The multi-specific human 17 beta-hydroxysteroid dehydrogenase type 7: Non-competitive inhibitors can target different...

Area of Science:

• Biochemistry
• Enzymology
• Oncology

Background:

• Human 17β-hydroxysteroid dehydrogenase type 7 (17β-HSD7) is a key enzyme in hormone metabolism, activating estrone and inactivating dihydrotestosterone.
• 17β-HSD7 inhibition is a promising strategy for hormone-dependent breast cancer, aiming to reduce estradiol and restore dihydrotestosterone levels.
• A significant concern is 17β-HSD7's role in cholesterol biosynthesis, potentially causing side effects upon inhibition.

Purpose of the Study:

• To investigate the mechanism of action of existing 17β-HSD7 inhibitors.
• To determine if selective inhibition of 17β-HSD7's different catalytic functions is achievable.
• To evaluate the potential of selective inhibitors for breast cancer therapy with reduced side effects.

Main Methods:

• Enzyme kinetics studies were performed to characterize inhibitor binding.
• Specific inhibitors like INH81 and 4-bromo-ethynylestradiol were used to assess selectivity.
• Comparative analysis of inhibitor effects on sex-hormone conversion and cholesterol biosynthesis pathways.

Main Results:

• All tested 17β-HSD7 inhibitors demonstrated non-competitive binding kinetics.
• Non-competitive inhibitors did not interfere with substrate binding to the enzyme.
• Selective inhibition was observed: INH81 primarily affected sex-hormone conversion, while 4-bromo-ethynylestradiol targeted zymosterone reduction in cholesterol biosynthesis.

Conclusions:

• This study provides the first evidence of non-competitive inhibitors selectively targeting distinct catalytic activities of 17β-HSD7.
• The selective action of these inhibitors offers a promising approach for breast cancer treatment by allowing targeted modulation of hormone pathways.
• Developing selective 17β-HSD7 inhibitors could lead to more effective breast cancer therapies with minimized adverse effects related to cholesterol metabolism.