as [16]
Letrozole blocks the conversion of androgens to estrogen.
“Letrozole blocks the conversion of androgens to estrogen (31).”
From Effects of letrozole on superovulation with gonadotropins in women undergoing intrauterine insemination (2003) · cites this paper as [31]
Aromatase is a cytochrome P-450 enzyme complex that catalyzes the rate-limiting step in estrogen production.
“Aromatase is a cytochrome P-450 enzyme complex that catalyzes the rate-limiting step in the production of estrogens (E), that is, the conversion of the androgens, androstenedione and testosterone, to estrone (E 1 ) and E 2 (9).”
From Aromatase inhibition improves ovarian response to follicle-stimulating hormone in poor responders (2002) · cites this paper as [9]
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- Authors
- Akhtar, M., Njar, V. C. O., & Neville Wright, J.
- Affiliations
- University of Southampton (GB)
- Corresponding author
- Akhtar, Muhammad
- Venue
- The Journal of Steroid Biochemistry and Molecular Biology
- Publisher
- Elsevier BV
- Published
- 1993-03
- Volume
- 44
- Issue
- 4-6
- Pages
- 375-387
- ISSN
- 0960-0760 (ISSN-L)
- OpenAlex
- W2015325021
- Cited by
- 193
- References
- 50
- Citations by year
- 2024: 2 · 2023: 3 · 2022: 6 · 2021: 3 · 2020: 6 · 2019: 3 · 2018: 3 · 2017: 31 · 2016: 4 · 2015: 29 · 2014: 4 · 2013: 2 · 2012: 3
- FWCI
- 5.29
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Steroid Biochemistry and Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Funders
- Wellcome Trust
- Topics
- Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
- Physical Sciences › Chemistry › Organic Chemistry › Oxidative Organic Chemistry Reactions
- Physical Sciences › Chemistry › Organic Chemistry › Chemical Reaction Mechanisms
- Keywords
- aromatase, cytochrome P450, C–C bond cleavage, reaction mechanism, hydroxyl radicals, heterolysis, steroid hydroxylation, alcohol oxidation
- MeSH terms
- Animals, Aromatase, Cytochrome P-450 Enzyme System, Female, Humans, Hydroxylation, Male, Models, Theoretical, Oxidation-Reduction, Substrate Specificity, Molecular Structure
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