First Structure–Activity Relationship of 17β-Hydroxysteroid Dehydrogenase Type 14 Nonsteroidal Inhibitors and Crystal Structures in Complex with the Enzyme

Braun, Florian; Bertoletti, Nicole; Möller, Gabriele; Adamski, Jerzy; Steinmetzer, Torsten; Salah, Mohamed; Abdelsamie, Ahmed S.; Koppen, Chris J. van; Heine, A.; Klebe, G.; Marchais‐Oberwinkler, Sandrine

doi:10.1021/acs.jmedchem.6b01436

Cited by 12 publications

(34 citation statements)

References 49 publications

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“…A small library of 17β-HSD1 and 17β-HSD2 inhibitors was tested for 17β-HSD14 inhibition. exhibited a Ki value of 7 nM (Braun et al 2016). The crystal structure of 17β-HSD14 in complex with NAD + and 96 is the first to be obtained from a human SDR 17β-HSD enzyme with a nonsteroidal compound.…”

Section: Inhibitors Of 17β-hsd14mentioning

confidence: 95%

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Inhibitors of 17β-hydroxysteroid dehydrogenase type 1, 2 and 14: Structures, biological activities and future challenges

Salah

Abdelsamie²,

Frotscher

2019

Molecular and Cellular Endocrinology

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During the past 25 years, the modulation of estrogen action by inhibition of 17β-hydroxysteroid dehydrogenase types 1 and 2 (17β-HSD1 and 17β-HSD2), respectively, has been pursued intensively. In the search for novel treatment options for estrogen-dependent diseases (EDD) and in order to explore estrogenic signaling pathways, a large number of steroidal and nonsteroidal inhibitors of these enzymes has been described in the literature. The present review gives a survey on the development of inhibitor classes as well as the structural formulas and properties of their most interesting representatives. In addition, rationally designed dual inhibitors of both 17β-HSD1 and steroid sulfatase (STS) as well as the first inhibitors of 17β-HSD14 are covered.

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Section: Inhibitors Of 17β-hsd14mentioning

confidence: 95%

“…Therefore, it is still unclear whether this enzyme may serve as a drug target in the future. Recently, the 3D-structures of the cytosolic protein as holo form and as ternary complexes with E1 and with a nonsteroidal inhibitor have been described (Bertoletti et al 2016;Braun et al 2016).…”

Section: Methodsmentioning

confidence: 99%

Inhibitors of 17β-hydroxysteroid dehydrogenase type 1, 2 and 14: Structures, biological activities and future challenges

Salah

Abdelsamie²,

Frotscher

2019

Molecular and Cellular Endocrinology

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“…5 ). In most SDRs the groove between α7 helix and α-turn αt1 is unobstructed and open to the solvent, but there are examples of active sites with the involvement of the second protein chain, for example: 17β hydroxysteroid dehydrogenase 14 from Homo sapiens (1yde, [ 40 , 41 ]), alcohol dehydrogenase from Arthrobacter sp . TS-15 (6qhe, [ 42 ]), and glucose dehydrogenase 4 from Bacillus megaterium (3auu, [ 43 ]).…”

Section: Resultsmentioning

confidence: 99%

Phylogenetics-based identification and characterization of a superior 2,3-butanediol dehydrogenase for Zymomonas mobilis expression

Subramanian

Лунин

Farmer

et al. 2020

Biotechnol Biofuels

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Background Zymomonas mobilis has recently been shown to be capable of producing the valuable platform biochemical, 2,3-butanediol (2,3-BDO). Despite this capability, the production of high titers of 2,3-BDO is restricted by several physiological parameters. One such bottleneck involves the conversion of acetoin to 2,3-BDO, a step catalyzed by 2,3-butanediol dehydrogenase (Bdh). Several Bdh enzymes have been successfully expressed in Z. mobilis, although a highly active enzyme is yet to be identified for expression in this host. Here, we report the application of a phylogenetic approach to identify and characterize a superior Bdh, followed by validation of its structural attributes using a mutagenesis approach. Results Of the 11 distinct bdh genes that were expressed in Z. mobilis, crude extracts expressing Serratia marcescens Bdh (SmBdh) were found to have the highest activity (8.89 µmol/min/mg), when compared to other Bdh enzymes (0.34–2.87 µmol/min/mg). The SmBdh crystal structure was determined through crystallization with cofactor (NAD+) and substrate (acetoin) molecules bound in the active site. Active SmBdh was shown to be a tetramer with the active site populated by a Gln247 residue contributed by the diagonally opposite subunit. SmBdh showed a more extensive supporting hydrogen-bond network in comparison to the other well-studied Bdh enzymes, which enables improved substrate positioning and substrate specificity. This protein also contains a short α6 helix, which provides more efficient entry and exit of molecules from the active site, thereby contributing to enhanced substrate turnover. Extending the α6 helix to mimic the lower activity Enterobacter cloacae (EcBdh) enzyme resulted in reduction of SmBdh function to nearly 3% of the total activity. In great contrast, reduction of the corresponding α6 helix of the EcBdh to mimic the SmBdh structure resulted in ~ 70% increase in its activity. Conclusions This study has demonstrated that SmBdh is superior to other Bdhs for expression in Z. mobilis for 2,3-BDO production. SmBdh possesses unique structural features that confer biochemical advantage to this protein. While coordinated active site formation is a unique structural characteristic of this tetrameric complex, the smaller α6 helix and extended hydrogen network contribute towards improved activity and substrate promiscuity of the enzyme.

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“…Three flexible ring-structures in close proximity and one or more acidic hydroxyl groups, stabilizing interactions through an extensive H-bonding network (Braun et al, 2016), characterize the interactions between pyridine derivatives and the active site in 17β-HSD. The drugs investigated in the present study do not have acidic hydroxyl groups.…”

Section: Discussionmentioning

confidence: 99%

Effects of antihistamines on the H295R steroidogenesis – Autocrine up-regulation following 3β-HSD inhibition

Munkboel

Hasselstrøm

Kristensen

et al. 2018

Toxicology in Vitro

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Millions of people of all ages suffer from allergies worldwide and as a consequence antihistamines are among the most commonly prescribed pharmaceuticals in the world. We investigated the disruptive effects of three antihistamines, promethazine (PMZ), cetirizine (CET) and fexofenadine (FEX) on the H295R steroidogenesis. A multi-steroid LC-MS/MS method was used to quantify 13 steroid hormones in the steroidogenesis. In addition, real-time RT-PCR was used to determine if exposure to antihistamines altered gene expression in the cell line. When exposing the H295R cells to PMZ and CET, significant increases in Δ-steroids and significant decreases in Δ-steroids were observed, indicating an inhibition of 3β-hydroxysteroid dehydrogenase (3β-HSD). A sequential decrease in corticosteroids, androgens and estrogens were also observed. Overall, FEX had no effect on the steroidogenesis even though minor effects were observed at the highest concentrations. Real-time RT-PCR showed that PMZ resulted in significant up-regulation of 3β-HSD and 17β-HSD, whereas CET only resulted in up-regulation of 3β-HSD. This indicated that the decrease in steroids downstream from 3β-HSD following PMZ and CT exposure induced a compensatory autocrine response in 3β-HSD gene expression. The effects on the steroidogenesis were observed at concentrations 30-50 times higher than the therapeutic plasma concentrations. However, antihistamines are lipophilic and may accumulate in adrenals and gonads. Thus, disruptive effects of PMZ and CET on human steroidogenesis cannot be excluded.

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First Structure–Activity Relationship of 17β-Hydroxysteroid Dehydrogenase Type 14 Nonsteroidal Inhibitors and Crystal Structures in Complex with the Enzyme

Cited by 12 publications

References 49 publications

Inhibitors of 17β-hydroxysteroid dehydrogenase type 1, 2 and 14: Structures, biological activities and future challenges

Inhibitors of 17β-hydroxysteroid dehydrogenase type 1, 2 and 14: Structures, biological activities and future challenges

Phylogenetics-based identification and characterization of a superior 2,3-butanediol dehydrogenase for Zymomonas mobilis expression

Effects of antihistamines on the H295R steroidogenesis – Autocrine up-regulation following 3β-HSD inhibition

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