4.7 Article

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

期刊

ENVIRONMENTAL POLLUTION
卷 268, 期 -, 页码 -

出版社

ELSEVIER SCI LTD
DOI: 10.1016/j.envpol.2020.115960

关键词

Organometallic compounds; Endocrine disrupting chemicals; Steroid isomerization; Detoxication; Hormone biosynthesis; Structural biology

资金

  1. Swedish Research Council [2015-04222, 2018-03406]
  2. Swedish Cancer Society
  3. ERDF/ESF, OP RDE, project IOCB Mobility [CZ.02.2.69/0.0/0.0/16_027/0008477]
  4. Swedish Research Council [2015-04222] Funding Source: Swedish Research Council
  5. Vinnova [2015-04222] Funding Source: Vinnova

向作者/读者索取更多资源

Organotin compounds are highly toxic environmental pollutants that disrupt the normal functioning of the nervous and endocrine systems. They inhibit glutathione transferases, impeding detoxification and antioxidant functions. Structural studies show that organotin compounds block enzyme activity by forming strong bonds, providing insight into their toxic effects.
Organotin compounds are highly toxic environmental pollutants with neurotoxic and endocrinedisrupting 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. (C) 2020 The Authors. Published by Elsevier Ltd.

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