Androgens, estrogens, and hydroxysteroid dehydrogenases.

Area of Science:

• Biochemistry
• Enzymology
• Steroid hormone regulation

Background:

• Hydroxysteroid dehydrogenases (HSDs) are crucial for regulating potent androgens and estrogens in human physiology.
• Despite over two dozen described HSD enzymes, the physiology of most remains poorly understood, with only one enzyme's function definitively linked to human mutations.

Purpose of the Study:

• To investigate the biochemical principles governing the dichotomous functions of HSD enzymes.
• To understand how enzyme structure and cofactor availability dictate the directionality of HSD activity in intact cells.

Main Methods:

• Studied pairs of HSD enzymes with opposing activities.
• Investigated the role of nicotinamide adenine dinucleotide (phosphate) cofactors [NAD(P)(H)] and their concentration gradients.
• Utilized site-directed mutagenesis in the cofactor-binding domain and glucose deprivation to alter enzyme directionality.

Main Results:

• Enzyme structure and cofactor availability are key determinants of HSD activity direction.
• Site-directed mutagenesis and glucose deprivation can attenuate or reverse the directional preference of reductive HSDs like human 17betaHSD type 1 and rat AKR1C9.
• The magnitude of these directional changes varies significantly between different enzymes.

Conclusions:

• The study elucidates the biochemical mechanisms controlling HSD enzyme directionality.
• Findings provide insights into modulating steroid hormone production and activity.
• Further research is needed to fully understand the diverse roles and regulation of HSD enzymes.