Molecular regulation of adrenal androgen biosynthesis

Idkowiak, Jan (2015). Molecular regulation of adrenal androgen biosynthesis. University of Birmingham. Ph.D.

[img]
Preview
Idkowiak15PhD.pdf
PDF - Accepted Version

Download (17MB)

Abstract

The biosynthesis of adrenal androgens is catalysed by steroid-modifying enzymes. Over the past decade, co-factors were explored to regulate these enzymes: P450 oxidoreductase (POR) delivers electrons to the key androgen-producing cytochrome P450 enzyme CYP17A1. In addition, sulfation of the principal androgen precursor dehydroepiandrosterone (DHEA) catalysed by the enzyme SULT2A1, supported by its co-factor 3’-phosphoadenosine-5’-phosphosulfate (PAPS) synthase 2 (PAPSS2), has been found more recently as a gatekeeper of androgen activation.

Here, we have further characterised children with defects of enzymes of the androgen pathway, namely CYP17A1 and POR. We report the first human missense mutation of cytochrome b5, which supports electron transfer from POR to CYP17A1. In addition, we have explored the molecular regulation of DHEA sulfation by \(in\) \(vitro\) and \(in\) \(vivo\) studies.

The results from our studies provide important information on the clinical course, the diagnostic steroid fingerprint and underlying molecular mechanisms of conditions affecting androgen generation. The \(in\) \(vitro\) studies on DHEA sulfation confirm that the PAPSS2 isoform crucially regulates SULT2A1. Our \(in\) \(vivo\) study in children with deficiencies of the steroid sulfatase (STS) enzyme, the counterpart of SULT2A1, suggests that STS does not play a major role in DHEA metabolism but is more active before puberty.

Type of Work: Thesis (Doctorates > Ph.D.)
Award Type: Doctorates > Ph.D.
Supervisor(s):
Supervisor(s)EmailORCID
Arlt, WiebkeUNSPECIFIEDUNSPECIFIED
Barrett, TimothyUNSPECIFIEDUNSPECIFIED
Licence:
College/Faculty: Colleges (2008 onwards) > College of Medical & Dental Sciences
School or Department: School of Clinical and Experimental Medicine
Funders: None/not applicable
Subjects: Q Science > QP Physiology
R Medicine > R Medicine (General)
URI: http://etheses.bham.ac.uk/id/eprint/5768

Actions

Request a Correction Request a Correction
View Item View Item

Downloads

Downloads per month over past year