Marmoset glutathione transferases with ketosteroid isomerase activity

• Main Authors: Aram Ismail, Julia Sawmi, Bengt Mannervik
• Format: Article
• Language: English
• Published: Elsevier 2021-09-01
• Series: Biochemistry and Biophysics Reports
• Subjects: 5-Androsten-3,17-dione; 5-Pregnen-3,20-dione; CjaGST A3-3; CjaGST A1-1; Alpha glutathione transferase; Steroid hormone synthesis
• Online Access: http://www.sciencedirect.com/science/article/pii/S2405580821001722

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 (Δ5-AD) of 62.1 ± 1.8 μmol min-1 mg-1, and a kcat value of 261 ± 49 s-1. The second ketosteroid isomerase CjaGST A1-1 has a 30-fold lower specific activity with Δ5-AD and a 37-fold lower kcat 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 (IC50=0.16 ± 0.004 μM) and ethacrynic acid (IC50=3.3 ± 0.2 μM) were found to be potent inhibitors of CjaGST A3-3, as previously demonstrated with the human and equine orthologs.