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Inhibition characteristics of equine steroid isomerase EcaGST A3-3
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.ORCID iD: 0000-0002-0236-1796
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.ORCID iD: 0000-0001-6258-1443
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.ORCID iD: 0000-0003-0999-3179
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.ORCID iD: 0000-0002-6416-064X
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Equine glutathione transferase A3-3 (EcaGST A3-3) belongs to the superfamily of detoxifying enzymes found in all organisms. However it is also the most efficient steroid double-bond isomerase known in mammals. In contrast to the rodents, Equus ferus caballus shares the steroidogenic pathway with Homo sapiens, which makes it a more suitable model for human steroidogenesis than the murine one. Inhibition of EcaGST A3-3 might help treat reproductive and neurodegenerative disorders. We screened an FDA-approved library of 1040 compounds for the ability as novel inhibitors of EcaGST A3-3. Our results revealed anthralin, sennoside A, tannic acid and ethacrynic acid as the most potent, submicromolar-range inhibitors of EcaGST A3-3 with the natural substrate Δ5-androstene-3,17-dione.

Keywords [en]
Steroidogenesis, Inhibition, Catalytic efficiency, Glutathione transferase A3-3, Androstenedione, Pregnenedione, Glutahione transferase M2-2
National Category
Biochemistry and Molecular Biology
Research subject
Neurochemistry with Molecular Neurobiology
Identifiers
URN: urn:nbn:se:su:diva-156298OAI: oai:DiVA.org:su-156298DiVA, id: diva2:1206305
Funder
Swedish Research CouncilAvailable from: 2018-05-16 Created: 2018-05-16 Last updated: 2018-06-21Bibliographically approved
In thesis
1. Equine glutathione transferase A3-3: an efficient steroid isomerase
Open this publication in new window or tab >>Equine glutathione transferase A3-3: an efficient steroid isomerase
2018 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

Glutathione transferases (GSTs) comprise a superfamily of enzymes prominently involved in detoxication by making toxic electrophiles more polar and therefore more easily excretable. However some GSTs have developed alternative functions. Thus, a member of the Alpha class GSTs in tissues of the ruminants, Sus scrofa and Homo sapiens is involved in biosynthesis of steroid hormones, catalyzing a double-bond isomerization reaction as the last step of synthesis of Δ4-pregnene-3,20-dione (progesterone) and the obligatory step in the synthesis of the last precursor of testosterone, Δ4-androstenene-3,17-dione. As neurosteroids, steroid hormones are involved in such diverse functions as cognition, depression and memory and are suggested to play a protective role in neuropathologies including Alzheimer’s disease, Parkinson’s disease and brain injury.

The human GST A3-3 is the most efficient steroid double-bond isomerase known so far in mammals. The current work extends discoveries of GST enzymes that act in the steroidogenic pathways in large mammals to Equus ferus caballus. In contrast to the rodents, Equus ferus caballus shares the steroidogenic pathway with Homo sapiens, which makes it a more suitable model for human steroidogenesis than the murine one.

In the present study, the mRNA encoding the steroid isomerase GST A3-3 was cloned from stallion testis. The equine GST A3-3 (EcaGST A3-3) was heterologously expressed in E. coli and purified by centrifugation, sonication, affinity chromatography and dialysis. The in vitro measurements of enzymatic activity were followed spectrophotometrically and revealed highly efficient steroid double-bond isomerase activity in the biosynthetic pathways to progesterone and testosterone. The enzyme now ranks as one of the most efficient steroid isomerases known in mammals.

The concentrations of EcaGSTA3 mRNA were highest in hormone-producing organs such as ovary, testis and adrenal gland. The high efficiency and the tissue distribution of EcaGST A3-3 support the view that the enzyme plays a physiologically significant role in the biosynthesis of steroid hormones.

Inhibition of EcaGST A3-3 might help treat reproductive and neurodegenerative disorders. An FDA-approved library of 1040 compounds was screened for novel inhibitors of EcaGST A3-3. The inhibition pattern of EcaGST A3-3 is similar to that of the human GST A3-3.

 

Place, publisher, year, edition, pages
Stockholm: Deprtment of Biochemistry and Biophysics, Stockholm University, 2018. p. 32
Keywords
Equine, glutatione transferase, steroidogenesis, steroid isomerase
National Category
Biochemistry and Molecular Biology
Research subject
Neurochemistry with Molecular Neurobiology
Identifiers
urn:nbn:se:su:diva-156395 (URN)
Presentation
2018-06-07, Heilbronnsalen, C 458, Svante Arrhenius väg 16 B, Stockholm, 13:00 (English)
Opponent
Supervisors
Available from: 2018-05-24 Created: 2018-05-22 Last updated: 2018-06-21Bibliographically approved

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