Structural and functional analysis of the inhibition of equine glutathione transferase A3-3 by organotin endocrine disrupting pollutants
Škerlová, Jana ; Ismail, Aram ; Lindström, Helena ; Sjödin, Birgitta ; Mannervik, Bengt and Stenmark, Pål LU
(2021)
In Environmental Pollution
268, Part B.
- Abstract
Organotin compounds are highly toxic environmental pollutants with neurotoxic and endocrine-disrupting effects. They are potent inhibitors of glutathione transferases (GSTs), thus impeding their detoxication and antioxidant functions. Several GSTs, including equine GST A3-3 (EcaGST A3-3), exhibit steroid double-bond isomerase activity and are involved in the biosynthesis of testosterone and progesterone. We have performed enzyme kinetics analyses of the inhibition of EcaGST A3-3 by organotin compounds. We have also solved crystal structures of EcaGST A3-3 in complexes with glutathione, and with glutathione together with covalently bound triethyltin. Our structural data indicate that the tin atom forms strong bonds with a covalent... (More)
Organotin compounds are highly toxic environmental pollutants with neurotoxic and endocrine-disrupting effects. They are potent inhibitors of glutathione transferases (GSTs), thus impeding their detoxication and antioxidant functions. Several GSTs, including equine GST A3-3 (EcaGST A3-3), exhibit steroid double-bond isomerase activity and are involved in the biosynthesis of testosterone and progesterone. We have performed enzyme kinetics analyses of the inhibition of EcaGST A3-3 by organotin compounds. We have also solved crystal structures of EcaGST A3-3 in complexes with glutathione, and with glutathione together with covalently bound triethyltin. Our structural data indicate that the tin atom forms strong bonds with a covalent character not only with the glutathione, but also with a tyrosyl residue of the enzyme itself, thereby preventing the release of the glutathione-organotin adduct and completely blocking the enzyme function. This work presents a structural basis for the general mechanism of GST inhibition by organotin compounds and contributes to the understanding of their neurotoxic and endocrine disrupting effects.
(Less)
- author
- Škerlová, Jana
; Ismail, Aram
; Lindström, Helena
; Sjödin, Birgitta
; Mannervik, Bengt
and Stenmark, Pål
LU
- organization
- publishing date
- 2021-01-01
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Environmental Pollution
- volume
- 268, Part B
- article number
- 115960
- publisher
- Elsevier
- external identifiers
-
- pmid:33162212
- scopus:85095721995
- ISSN
- 0269-7491
- DOI
- 10.1016/j.envpol.2020.115960
- language
- English
- LU publication?
- yes
- additional info
- Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.
- id
- 6746db37-2f2e-4d9d-b028-2bfde8dc3eda
- date added to LUP
- 2020-11-15 15:46:19
- date last changed
- 2024-06-12 23:56:10
@article{6746db37-2f2e-4d9d-b028-2bfde8dc3eda,
abstract = {{<p>Organotin compounds are highly toxic environmental pollutants with neurotoxic and endocrine-disrupting effects. They are potent inhibitors of glutathione transferases (GSTs), thus impeding their detoxication and antioxidant functions. Several GSTs, including equine GST A3-3 (EcaGST A3-3), exhibit steroid double-bond isomerase activity and are involved in the biosynthesis of testosterone and progesterone. We have performed enzyme kinetics analyses of the inhibition of EcaGST A3-3 by organotin compounds. We have also solved crystal structures of EcaGST A3-3 in complexes with glutathione, and with glutathione together with covalently bound triethyltin. Our structural data indicate that the tin atom forms strong bonds with a covalent character not only with the glutathione, but also with a tyrosyl residue of the enzyme itself, thereby preventing the release of the glutathione-organotin adduct and completely blocking the enzyme function. This work presents a structural basis for the general mechanism of GST inhibition by organotin compounds and contributes to the understanding of their neurotoxic and endocrine disrupting effects.</p>}},
author = {{Škerlová, Jana and Ismail, Aram and Lindström, Helena and Sjödin, Birgitta and Mannervik, Bengt and Stenmark, Pål}},
issn = {{0269-7491}},
language = {{eng}},
month = {{01}},
publisher = {{Elsevier}},
series = {{Environmental Pollution}},
title = {{Structural and functional analysis of the inhibition of equine glutathione transferase A3-3 by organotin endocrine disrupting pollutants}},
url = {{http://dx.doi.org/10.1016/j.envpol.2020.115960}},
doi = {{10.1016/j.envpol.2020.115960}},
volume = {{268, Part B}},
year = {{2021}},
}