The glucocorticoid-activating enzyme 11β-hydroxysteroid dehydrogenase type 1 catalyzes the activation of testosterone

Imken Oestlund; Jacky Snoep; Lina Schiffer; Martin Wabitsch; Wiebke Arlt; Karl-Heinz Storbeck

doi:10.1016/j.jsbmb.2023.106436

The glucocorticoid-activating enzyme 11β-hydroxysteroid dehydrogenase type 1 catalyzes the activation of testosterone

J Steroid Biochem Mol Biol. 2024 Feb:236:106436. doi: 10.1016/j.jsbmb.2023.106436. Epub 2023 Nov 28.

Authors

Imken Oestlund¹, Jacky Snoep², Lina Schiffer³, Martin Wabitsch⁴, Wiebke Arlt⁵, Karl-Heinz Storbeck⁶

Affiliations

¹ Department of Biochemistry, Stellenbosch University, Stellenbosch, South Africa.
² Department of Biochemistry, Stellenbosch University, Stellenbosch, South Africa; Molecular Cell Biology, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
³ Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK.
⁴ Division of Pediatric Endocrinology and Diabetes, University Hospital of Ulm, Ulm, Germany.
⁵ Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK; Institute of Clinical Sciences, Faculty of Medicine, Imperial College, London, UK; Medical Research Council Laboratory of Medical Sciences, London, UK.
⁶ Department of Biochemistry, Stellenbosch University, Stellenbosch, South Africa; Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK. Electronic address: storbeck@sun.ac.za.

PMID: 38035948
DOI: 10.1016/j.jsbmb.2023.106436

Abstract

Testosterone biosynthesis from its precursor androstenedione is thought to be exclusively catalysed by the 17β-hydroxysteroid dehydrogenases-HSD17B3 in testes, and AKR1C3 in the ovary, adrenal and peripheral tissues. Here we show for the first time that the glucocorticoid activating enzyme 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can also catalyse the 17β-reduction of androstenedione to testosterone, using a combination of in vitro enzyme kinetic assays, mathematical modelling, and molecular docking analysis. Furthermore, we show that co-expression of HSD11B1 and AKR1C3 increases testosterone production several-fold compared to the rate observed with AKR1C3 only, and that HSD11B1 is likely to contribute significantly to testosterone production in peripheral tissues.

Keywords: 17β-hydroxysteroid dehydrogenase; AKR1C3; Androgen biosynthesis; HSD11B1; HSD17B3; Intracrinology.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

11-beta-Hydroxysteroid Dehydrogenase Type 1 / genetics
17-Hydroxysteroid Dehydrogenases / genetics
3-Hydroxysteroid Dehydrogenases
Androstenedione*
Female
Glucocorticoids
Humans
Hydroxyprostaglandin Dehydrogenases
Molecular Docking Simulation
Testosterone*

Substances

Testosterone
Androstenedione
11-beta-Hydroxysteroid Dehydrogenase Type 1
Glucocorticoids
Hydroxyprostaglandin Dehydrogenases
3-Hydroxysteroid Dehydrogenases
17-Hydroxysteroid Dehydrogenases

Abstract

Publication types

MeSH terms

Substances

Grants and funding