Characterization of equine GST A3-3 as a steroid isomerase.
Abstract: 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 pig and human tissues is involved in steroid hormone biosynthesis, catalyzing the obligatory double-bond isomerization of Δ-androstene-3,17-dione to Δ-androstene-3,17-dione and of Δ-pregnene-3,20-dione to Δ-pregnene-3,20-dione on the biosynthetic pathways to testosterone and progesterone. 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. The mRNA encoding the steroid isomerase GST A3-3 was cloned from testis of the horse (Equus ferus caballus). The concentrations of GSTA3 mRNA were highest in hormone-producing organs such as ovary, testis and adrenal gland. EcaGST A3-3 produced in E. coli has been characterized and shown to have highly efficient steroid double-bond isomerase activity, exceeding its activities with conventional GST substrates. The enzyme now ranks as one of the most efficient steroid isomerases known in mammals and approaches the activity of the bacterial ketosteroid isomerase, one of the most efficient enzymes of all categories known today. 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.
Copyright © 2017 Elsevier Ltd. All rights reserved.
Publication Date: 2017-11-24 PubMed ID: 29180167DOI: 10.1016/j.jsbmb.2017.11.011Google Scholar: Lookup
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- Journal Article
- Research Support
- Non-U.S. Gov't
Summary
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This research article explores the function of the enzyme glutathione transferase A3-3 (GST A3-3) in horses and identifies it as highly efficient at steroid isomerase activity, which influences the biosynthesis of steroid hormones.
Background on Glutathione Transferases (GSTs)
- GSTs are a large family of enzymes that play a major role in detoxification processes. These enzymes transform toxic electrophiles, making them more polar and easy to excrete.
- In addition to detoxification, some GSTs perform alternative functions, such as involving in steroid hormone biosynthesis. This process involves isomerization of specific steroid substances which forms an integral part of the biosynthetic pathways leading to hormones like testosterone and progesterone.
- Among the GSTs in mammals, the human GST A3-3 enzyme has shown to have the highest efficiency at double-bond isomerization of steroids.
Research Findings on equine GST A3-3
- The study extends the understanding of GST A3-3 enzyme in large mammals like horses (Equus ferus caballus).
- The researchers cloned the mRNA encoding the steroid isomerase GST A3-3 from horse testis. The expression of this mRNA was discovered to be highest in hormone-producing organs such as ovary, testis and adrenal gland.
- The horse equivalent (EcaGST A3-3) of this enzyme produced in E. coli bacteria was characterized and found to exhibit highly efficient steroid double-bond isomerase activity, even exceeding its activities with usual GST substrates.
Significance of the Findings
- The identification and characterization of EcaGST A3-3 as an extremely efficient steroid isomerase place it among the prominent enzymes known today in mammals, comparable even to the bacterial ketosteroid isomerase.
- The distribution and high efficiency of EcaGST A3-3 in hormone-producing organs provide evidence for its significant role in the biosynthesis of steroid hormones in horses.
Cite This Article
APA
Lindström H, Peer SM, Ing NH, Mannervik B.
(2017).
Characterization of equine GST A3-3 as a steroid isomerase.
J Steroid Biochem Mol Biol, 178, 117-126.
https://doi.org/10.1016/j.jsbmb.2017.11.011 Publication
Researcher Affiliations
- Department of Neurochemistry, Stockholm University, Arrhenius Laboratories, SE-10691 Stockholm, Sweden.
- Department of Animal Science, Texas A&M University, 2471 TAMU, College Station, TX 77843-2471, USA.
- Department of Animal Science, Texas A&M University, 2471 TAMU, College Station, TX 77843-2471, USA. Electronic address: NING@cvm.tamu.edu.
- Department of Neurochemistry, Stockholm University, Arrhenius Laboratories, SE-10691 Stockholm, Sweden. Electronic address: bengt.mannervik@neurochem.su.se.
MeSH Terms
- Amino Acid Sequence
- Animals
- Glutathione Transferase / metabolism
- Horses
- Isoenzymes / metabolism
- Male
- Sequence Homology
- Stereoisomerism
- Steroids / metabolism
- Substrate Specificity
Citations
This article has been cited 8 times.- Ahmed YB, Al-Bzour AN, Ababneh OE, Abushukair HM, Saeed A. Genomic and Transcriptomic Predictors of Response to Immune Checkpoint Inhibitors in Melanoma Patients: A Machine Learning Approach. Cancers (Basel) 2022 Nov 15;14(22).
- Mannervik B, Ismail A, Lindström H, Sjödin B, Ing NH. Glutathione Transferases as Efficient Ketosteroid Isomerases. Front Mol Biosci 2021;8:765970.
- Ismail A, Sawmi J, Mannervik B. Marmoset glutathione transferases with ketosteroid isomerase activity. Biochem Biophys Rep 2021 Sep;27:101078.
- Lindström H, Mazari AMA, Musdal Y, Mannervik B. Potent inhibitors of equine steroid isomerase EcaGST A3-3. PLoS One 2019;14(3):e0214160.
- Bai M, Zhang L, Wu W, Weng R, Wu H, Li Y, Ling S, Zheng Y. Quantitative proteomic analysis of pathological and physiological ovarian aging: model evaluation, molecular mechanisms, and identification of early biomarkers and therapeutic targets. J Ovarian Res 2025 Nov 28;18(1):287.
- de Barros JWF, Joule Pierre K, Kempinas WG, Tremblay JJ. Ethylene dimethanesulfonate effects on gene promoter activities related to the endocrine function of immortalized Leydig cell lines R2C and MA-10. Curr Res Toxicol 2024;6:100147.
- Hubert SM, Samollow PB, Lindström H, Mannervik B, Ing NH. Conservation of Glutathione Transferase mRNA and Protein Sequences Similar to Human and Horse Alpha Class GST A3-3 across Dog, Goat, and Opossum Species. Biomolecules 2023 Sep 20;13(9).
- Musdal Y, Ismail A, Sjödin B, Mannervik B. Potent GST Ketosteroid Isomerase Activity Relevant to Ecdysteroidogenesis in the Malaria Vector Anopheles gambiae. Biomolecules 2023 Jun 11;13(6).
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