Islam Mohammad Sayful, Uwada Junsuke, Hayashi Junki, Kikuya Kei-Ichiro, Muranishi Yuki, Watanabe Hiroyuki, Yaegashi Kazuhide, Hasegawa Kazuya, Ida Takanori, Sato Takahiro, Imamichi Yoshitaka, Kitano Takeshi, Miyashiro Yoshimichi, Khan Rafiqul Islam, Takahashi Satoru, Umezawa Akihiro, Suzuki Nobuo, Sekiguchi Toshio, Yazawa Takashi
Department of Biochemistry, Asahikawa Medical University, Asahikawa 078-8510, Japan.
Department of Life and Food Science, Obihiro University of Agriculture and Veterinary Medicine, Obihiro 080-8555, Japan.
Animals (Basel). 2021 Sep 30;11(10):2876. doi: 10.3390/ani11102876.
17β-hydroxysteroid dehydrogenase type 3 (HSD17B3) converts androstenedione (A4) into testosterone (T), which regulates sex steroid production. Because various mutations of the HSD17B3 gene cause disorder of sex differentiation (DSD) in multiple mammalian species, it is very important to reveal the molecular characteristics of this gene in various species. Here, we revealed the open reading frame of the ovine HSD17B3 gene. Enzymatic activities of ovine HSD17B3 and HSD17B1 for converting A4 to T were detected using ovine androgen receptor-mediated transactivation in reporter assays. Although HSD17B3 also converted estrone to estradiol, this activity was much weaker than those of HSD17B1. Although ovine HSD17B3 has an amino acid sequence that is conserved compared with other mammalian species, it possesses two amino acid substitutions that are consistent with the reported variants of human HSD17B3. Substitutions of these amino acids in ovine HSD17B3 for those in human did not affect the enzymatic activities. However, enzymatic activities declined upon missense mutations of the HSD17B3 gene associated with 46,XY DSD, affecting amino acids that are conserved between these two species. The present study provides basic information and tools to investigate the molecular mechanisms behind DSD not only in ovine, but also in various mammalian species.
17β-羟类固醇脱氢酶3型（HSD17B3）将雄烯二酮（A4）转化为睾酮（T），从而调节性类固醇的产生。由于HSD17B3基因的各种突变会导致多种哺乳动物物种出现性分化障碍（DSD），因此揭示该基因在不同物种中的分子特征非常重要。在此，我们揭示了绵羊HSD17B3基因的开放阅读框。在报告基因检测中，利用绵羊雄激素受体介导的反式激活作用检测了绵羊HSD17B3和HSD17B1将A4转化为T的酶活性。虽然HSD17B3也能将雌酮转化为雌二醇，但其活性远低于HSD17B1。尽管绵羊HSD17B3的氨基酸序列与其他哺乳动物物种相比具有保守性，但它有两个氨基酸替代，与报道的人类HSD17B3变体一致。将绵羊HSD17B3中的这些氨基酸替换为人类的氨基酸并不影响酶活性。然而，与46,XY DSD相关的HSD17B3基因错义突变会导致酶活性下降，这些突变影响了这两个物种之间保守的氨基酸。本研究不仅为研究绵羊，也为研究各种哺乳动物物种DSD背后的分子机制提供了基础信息和工具。
