3-Hydroxysteroid dehydrogenase

3-Hydroxysteroid dehydrogenase (3-HSD) is an enzyme that catalyzes the oxidation and reduction of steroids in the production and degradation of hormones. This enzyme plays a crucial role in the biosynthesis of all classes of hormonal steroids: estrogens, androgens, glucocorticoids, and mineralocorticoids. 3-HSD is part of the steroid hormone biosynthesis pathway, converting pregnenolone to progesterone, dehydroepiandrosterone (DHEA) to androstenedione, and 17α-hydroxypregnenolone to 17α-hydroxyprogesterone.

Function

3-HSD is involved in the conversion of 3β-hydroxysteroids to their corresponding 3-keto steroids. This conversion is a key step in the formation of steroid hormones. The enzyme is present in various tissues, including the adrenal glands, ovaries, testes, and placenta, reflecting its essential role in steroid hormone production. There are two isoforms of the enzyme, 3-HSD1 and 3-HSD2, each encoded by separate genes and having distinct tissue distributions and substrate specificities.

Clinical Significance

Mutations or deficiencies in 3-HSD can lead to disorders of steroidogenesis, affecting sexual development and adrenal function. One such condition is 3β-Hydroxysteroid Dehydrogenase Deficiency, a form of congenital adrenal hyperplasia (CAH), which can result in ambiguous genitalia in newborns, salt wasting, and potentially life-threatening adrenal insufficiency. Diagnosis is typically made through hormonal assays and genetic testing, and treatment involves glucocorticoid and mineralocorticoid replacement therapy.

Structure

3-HSD belongs to the short-chain dehydrogenase/reductase (SDR) family. The enzyme's structure includes a conserved NAD+/NADP+ binding domain, which is crucial for its catalytic activity. Crystal structures of 3-HSD with various substrates have provided insights into the mechanism of action and substrate specificity of the enzyme.

Isoforms

There are two main isoforms of 3-HSD:

• 3-HSD1: Predominantly found in the placenta and peripheral tissues, it plays a significant role in the local synthesis of active steroids.
• 3-HSD2: Expressed mainly in the adrenal glands, ovaries, and testes, it is essential for the systemic production of steroid hormones.

Pathway

The enzyme is a key player in the steroidogenesis pathway, facilitating the conversion of:

• Pregnenolone to progesterone
• 17α-hydroxypregnenolone to 17α-hydroxyprogesterone
• DHEA to androstenedione

These reactions are vital for the production of glucocorticoids, mineralocorticoids, androgens, and estrogens.

Inhibitors

Certain compounds can inhibit the activity of 3-HSD, affecting steroid hormone levels. These inhibitors have potential therapeutic applications in diseases related to excessive or deficient steroid hormone production, such as CAH, prostate cancer, and endometriosis.

See Also

• Steroidogenesis
• Congenital adrenal hyperplasia
• Adrenal gland
• Hormone