Glutathione Transferases as Efficient Ketosteroid Isomerases

In addition to their well-established role in detoxication, glutathione transferases (GSTs) have other biological functions. We are focusing on the ketosteroid isomerase activity, which appears to contribute to steroid hormone biosynthesis in mammalian tissues. A highly efficient GST A3-3 is present...

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Autores principales:	Bengt Mannervik, Aram Ismail, Helena Lindström, Birgitta Sjödin, Nancy H. Ing
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	ketosteroid isomerase androstenedione progesterone ecdysteroid glutathione steroid hormone Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/d4800cb548f749609ae0faaf5fa5522e
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spelling	oai:doaj.org-article:d4800cb548f749609ae0faaf5fa5522e2021-11-22T05:02:12ZGlutathione Transferases as Efficient Ketosteroid Isomerases2296-889X10.3389/fmolb.2021.765970https://doaj.org/article/d4800cb548f749609ae0faaf5fa5522e2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fmolb.2021.765970/fullhttps://doaj.org/toc/2296-889XIn addition to their well-established role in detoxication, glutathione transferases (GSTs) have other biological functions. We are focusing on the ketosteroid isomerase activity, which appears to contribute to steroid hormone biosynthesis in mammalian tissues. A highly efficient GST A3-3 is present in some, but not all, mammals. The alpha class enzyme GST A3-3 in humans and the horse shows the highest catalytic efficiency with kcat/Km values of approximately 107 M−1s−1, ranking close to the most active enzymes known. The expression of GST A3-3 in steroidogenic tissues suggests that the enzyme has evolved to support the activity of 3β-hydroxysteroid dehydrogenase, which catalyzes the formation of 5-androsten-3,17-dione and 5-pregnen-3,20-dione that are substrates for the double-bond isomerization catalyzed by GST A3-3. The dehydrogenase also catalyzes the isomerization, but its kcat of approximately 1 s−1 is 200-fold lower than the kcat values of human and equine GST A3-3. Inhibition of GST A3-3 in progesterone-producing human cells suppress the formation of the hormone. Glutathione serves as a coenzyme contributing a thiolate as a base in the isomerase mechanism, which also involves the active-site Tyr9 and Arg15. These conserved residues are necessary but not sufficient for the ketosteroid isomerase activity. A proper assortment of H-site residues is crucial to efficient catalysis by forming the cavity binding the hydrophobic substrate. It remains to elucidate why some mammals, such as rats and mice, lack GSTs with the prominent ketosteroid isomerase activity found in certain other species. Remarkably, the fruit fly Drosophila melanogaster, expresses a GSTE14 with notable steroid isomerase activity, even though Ser14 has evolved as the active-site residue corresponding to Tyr9 in the mammalian alpha class.Bengt MannervikAram IsmailHelena LindströmBirgitta SjödinNancy H. IngFrontiers Media S.A.articleketosteroid isomeraseandrostenedioneprogesteroneecdysteroidglutathionesteroid hormoneBiology (General)QH301-705.5ENFrontiers in Molecular Biosciences, Vol 8 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	ketosteroid isomerase androstenedione progesterone ecdysteroid glutathione steroid hormone Biology (General) QH301-705.5
spellingShingle	ketosteroid isomerase androstenedione progesterone ecdysteroid glutathione steroid hormone Biology (General) QH301-705.5 Bengt Mannervik Aram Ismail Helena Lindström Birgitta Sjödin Nancy H. Ing Glutathione Transferases as Efficient Ketosteroid Isomerases
description	In addition to their well-established role in detoxication, glutathione transferases (GSTs) have other biological functions. We are focusing on the ketosteroid isomerase activity, which appears to contribute to steroid hormone biosynthesis in mammalian tissues. A highly efficient GST A3-3 is present in some, but not all, mammals. The alpha class enzyme GST A3-3 in humans and the horse shows the highest catalytic efficiency with kcat/Km values of approximately 107 M−1s−1, ranking close to the most active enzymes known. The expression of GST A3-3 in steroidogenic tissues suggests that the enzyme has evolved to support the activity of 3β-hydroxysteroid dehydrogenase, which catalyzes the formation of 5-androsten-3,17-dione and 5-pregnen-3,20-dione that are substrates for the double-bond isomerization catalyzed by GST A3-3. The dehydrogenase also catalyzes the isomerization, but its kcat of approximately 1 s−1 is 200-fold lower than the kcat values of human and equine GST A3-3. Inhibition of GST A3-3 in progesterone-producing human cells suppress the formation of the hormone. Glutathione serves as a coenzyme contributing a thiolate as a base in the isomerase mechanism, which also involves the active-site Tyr9 and Arg15. These conserved residues are necessary but not sufficient for the ketosteroid isomerase activity. A proper assortment of H-site residues is crucial to efficient catalysis by forming the cavity binding the hydrophobic substrate. It remains to elucidate why some mammals, such as rats and mice, lack GSTs with the prominent ketosteroid isomerase activity found in certain other species. Remarkably, the fruit fly Drosophila melanogaster, expresses a GSTE14 with notable steroid isomerase activity, even though Ser14 has evolved as the active-site residue corresponding to Tyr9 in the mammalian alpha class.
format	article
author	Bengt Mannervik Aram Ismail Helena Lindström Birgitta Sjödin Nancy H. Ing
author_facet	Bengt Mannervik Aram Ismail Helena Lindström Birgitta Sjödin Nancy H. Ing
author_sort	Bengt Mannervik
title	Glutathione Transferases as Efficient Ketosteroid Isomerases
title_short	Glutathione Transferases as Efficient Ketosteroid Isomerases
title_full	Glutathione Transferases as Efficient Ketosteroid Isomerases
title_fullStr	Glutathione Transferases as Efficient Ketosteroid Isomerases
title_full_unstemmed	Glutathione Transferases as Efficient Ketosteroid Isomerases
title_sort	glutathione transferases as efficient ketosteroid isomerases
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/d4800cb548f749609ae0faaf5fa5522e
work_keys_str_mv	AT bengtmannervik glutathionetransferasesasefficientketosteroidisomerases AT aramismail glutathionetransferasesasefficientketosteroidisomerases AT helenalindstrom glutathionetransferasesasefficientketosteroidisomerases AT birgittasjodin glutathionetransferasesasefficientketosteroidisomerases AT nancyhing glutathionetransferasesasefficientketosteroidisomerases
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Glutathione Transferases as Efficient Ketosteroid Isomerases

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