The University of Southampton
University of Southampton Institutional Repository

A review of mechanistic studies on aromatase (CYP19) and 17?-hydroxylase-17,20-lyase (CYP17)

A review of mechanistic studies on aromatase (CYP19) and 17?-hydroxylase-17,20-lyase (CYP17)
A review of mechanistic studies on aromatase (CYP19) and 17?-hydroxylase-17,20-lyase (CYP17)
In the conventional P-450 dependent hydroxylation reaction, the FeIII resting state of the enzyme, by a single electron transfer, is reduced to FeII, which reacts with O2 to produce a FeIII–O–O intermediate. The latter following the transfer of another electron furnishes a ferric-peroxyanion, FeIII–O–O?, which after protonation leads to the fission of the O–O bond resulting in the formation of FeVO, the key player in the hydroxylation process. Certain members of the P-450 family, including CYP17 and CYP19, catalyze, at the same active site, not only the hydroxylation process but also an acyl–carbon bond cleavage reaction which has been interpreted to involve the nucleophilic attack of the ferric-peroxyanion, FeIII–O–O?, on the acyl carbon to furnish a tetrahedral intermediate which fragments, leading to acyl–carbon cleavage. Evidence is presented to show that in the case of CYP17 the attack of FeIII–O–O? on the target carbon is promoted by cytochrome b5, which acts as a conformational regulator of CYP17. It is this regulation of CYP17 that provides a safety mechanism which ensures that during corticoid biosynthesis, which involves 17?-hydroxylation by CYP17, androgen formation is avoided. Finally, a brief account is presented of the inhibitors, of the two enzymes, which have been designed on the basis of their mechanism of action.
P-450c17, P450c17, P-450 17alpha CYP19, aromatase, CYP17, cytochrome b5, androgen biosynthesis, iron-oxygen species, steroid biosynthesis
0960-0760
2-12
Akhtar, Muhammad
a4174002-a6bd-4678-8e63-4cbe607a672d
Wright, J. Neville
e53ee4b9-10f5-4365-a9f2-5a7b0eacd86d
Lee-Robichaud, Peter
478f889c-236a-4084-9777-2e3d524b0aaa
Akhtar, Muhammad
a4174002-a6bd-4678-8e63-4cbe607a672d
Wright, J. Neville
e53ee4b9-10f5-4365-a9f2-5a7b0eacd86d
Lee-Robichaud, Peter
478f889c-236a-4084-9777-2e3d524b0aaa

Akhtar, Muhammad, Wright, J. Neville and Lee-Robichaud, Peter (2011) A review of mechanistic studies on aromatase (CYP19) and 17?-hydroxylase-17,20-lyase (CYP17). [in special issue: Targeted inhibitors] The Journal of Steroid Biochemistry and Molecular Biology, 125 (1-2), 2-12. (doi:10.1016/j.jsbmb.2010.11.003). (PMID:21094255)

Record type: Article

Abstract

In the conventional P-450 dependent hydroxylation reaction, the FeIII resting state of the enzyme, by a single electron transfer, is reduced to FeII, which reacts with O2 to produce a FeIII–O–O intermediate. The latter following the transfer of another electron furnishes a ferric-peroxyanion, FeIII–O–O?, which after protonation leads to the fission of the O–O bond resulting in the formation of FeVO, the key player in the hydroxylation process. Certain members of the P-450 family, including CYP17 and CYP19, catalyze, at the same active site, not only the hydroxylation process but also an acyl–carbon bond cleavage reaction which has been interpreted to involve the nucleophilic attack of the ferric-peroxyanion, FeIII–O–O?, on the acyl carbon to furnish a tetrahedral intermediate which fragments, leading to acyl–carbon cleavage. Evidence is presented to show that in the case of CYP17 the attack of FeIII–O–O? on the target carbon is promoted by cytochrome b5, which acts as a conformational regulator of CYP17. It is this regulation of CYP17 that provides a safety mechanism which ensures that during corticoid biosynthesis, which involves 17?-hydroxylation by CYP17, androgen formation is avoided. Finally, a brief account is presented of the inhibitors, of the two enzymes, which have been designed on the basis of their mechanism of action.

Text
Aromatase_Review.pdf - Version of Record
Restricted to Repository staff only
Request a copy

More information

Published date: May 2011
Keywords: P-450c17, P450c17, P-450 17alpha CYP19, aromatase, CYP17, cytochrome b5, androgen biosynthesis, iron-oxygen species, steroid biosynthesis
Organisations: Centre for Biological Sciences

Identifiers

Local EPrints ID: 335648
URI: https://eprints.soton.ac.uk/id/eprint/335648
ISSN: 0960-0760
PURE UUID: 64577e49-288c-4775-ad36-d7eaf9284903

Catalogue record

Date deposited: 13 Mar 2012 13:14
Last modified: 04 Nov 2019 20:43

Export record

Altmetrics

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of https://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×