Consequences of steroid-5α-reductase deficiency and inhibition in vertebrates

Robitaille, Julie; Langlois, Valérie S.

doi:10.1016/j.ygcen.2020.113400

Cited by 32 publications

(34 citation statements)

References 210 publications

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“…1). This suggests that although all the SRD5A family members use NADPH as the cofactor to reduce their substrates, they have evolved specific structural features to recognize different steroid or lipid substrates 1,7 . We further mapped the residue conservation to the SRD5A2 structure, which showed that the region around the tert-butylacetamide tail group of DHF is the least conserved part of the ligand-binding pocket (Extended Data Fig.…”

Section: Resultsmentioning

confidence: 99%

“…A large number of mutations identified in the SRD5A2 gene can result in insufficient levels of DHT, leading to an autosomal recessive disorder named 5α-reductase deficiency, which is associated with underdeveloped and atypical genitalia 9 – 11 . On the other hand, overproduction of DHT by SRD5A2 is associated with benign prostatic hyperplasia (BPH), androgenic alopecia, and prostate cancer due to excessive androgen receptor signaling 7 , 12 . 5α-Reductase inhibitors (5ARIs) including finasteride and dutasteride (Fig.…”

Section: Introductionmentioning

confidence: 99%

“…SRD5A1 and SRD5A3 have been indicated to function in the metabolism of neurosteroids 4,5 and in protein N-linked glycosylation 3,6 , respectively. SRD5A2 is the most intensively investigated SRD5A, and has well-characterized roles in androgen metabolism and androgen-related disorders 1,7 . All three SRD5As are located in the membrane of endoplasmic reticulum (ER) in the cells 8 .…”

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confidence: 99%

“…SRD5A2 is highly expressed in male reproductive systems 7 to convert testosterone to 5α-dihydrotestosterone (DHT; Fig. 1a), the major steroid hormone for androgen receptor 1 .…”

mentioning

confidence: 99%

“…5α-Reductase inhibitors (5ARIs) including finasteride and dutasteride ( Fig. 1b), which mainly target SRD5A2, but also act on other SRD5As 13 , have been used as a major class of antiandrogenic drugs to treat BPH and androgenic alopecia 1,7,12,14 , and are indicated in the treatment of prostate cancer 15 . In particular, finasteride is among the top 100 most prescribed drugs in the United States and is associated with an irreversible action on SRD5A2 (refs.…”

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Structure of human steroid 5α-reductase 2 with the anti-androgen drug finasteride

et al. 2020

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Human steroid 5α-reductase 2 (SRD5A2) is an integral membrane enzyme in steroid metabolism and catalyzes the reduction of testosterone to dihydrotestosterone. Mutations in the SRD5A2 gene have been linked to 5α-reductase deficiency and prostate cancer. Finasteride and dutasteride, as SRD5A2 inhibitors, are widely used antiandrogen drugs for benign prostate hyperplasia. The molecular mechanisms underlying enzyme catalysis and inhibition for SRD5A2 and other eukaryotic integral membrane steroid reductases remain elusive due to a lack of structural information. Here, we report a crystal structure of human SRD5A2 at 2.8 Å, revealing a unique 7-TM structural topology and an intermediate adduct of finasteride and NADPH as NADP-dihydrofinasteride in a largely enclosed binding cavity inside the transmembrane domain. Structural analysis together with computational and mutagenesis studies reveal the molecular mechanisms of the catalyzed reaction and of finasteride inhibition involving residues E57 and Y91. Molecular dynamics simulation results indicate high conformational dynamics of the cytosolic region that regulate NADPH/NADP+ exchange. Mapping disease-causing mutations of SRD5A2 to our structure suggests molecular mechanisms for their pathological effects. Our results offer critical structural insights into the function of integral membrane steroid reductases and may facilitate drug development.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

“…SRD5A2 is highly expressed in male reproductive systems 7 to convert testosterone to 5α-dihydrotestosterone (DHT; Fig. 1a), the major steroid hormone for androgen receptor 1 .…”

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Structure of human steroid 5α-reductase 2 with the anti-androgen drug finasteride

et al. 2020

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AOP Report: An Upstream Network for Reduced Androgen Signaling Leading to Altered Gene Expression of Androgen Receptor–Responsive Genes in Target Tissues

Draskau,

Rosenmai,

Bouftas

et al. 2024

Enviro Toxic and Chemistry

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Adverse outcome pathways (AOPs) can aid with chemical risk assessment by providing plausible links between chemical activity at the molecular level and effect outcomes in intact organisms. Because AOPs can be used to infer causality between upstream and downstream events in toxicological pathways, the AOP framework can also facilitate increased uptake of alternative methods and new approach methodologies to help inform hazard identification. However, a prevailing challenge is the limited number of fully developed and endorsed AOPs, primarily due to the substantial amount of work required by AOP developers and reviewers. Consequently, a more pragmatic approach to AOP development has been proposed where smaller units of knowledge are developed and reviewed independent of full AOPs. In this context, we have developed an upstream network comprising key events (KEs) and KE relationships related to decreased androgen signaling, converging at a nodal KE that can branch out to numerous adverse outcomes (AOs) relevant to androgen‐sensitive toxicological pathways. Androgen signaling represents an extensively studied pathway for endocrine disruption. It is linked to numerous disease outcomes and can be affected by many different endocrine‐disrupting chemicals. Still, pathways related to disrupted androgen signaling remain underrepresented in the AOP‐wiki, and endorsed AOPs are lacking. Given the pivotal role of androgen signaling in development and function across vertebrate taxa and life stages of both sexes, this upstream AOP network serves as a foundational element for developing numerous AOPs. By connecting the upstream network with various downstream AOs, encompassing different species, it can also facilitate cross‐species extrapolations for hazard and risk assessment of chemicals. Environ Toxicol Chem 2024;00:1–9. © 2024 The Author(s). Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

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Chronic Exposure to Two Gestagens Differentially Alters Morphology and Gene Expression in Silurana tropicalis

Thomson

Pineda

Yargeau

et al. 2021

Arch Environ Contam Toxicol

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Consequences of steroid-5α-reductase deficiency and inhibition in vertebrates

Cited by 32 publications

References 210 publications

Structure of human steroid 5α-reductase 2 with the anti-androgen drug finasteride

Structure of human steroid 5α-reductase 2 with the anti-androgen drug finasteride

AOP Report: An Upstream Network for Reduced Androgen Signaling Leading to Altered Gene Expression of Androgen Receptor–Responsive Genes in Target Tissues

Chronic Exposure to Two Gestagens Differentially Alters Morphology and Gene Expression in Silurana tropicalis

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