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Targeting human glu...
Targeting human glutathione transferase A3-3 attenuates progesterone production in human steroidogenic cells
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- Raffalli-Mathieu, Françoise (författare)
- Uppsala universitet,Institutionen för biokemi och organisk kemi,Biokemi I
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Orre, Carolina (författare)
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- Stridsberg, Mats (författare)
- Uppsala universitet,Klinisk kemi
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- Hansson Edalat, Maryam (författare)
- Uppsala universitet,Institutionen för biokemi och organisk kemi,Biokemi I
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- Mannervik, Bengt (författare)
- Uppsala universitet,Institutionen för biokemi och organisk kemi,Biokemi I
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(creator_code:org_t)
- 2008
- 2008
- Engelska.
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Ingår i: Biochemical Journal. - 0264-6021 .- 1470-8728. ; 414:1, s. 103-109
- Relaterad länk:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- hGSTA3-3 (human Alpha-class glutathione transferase 3-3) efficiently catalyses steroid Delta(5)-Delta(4) double-bond isomerization in vitro, using glutathione as a cofactor. This chemical transformation is an obligatory reaction in the biosynthesis of steroid hormones and follows the oxidation of 3beta-hydroxysteroids catalysed by 3beta-HSD (3beta-hydroxysteroid dehydrogenase). The isomerization has commonly been ascribed to a supplementary function of 3beta-HSD. The present study is the first to provide evidence that hGSTA3-3 contributes to this step in steroid hormone biosynthesis in complex cellular systems. First, we find glutathione-dependent Delta(5)-Delta(4) isomerase activity in whole-cell extracts prepared from human steroidogenic cells. Secondly, effective inhibitors of hGSTA3-3 dramatically decrease the conversion of Delta(5)-androstene-3,17-dione into Delta(4)-androstene-3,17-dione in cell lysates. Thirdly, we show that RNAi (RNA interference) targeting hGSTA3-3 expression decreases by 30% the forskolin-stimulated production of the steroid hormone progesterone in a human placental cell line. This effect is achieved at low concentrations of two small interfering RNAs directed against distinct regions of hGSTA3-3 mRNA, and is weaker in unstimulated cells, in which hGSTA3-3 expression is low. The results concordantly show that hGSTA3-3 makes a significant contribution to the double-bond isomerization necessary for steroid hormone biosynthesis and thereby complements the indispensable 3beta-hydroxysteroid oxidoreductase activity of 3beta-HSD. The results indicate that the lower isomerase activity of 3beta-HSD is insufficient for maximal rate of cellular sex hormone production and identify hGSTA3-3 as a possible target for pharmaceutical intervention in steroid hormone-dependent diseases.
Nyckelord
- alpha-class glutathione transferase A (GSTA)
- forskolin
- human Alpha-class glutathione transferase 3-3 (hGSTA3-3)
- progesterone; steroid isomerase
- steroidogenic cell
- MEDICINE
- MEDICIN
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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