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Enzyme Catalysis
Published in Harvey W. Blanch, Douglas S. Clark, Biochemical Engineering, 1997
Harvey W. Blanch, Douglas S. Clark
Steroids have been employed for the treatment of inflamatory diseases since the late 1940 's. The sources of steroids are plant and animal tissues, and most steroids are derived by either chemical or microbial conversion of starting materials, typically phytosterols, such as diosgenin and stigmasterol. Diosgenin is obtained from the root of the barbasco plant, grown in Mexico and Central America; stigmasterol is obtained from soybean seed oil. Diosgenin is a starting material in the formation of pregnenolone, and stigmasterol is the precursor for progesterone. The 3 -one-4-ene A-ring of corticosteriods can be obtained from pregnenolone which is converted to progesterone. The most therapeutically important steroids (cortisone, hydrocortisone, prednisone, prednisolone etc) have an 11 -hydroxyl or 11 -keto function, in addition to a 17 a-hydroxyl function. The ring numbering system of steroids and the carbon numbering scheme are illustrated in Figure 8.6.
Conversion of Natural Products from Renewable Resources in Pharmaceuticals by Cytochromes P450
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Giovanna Di Nardo, Gianfranco Gilardi
Mammalian cytochromes P450 have also been used as biocatalyst for steroid hydroxylation in yeast recombinant systems. In the late 1990s, the self-sufficient biosynthesis of pregnenolone and progesterone were achieved by engineering six genes in Saccaromyces cerevisiae (Duport et al., 1998). The bovine cytochrome P450 11A1 was introduced, together with the redox partner, in the fungus engineered to accumulate ergosta-5-ene-ol and ergosta-5,22-diene-ol from the endogenous ergosterol. The two compounds are substrates of P450 11A1, which produces pregnenolone, which is then converted to progesterone through the action of 3-β-hydroxysteroid dehydrogenase.
Cytochrome P450 Enzymes for the Synthesis of Novel and Known Drugs and Drug Metabolites
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Sanjana Haque, Yuqing Gong, Sunitha Kodidela, Mohammad A. Rahman, Sabina Ranjit, Santosh Kumar
CYP106 obtained from B. megaterium, is a potential candidate for the preparative scale biotechnological production of hydroxysteroids (Rauschenbach et al., 1993; Schmitz et al., 2014). Chul-Ho Yun and his group in their study with CYP106A1 from B. megaterium ATCC 14581 strain showed that the enzyme can hydroxylate steroids (e.g., testosterone, progesterone, 17α-hydroxyprogesterone, 11-deoxycorticosterone, corticosterone, and 11-deoxycortisol). Monohydroxylated compounds are produced as major metabolites by hydroxylation (Lee et al., 2015). Hydroxylation by CYPs can be useful to produce intermediates or to structurally modify steroids for therapeutic applications (Sedlaczek and Smith, 1988). Enzymatic reactions by CYP106A1 could replace several chemical reaction steps in the industrial manufacturing of natural hormones and steroidal drugs (Lee et al., 2015). Recently, studies conducted on B. megaterium DSM319 strain have identified the potential of CYP106A1 to convert pentacyclic triterpene 11-keto-β-boswellic acid (KBA), a constituent of resin extracts, used to treat inflammatory disorders and arthritis. Conversion rate of KBA by CYP106A1 whole system was found to be 100 min−1 with 80% selectivity towards the main product. The hydroxylated KBA derivatives obtained from this enzymatic reaction are assumed to possess enhanced bioavailability, improved pharmacological activities, or can be modified by chemical methods (Brill et al., 2014). CYP106A2 hydroxylases tricyclic diterpene and pentacyclic triterpene acids (Bleif et al., 2012). A research group led by Rita Bernhardt, screened a steroid library to identify new substrates for CYP106A2, which included dehydroepiandrosterone (DHEA) and pregnenolone. At a preparative scale, they were able to hydroxylate DHEA and pregnenolone primarily at 7β position. Conversion rate of DHEA to 7β-OH-DHEA using B. megaterium was high with a volumetric yield of 103 mg/L/h (Schmitz et al., 2014).
Expression and characterization of cholesterol oxidase with high thermal and pH stability from Janthinobacterium agaricidamnosum
Published in Preparative Biochemistry & Biotechnology, 2023
Noriyuki Doukyu, Yuuki Ikehata, Taichi Sasaki
The ChoJ oxidized cholesterol and β-cholestanol at higher rates than other sterols tested, but the oxidation rates of sterols with side-chain structures different from that of cholesterol were lower than that of cholesterol. Although J. agaricidamnosum is a soft rot pathogen of mushroom, the ChoJ showed lower activity toward ergosterol, which is the main sterol in mushrooms, than toward cholesterol. In addition, the oxidation rates of side-chain-cleaved sterols such as pregnenolone and dehydroepiandrosterone were lower than those of other sterols. A similar trend was found in VAO family COXases, including enzymes from B. cepacia ST-200,[16]Chromobacterium sp. DS-1,[17]P. aeruginosa PA157,[18] and R. erythropolis PR4 (ChoRI).[12] On the other hand, the COXase from R. erythropolis PR4 (ChoRII) displayed 96% relative activity toward pregnenolone compared to the activity for cholesterol. Interestingly, ChoRII oxidized phytosterols such as β-sitosterol and stigmasterol at about 2-fold higher rates than cholesterol.[12]
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.
Non-targeted metabolomics analyses by mass spectrometry to explore metabolic stress after six training weeks in high level swimmers.
Published in Journal of Sports Sciences, 2021
Robin Pla, Estelle Pujos-Guillot, Stéphanie Durand, Marion Brandolini-Bunlon, Delphine Centeno, David B. Pyne, Jean-François Toussaint, Philippe Hellard
Another important result of our study is that abundance of Pregnanediol-3-glucuronide were higher in the threshold training group and the most fatigued swimmers. Pregnanediol-3-glucuronide is the main metabolite of progesterone which is a steroid sex hormone, close to oestrogens, synthesised in women by the corpus luteum, or in the placenta, from pregnenolone. In humans, progesterone is synthesised by the testicles and adrenal glands under the action of the luteinizing hormone (LH). It appears that six weeks of threshold training performed by swimmers did not affect the functioning of the hypothalamic-pituitary axis and production of the LH gonadotropin regulating progesterone concentration.