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Structural and functional analysis of the inhibition of equine glutathione transferase A3-3 by organotin endocrine disrupting pollutants

DOI: 10.1016/j.envpol.2020.115960 DOI Help

Authors: Jana Skerlova (Stockholm University) , Aram Ismail (Stockholm University) , Helena Lindström (Stockholm University) , Birgitta Sjödin (Stockholm University) , Bengt Mannervik (Stockholm University) , Pal Stenmark (Stockholm University; Lund University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Environmental Pollution

State: Published (Approved)
Published: October 2020
Diamond Proposal Number(s): 21625

Open Access Open Access

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 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. Our enzyme kinetics and structural data on EcaGST A3-3 explain on a molecular level the neurotoxic and endocrine disrupting effects of organotin pollutants.

Journal Keywords: Organometallic compounds; endocrine disrupting chemicals; steroid isomerization; detoxication; hormone biosynthesis; structural biology

Diamond Keywords: Enzymes

Subject Areas: Biology and Bio-materials, Chemistry, Environment

Instruments: I24-Microfocus Macromolecular Crystallography

Added On: 04/11/2020 09:04

Discipline Tags:

Catalysis Inorganic Chemistry Organic Chemistry Earth Sciences & Environment Desertification & Pollution Life Sciences & Biotech Structural biology Chemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)