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, B.; Mannervik, Bengt; Stenmark, Pål

doi:10.1016/j.envpol.2020.115960

Cited by 4 publications

(3 citation statements)

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“…Regarding the organotin compounds, a structure of triethyltin bromide as an inhibitor of the Alpha class GST A3-3 from horse was analyzed [40]. A corresponding homology model of the dog GST P1-1 in complex with triethyltin shows that the heavy atom can coordinate the oxygen of Tyr8, as well as the sulfur of glutathione, in a trigonal bipyramid structure similar to the one in the equine enzyme.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Dog Glutathione Transferase P1-1, an Enzyme Relevant to Veterinary Medicine

Ismail

Lewis

Sjödin

et al. 2021

IJMS

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Glutathione transferases (GSTs) form a family of detoxication enzymes instrumental in the inactivation and elimination of electrophilic mutagenic and carcinogenic compounds. The Pi class GST P1-1 is present in most tissues and is commonly overexpressed in neoplastic cells. GST P1-1 in the dog, Canis lupus familiaris, has merits as a marker for tumors and as a target for enzyme-activated prodrugs. We produced the canine enzyme CluGST P1-1 by heterologous bacterial expression and verified its cross-reactivity with antihuman-GST P1-1 antibodies. The catalytic activity with alternative substrates of biological significance was determined, and the most active substrate found was benzyl isothiocyanate. Among established GST inhibitors, Cibacron Blue showed positive cooperativity with an IC50 value of 43 nM. Dog GST P1-1 catalyzes activation of the prodrug Telcyta, but the activity is significantly lower than that of the human homolog.

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Section: Discussionmentioning

confidence: 99%

Characterization of Dog Glutathione Transferase P1-1, an Enzyme Relevant to Veterinary Medicine

Ismail

Lewis

Sjödin

et al. 2021

IJMS

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“…6 A). The same compound gave IC 50 values of 0.28 ± 0.02 μM for EcaGST A3-3 [ 16 ] and 0.0023 μM for HsaGST A3-3 [ 2 ]. Ethacrynic acid likewise inhibited CjaGST A3-3 with an IC 50 value of 3.3 ± 0.2 μM ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Marmoset glutathione transferases with ketosteroid isomerase activity

Ismail

Sawmi

Mannervik

2021

Biochemistry and Biophysics Reports

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The common marmoset Callithrix jacchus encodes two glutathione transferase (GST) enzymes with ketosteroid double-bond isomerase activity. The most active enzyme is CjaGST A3-3 showing a specific activity with 5-androsten-3,17-dione (Δ 5 -AD) of 62.1 ± 1.8 μmol min -1 mg -1 , and a k cat value of 261 ± 49 s -1 . The second ketosteroid isomerase CjaGST A1-1 has a 30-fold lower specific activity with Δ 5 -AD and a 37-fold lower k cat value. Thus, the marmoset CjaGST A3-3 would be the main contributor to the biosynthesis of the steroid hormones testosterone and progesterone, like the human ortholog HsaGST A3-3. Two residues differ in the H-site of the 91.4% sequence identical CjaGST A1-1 and CjaGST A3-3, and modeling of the structures suggests that the bulky phenyl ring of Phe111 in CjaGST A1-1 causes steric hindrance in the binding of the steroid substrate. Tributyltin acetate (IC 50 =0.16 ± 0.004 μM) and ethacrynic acid (IC 50 =3.3 ± 0.2 μM) were found to be potent inhibitors of CjaGST A3-3, as previously demonstrated with the human and equine orthologs.

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“…In addition, inhibitors of the GSTA3-3 enzyme have been identified that may be medically useful for reducing fertility or progression of steroid-dependent diseases [ 15 ]. These include the GST A3-3 enzyme inhibitors ethacrynic acid or tributyltin [ 32 ], or the small interfering RNAs that reduce GSTA3 gene expression [ 18 ].…”

Section: Discussionmentioning

confidence: 99%

Conservation of Glutathione Transferase mRNA and Protein Sequences Similar to Human and Horse Alpha Class GST A3-3 across Dog, Goat, and Opossum Species

Hubert,

Samollow,

Lindström

et al. 2023

Biomolecules

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The glutathione transferase A3-3 (GST A3-3) homodimeric enzyme is the most efficient enzyme that catalyzes isomerization of the precursors of testosterone, estradiol, and progesterone in the gonads of humans and horses. However, the presence of GST A3-3 orthologs with equally high ketosteroid isomerase activity has not been verified in other mammalian species, even though pig and cattle homologs have been cloned and studied. Identifying GSTA3 genes is a challenge because of multiple GSTA gene duplications (e.g., 12 in the human genome); consequently, the GSTA3 gene is not annotated in most genomes. To improve our understanding of GSTA3 gene products and their functions across diverse mammalian species, we cloned homologs of the horse and human GSTA3 mRNAs from the testes of a dog, goat, and gray short-tailed opossum, the genomes of which all currently lack GSTA3 gene annotations. The resultant novel GSTA3 mRNA and inferred protein sequences had a high level of conservation with human GSTA3 mRNA and protein sequences (≥70% and ≥64% identities, respectively). Sequence conservation was also apparent for the 12 residues of the “H-site” in the 222 amino acid GSTA3 protein that is known to interact with the steroid substrates. Modeling predicted that the dog GSTA3-3 may be a more active ketosteroid isomerase than the corresponding goat or opossum enzymes. However, expression of the GSTA3 gene was higher in liver than in other dog tissue. Our results improve understanding of the active sites of mammalian GST A3-3 enzymes, inhibitors of which might be useful for reducing steroidogenesis for medical purposes, such as fertility control or treatment of steroid-dependent diseases.

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

Cited by 4 publications

References 50 publications

Characterization of Dog Glutathione Transferase P1-1, an Enzyme Relevant to Veterinary Medicine

Characterization of Dog Glutathione Transferase P1-1, an Enzyme Relevant to Veterinary Medicine

Marmoset glutathione transferases with ketosteroid isomerase activity

Conservation of Glutathione Transferase mRNA and Protein Sequences Similar to Human and Horse Alpha Class GST A3-3 across Dog, Goat, and Opossum Species

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