HSD17B1

HSD17B1 Full Name

hydroxysteroid (17-beta) dehydrogenase 1

HSD17B1 Introduction

17β-Hydroxysteroid dehydrogenase 1 (HSD17B1) is an enzyme encoded by the HSD17B1 gene in humans. This enzyme oxidizes or reduces the C17 hydroxyl/ketone groups of androgens and estrogens, thus regulating the potency of these sex steroids. 17 β - hydroxysteroid dehydrogenase type 1 (HSD17B1), also known as 17 ketosteroid reductase, is an important member of the 17 β - HSD enzyme family. Its main and most important function is to catalyze the final and rate limiting step in the biosynthesis of the most effective estrogen estradiol (E2). It achieves this goal by using NADPH as a cofactor to reduce weak estrogen estrone (E1) to highly active 17 β - estradiol (E2). Therefore, HSD17B1 is a central regulatory factor of local estrogen concentration in tissues, playing a key role in normal female reproductive physiology and the pathogenesis of estrogen dependent diseases.

Figure. Structure of hydroxysteroid (17-beta) dehydrogenase 1.

Structure
This enzyme contains a short chain dehydrogenase domain, which contains a characteristic 3-layer (alpha beta alpha) sandwich called 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 sites for NADP+/NADPH cofactors. A narrow hydrophobic C-terminal domain contains a binding pocket for steroid substrates. The HSD17B1 gene is located on chromosome 17q21. The enzyme functions as a homodimer, with each subunit having a molecular weight of approximately 35 kDa. Its crystal structure has been elucidated, revealing crucial details for substrate and inhibitor binding.

HSD17B1 as Therapeutic Target
Given its role as an "estrogen amplifier" in diseases, HSD17B1 is a promising and attractive therapeutic target. The goal is to develop specific inhibitors that can block the local production of estradiol in diseased tissues without affecting systemic estrogen levels (unlike aromatase inhibitors that cause systemic estrogen deprivation).
Strategy: Design selective HSD17B1 inhibitors.
Potential benefits: for the treatment of ER positive breast cancer, endometriosis and endometrial cancer, compared with global estrogen blockade, there are fewer potential systemic side effects (such as reducing bone loss and hot flashes).
Current situation: Several potent and selective inhibitors have been developed (such as compounds based on steroid or nonsteroidal frameworks) and have shown efficacy in preclinical models. Some have already entered the early stage of clinical trials.

Alternate Names for HSD17B1

HSD17B1; hydroxysteroid (17-beta) dehydrogenase 1; estradiol 17-beta-dehydrogenase 1; 17-beta-HSD 1; 17-beta-hydroxysteroid dehydrogenase type 1; Hydroxysteroid dehydrogenase 17 beta, type 1; 17BHD1;