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A review of 18O labelling studies to probe the mechanism of aromatase (CYP191A)

A review of 18O labelling studies to probe the mechanism of aromatase (CYP191A)
A review of 18O labelling studies to probe the mechanism of aromatase (CYP191A)

Our previous studies, using precursors for two classes of estrogens, estrone and estriol, have highlighted the following facets of aromatase. The overall reaction, converting androgens into estrogens, occurs in three steps, each requiring NADPH and O 2. In Step 1, a 19-hydroxy intermediate is produced, which in Step 2, is converted into a 19-oxo derivative via a gem -diol intermediate with the stereospecific loss of H Re. In Step 3, a scission of the C-10-C-19 bond occurs releasing C-19 as formic acid (HCOOH) and incorporating an atom of oxygen from O 2, The other oxygen atom of formic acid is derived from the hydroxyl group introduced in Step 1. These experiments were performed using the classical placental microsomal system. Our findings were confirmed and extended by (the late) Caspi's group. However, incorporation of oxygen in Step 3, has been challenged in a subsequent study using a soluble reconstituted system. The latter authors have implied the superiority of their system over the microsomal preparation. However, several assumptions under pinning their own work were derived from the use of placental microsomes. Furthermore, the authors have not considered that when a previous work is challenged it needs to be repeated under the conditions described in the original publication.

Acyl-carbon cleaving P450, CYP 51A1 (sterol 14α-demethylase), CYP17A1 (17α-hydroxylase-177,20-lyase), O-incorporation, estriol biosynthesis
0960-0760
Akhtar, Muhammad
a4174002-a6bd-4678-8e63-4cbe607a672d
Wright, James N
e53ee4b9-10f5-4365-a9f2-5a7b0eacd86d
Akhtar, Muhammad
a4174002-a6bd-4678-8e63-4cbe607a672d
Wright, James N
e53ee4b9-10f5-4365-a9f2-5a7b0eacd86d

Akhtar, Muhammad and Wright, James N (2022) A review of 18O labelling studies to probe the mechanism of aromatase (CYP191A). The Journal of Steroid Biochemistry and Molecular Biology, 216, [106010]. (doi:10.1016/j.jsbmb.2021.106010).

Record type: Review

Abstract

Our previous studies, using precursors for two classes of estrogens, estrone and estriol, have highlighted the following facets of aromatase. The overall reaction, converting androgens into estrogens, occurs in three steps, each requiring NADPH and O 2. In Step 1, a 19-hydroxy intermediate is produced, which in Step 2, is converted into a 19-oxo derivative via a gem -diol intermediate with the stereospecific loss of H Re. In Step 3, a scission of the C-10-C-19 bond occurs releasing C-19 as formic acid (HCOOH) and incorporating an atom of oxygen from O 2, The other oxygen atom of formic acid is derived from the hydroxyl group introduced in Step 1. These experiments were performed using the classical placental microsomal system. Our findings were confirmed and extended by (the late) Caspi's group. However, incorporation of oxygen in Step 3, has been challenged in a subsequent study using a soluble reconstituted system. The latter authors have implied the superiority of their system over the microsomal preparation. However, several assumptions under pinning their own work were derived from the use of placental microsomes. Furthermore, the authors have not considered that when a previous work is challenged it needs to be repeated under the conditions described in the original publication.

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Accepted/In Press date: 18 October 2021
e-pub ahead of print date: 30 October 2021
Published date: February 2022
Additional Information: Funding Information: WE thank Monika E Akhtar for encouragement, help with the manuscript and obtaining the images from various PhD theses shown in the Supplementary Section. We are also thankful to Professor David C Wilton and Dr Peter Lee-Robichaud for critical editing of the manuscript. Publisher Copyright: © 2021 Elsevier Ltd
Keywords: Acyl-carbon cleaving P450, CYP 51A1 (sterol 14α-demethylase), CYP17A1 (17α-hydroxylase-177,20-lyase), O-incorporation, estriol biosynthesis

Identifiers

Local EPrints ID: 454128
URI: http://eprints.soton.ac.uk/id/eprint/454128
ISSN: 0960-0760
PURE UUID: 2403dfed-6929-4180-980f-39ad6fe32e54

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Date deposited: 01 Feb 2022 17:34
Last modified: 30 Oct 2022 05:01

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Author: Muhammad Akhtar
Author: James N Wright

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