HSD17B1

Function

This enzyme is responsible for the interconversion of estrone (E1) and estradiol (E2) and for the interconversion of androstenedione and testosterone:

: 17β-estradiol + NADP+ + \rightleftharpoons estrone + NADPH + H+ : testosterone + NADP+ + \rightleftharpoons androstenedione + NADPH + H+

The human 17β-HSD1 isozyme is highly specific for estrogens over androgens whereas the rodent isozyme is less specific.

Discovery

Human 17β-HSD1 was the first enzyme of the 17β-HSD family to be cloned and to have its sequence identified. Its three-dimensional structure is also the first example of any human steroid-converting enzyme.

Structure

This enzyme contains a short-chain dehydrogenase domain that contains a characteristic 3-layer (αβα) sandwich known as a Rossmann fold. The human enzyme contains 327 amino acids and exists as a homodimer with two identical subunits of 34.5 kDa The N-terminal short-chain dehydrogenase domain contains binding site for the NADP+/NADPH cofactor. A narrow, hydrophobic C-terminal domain contains a binding pocket for the steroid substrate.

Clinical significance

Estradiol stimulates while dihydrotestosterone (DHT) inhibits breast cancer growth. Furthermore 17β-HSD1 levels positively correlate with estradiol and negatively correlate with DHT levels in breast cancer cells. Hence 17β-HSD1 represents a possible drug target for breast cancer treatment.

Inhibitors

• Linustedastat

Notes

References

References

1. (Feb 1990). "Structure of two in tandem human 17 beta-hydroxysteroid dehydrogenase genes". Molecular Endocrinology.
2. (Mar 2009). "The SDR (short-chain dehydrogenase/reductase and related enzymes) nomenclature initiative". Chemico-Biological Interactions.
3. "Entrez Gene: HSD17B1 Hydroxysteroid (17-beta) dehydrogenase 1".
4. (2012). "The diversity of sex steroid action: novel functions of hydroxysteroid (17β) dehydrogenases as revealed by genetically modified mouse models". The Journal of Endocrinology.
5. (Aug 1989). "Characterization of cDNAs for human estradiol 17 beta-dehydrogenase and assignment of the gene to chromosome 17: evidence of two mRNA species with distinct 5'-termini in human placenta". Molecular Endocrinology.
6. (Oct 1988). "Complete amino acid sequence of human placental 17 beta-hydroxysteroid dehydrogenase deduced from cDNA". FEBS Letters.
7. (May 1995). "Structure of human estrogenic 17 beta-hydroxysteroid dehydrogenase at 2.20 A resolution". Structure.
8. (Aug 1992). "Subunit identity of the dimeric 17 beta-hydroxysteroid dehydrogenase from human placenta". The Journal of Biological Chemistry.
9. (Apr 2010). "17beta-hydroxysteroid dehydrogenase type 1 stimulates breast cancer by dihydrotestosterone inactivation in addition to estradiol production". Molecular Endocrinology.
10. "International Nonproprietary Names for Pharmaceutical Substances (INN) Proposed INN List 130".