Human dehydrogenase/reductase SDR family member 11 (DHRS11) and aldo-keto reductase 1C isoforms in comparison: Substrate and reaction specificity in the reduction of 11-keto-C19-steroids

Publication date: Available online 8 January 2020Source: The Journal of Steroid Biochemistry and Molecular BiologyAuthor(s): Satoshi Endo, Yoshifumi Morikawa, Yudai Kudo, Koichi Suenami, Toshiyuki Matsunaga, Akira Ikari, Akira HaraAbstractRecent studies have shown that an adrenal steroid 11β-hydroxy-4-androstene-3,17-dione serves as the precursor to androgens, 11-ketotestosterone and 11-ketodihydrotestosterone (11KDHT). The biosynthetic pathways include the reduction of 3- and 17-keto groups of the androgen precursors 11-keto-C19-steroids, which has been reported to be mediated by three human enzymes; aldo-keto reductase (AKR)1C2, AKR1C3 and 17β-hydroxysteroid dehydrogenase (HSD) type-3. To explore the contribution of the enzymes in the reductive metabolism, we kinetically compared the substrate specificity for 11-keto-C19-steroids among purified recombinant preparations of four AKRs (1C1, 1C2,1C3 and 1C4) and DHRS11, which shows 17β-HSD activity. Although AKR1C1 did not reduce the 11-keto-C19-steroids, AKR1C3 and DHRS11 reduced 17-keto groups of 11-keto-4-androstene-3,17-dione, 11-keto-5α-androstane-3,17-dione (11K-Adione) and 11-ketoandrosterone with Km values of 5 – 28 μM. The 3-keto groups of 11KDHT and 11K-Adione were reduced by AKR1C4 (Km 1 μM) more efficiently than by AKR1C2 (Km 5 and 8 μM, respectively). GC/MS analysis of the products showed that DHRS11 acts as 17β-HSD, and that AKR1C2 and AKR1C4 are predominantly 3α-HSDs, but formed a minor 3β-metab...
Source: The Journal of Steroid Biochemistry and Molecular Biology - Category: Biochemistry Source Type: research