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Conversion of Natural Products from Renewable Resources in Pharmaceuticals by Cytochromes P450
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Giovanna Di Nardo, Gianfranco Gilardi
In another work, more mammalian cytochromes P450 were introduced in yeast to produce different steroids, with hydrocortisone as the major one (Szczebara et al., 2003). Hydrocortison is the major steroid in mammals and it is used as starting compound for the synthesis of many drugs. Part of the mammalian biosynthetic pathway leading to this compound was reconstructed in the recombinant yeast starting from a simple carbon source such as glucose or ethanol. The enzymes heterologously expressed were 3-β-hydroxysteroid dehydrogenase (3β-HSD), CYP17A1, CYP21A1, and CYP11B1, which can convert pregnenolone into progesterone, 17-hydroxy-progesterone, 11-deoxycortisol, andhydrocortisone, respectively(Fig. 17.4)(Szczebara et al., 2003). Biosynthetic steps for different steroids catalyzed by different mammalian cytochromes P450 that were successfully expressed in yeast.
Zearalenone perturbs the circadian clock and inhibits testosterone synthesis in mouse Leydig cells
Published in Journal of Toxicology and Environmental Health, Part A, 2021
Lijia Zhao, Yaoyao Xiao, Cuimei Li, Jing Zhang, Yaojia Zhang, Meina Wu, Tiantian Ma, Luda Yang, Xiaoyu Wang, Haizhen Jiang, Qian Li, Hongcong Zhao, Yiqun Wang, Aihua Wang, Yaping Jin, Huatao Chen
Leydig cells are the primary producers of androgens. StAR, Cyp11a1, Cyp17a1, Hsd3b2, and Hsd17b3 are steroidogenic genes expressed in LCs that encode enzymes critical for androgen synthesis. The hypothalamic-pituitary axis plays an important role in regulating testosterone production. LH is produced by gonadotropic cells in the anterior pituitary gland. The released LH binds to its receptor on LCs and facilitates production of cAMP. Increases in cAMP levels stimulate translocation of cholesterol to the outer mitochondrial membrane. After transfer to the inner mitochondrial membrane through the action of StAR, this cholesterol is converted to pregnenolone by CYP11A1. Pregnenolone is finally metabolized to testosterone by the combined actions of HSD3B, CYP17A1, and HSD17B in the smooth endoplasmic reticulum (Tremblay 2015). Previous investigators demonstrated that plasma testosterone concentrations exhibit diurnal fluctuations in healthy young men, rats, and mice (Faiman and Winter 1971; Kinson and Liu 1973; Sayegh et al. 1990). It is of interest that Alvarez et al. (2008) noted that the expression levels of testosterone synthesis-related genes and proteins are decreased in testes of Bmal1-/- mice resulting in low serum testosterone levels. Zheng et al. (2019) reported that ZEA impaired synthesis and secretion of testosterone, consequently affecting the reproductive capability of male mammals. However, it is not known whether ZEA-mediated effects on testosterone production are associated with impairment of the circadian clock in mammalian LCs.