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PloS one2019; 14(3); e0214160; doi: 10.1371/journal.pone.0214160

Potent inhibitors of equine steroid isomerase EcaGST A3-3.

Abstract: Equine glutathione transferase A3-3 (EcaGST A3-3) belongs to the superfamily of detoxication enzymes found in all higher organisms. However, it is also the most efficient steroid double-bond isomerase known in mammals. Equus ferus caballus shares the steroidogenic pathway with Homo sapiens, which makes the horse a suitable animal model for investigations of human steroidogenesis. Inhibition of the enzyme has potential for treatment of steroid-hormone-dependent disorders. Screening of a library of FDA-approved drugs identified 16 out of 1040 compounds, which at 10 μM concentration afforded at least 50% inhibition of EcaGST A3-3. The most potent inhibitors, anthralin, sennoside A, tannic acid, and ethacrynic acid, were characterized by IC50 values in the submicromolar range when assayed with the natural substrate Δ5-androstene-3,17-dione.
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Publication Date: 2019-03-21 PubMed ID: 30897163PubMed Central: PMC6428247DOI: 10.1371/journal.pone.0214160Google Scholar: Lookup
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Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The research paper focuses on the discovery of significant inhibitors for the enzyme equine glutathione transferase A3-3 (EcaGST A3-3), a part of detoxification enzymes found in higher organisms. These inhibitors, which have potential for the treatment of steroid-hormone-dependent disorders, were identified from a pool of FDA-approved drugs.

Understanding EcaGST A3-3 and Its Function

  • EcaGST A3-3 is an enzyme in the detoxification superfamily, which means it plays a crucial role in cleansing biological systems by eliminating toxins.
  • Interestingly, this enzyme also serves as the most powerful steroid double-bond isomerase recognized in mammals. It modifies steroids, compounds that play various important roles in the body, by changing the position of their double bonds.
  • Since horses (Equus ferus caballus) share a similar steroid generation pathway with humans (Homo sapiens), the horse serves as an appropriate animal model for exploring human steroidogenesis – the process of generating steroids in the body.

Search for EcaGST A3-3 Inhibitors

  • The research set out to find effective inhibitors of EcaGST A3-3, which could potentially be used to treat disorders dependent on steroid hormones.
  • A library of FDA-approved drugs was screened, resulting in the identification of 16 potential inhibitors from 1040 compounds. These inhibitors showed at least 50% inhibition of EcaGST A3-3 at a concentration of 10 μM.

Identifying the Most Potent Inhibitors

  • From the identified inhibitors, four–anthralin, sennoside A, tannic acid, and ethacrynic acid–showed the most potent inhibition potential. They exhibited IC50 values in the submicromolar range when they were tested with the naturally occurring substrate, Δ5-androstene-3,17-dione.
  • The IC50 value indicates the concentration of an inhibitor needed to inhibit a biological process by half. A low IC50 value indicates high potency, so these four drugs display powerful inhibition of the enzyme.

The study’s findings provide a significant starting point for further research and potentially lead to effective treatments of steroid-hormone-dependent disorders.

Cite This Article

APA
Lindström H, Mazari AMA, Musdal Y, Mannervik B. (2019). Potent inhibitors of equine steroid isomerase EcaGST A3-3. PLoS One, 14(3), e0214160. https://doi.org/10.1371/journal.pone.0214160

Publication

PloS one
ISSN: 1932-6203
NlmUniqueID: 101285081
Country: United States
Language: English
Volume: 14
Issue: 3
Pages: e0214160
PII: e0214160

Researcher Affiliations

Lindström, Helena
  • Department of Biochemistry and Biophysics, Arrhenius Laboratories, Stockholm University, Stockholm, Sweden.
Mazari, Aslam M A
  • Department of Biochemistry and Biophysics, Arrhenius Laboratories, Stockholm University, Stockholm, Sweden.
Musdal, Yaman
  • Department of Biochemistry and Biophysics, Arrhenius Laboratories, Stockholm University, Stockholm, Sweden.
Mannervik, Bengt
  • Department of Biochemistry and Biophysics, Arrhenius Laboratories, Stockholm University, Stockholm, Sweden.

MeSH Terms

  • Animals
  • Anthralin / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Ethacrynic Acid / pharmacology
  • Glutathione Transferase / antagonists & inhibitors
  • Glutathione Transferase / metabolism
  • Horses
  • Sennosides / pharmacology
  • Substrate Specificity
  • Tannins / pharmacology

Conflict of Interest Statement

The authors have declared that no competing interests exist.

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Citations

This article has been cited 3 times.
  1. Seo M, Lim C, Kwon H. In silico prediction models for thyroid peroxidase inhibitors and their application to synthetic flavors. Food Sci Biotechnol 2022 Apr;31(4):483-495.
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  2. Ismail A, Sawmi J, Mannervik B. Marmoset glutathione transferases with ketosteroid isomerase activity. Biochem Biophys Rep 2021 Sep;27:101078.
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  3. Ismail A, Lewis E, Sjödin B, Mannervik B. Characterization of Dog Glutathione Transferase P1-1, an Enzyme Relevant to Veterinary Medicine. Int J Mol Sci 2021 Apr 15;22(8).
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