Cascate reactions of progesterone by mycelia and culture broth from marine-derived fungus Aspergillus sydowii CBMAI 935
Introduction
The presence of steroidal drugs in waters due to incorrect use and disposal of drugs into the environment is a world-wide preoccupation. The ocean is the final destination of these compounds if they are not previously metabolized by microorganisms present in the soil and rivers. Concern regarding the presence of steroids in the environment is justified by some studies (Coleman et al., 2005; Solomon and Schettler, 2000; Gray, 1998; Daston et al., 1997; Sumpter, 1998; Tyler et al., 1998), which have shown a possible relation between the presence of steroidal drugs in environment and effects on human health including breast cancer, a normal sexual development, and reduction of fertility in males. Futhermore, it has been demonstrated that natural and synthetic hormones, when disposed into the environment, can trigger endocrine effects in male fish such as the feminization of reproductive organs (Coleman et al., 2005; Sumpter, 1998; Tyler et al., 1998).
Progesterone is a natural steroidal hormone produced by female mammals and is used as in contraceptives such as noretindrone, norgestimate, medroxiprogesterone acetate, levonorgestrel, and desogestrel (Phillips et al., 1987).
The biotransformation of progesterone into testosterone, an important male hormone known directly responsible by sexual and dimorphic characters, has been reported in the literature with Penicillium simplicissimun WY134-2 (Yang et al., 2014), Aspergillus tamarii MRC72400 (Yildirim et al., 2011), and Aspergillus ochraceus TS (Dutta and Samanta, 1997). The fungus Penicillium notatum KCH 904 (Bartmańska et al., 2005) and Penicilium citreo-viride ACCC 0402 (Liu et al., 2006) catalyzed the biotransformation of progesterone into testololactone, a steroid compound than can suppress the inhibition of aromatase enzymes (Cocconi, 1994). The testololactone can also be used in the treatment of breast cancer (Budnick and Dao, 1980), prostatic hyperplasia, and prostate cancer (Li and Parish, 1996), and can be used as a therapeutic agent in the treatment of disorders caused by the imbalance between the actions of estrogens and androgens such as gynecomastia (Braunstein, 1999) and precocious puberty (Feuillan et al., 1999).
This paper describes the biotransformation of progesterone using mycelia and culture broth from marine-derived fungus Aspergillus sydowii CBMAI 935, yielding the products testosterone and testololactone (Scheme 1). Microbial bio-oxidation of hormones is important for understanding the possible pathways of xenobiotic compounds as well as contributing to the environmental impact due to their inappropriate disposal.
Section snippets
Chemical reagents, solvents and culture media
Agar (KASVI), malt extract (KASVI), progesterone (99%) (Sigma-Aldrich), ethyl acetate – EtOAc (Synth), n-hexane (Synth), dimethylsulfoxide - DMSO (TEDIA), CDCl3 (Cambridge Isotopes Laboratories Inc.), acetonitrile spectroscopical grade (Panreac), formic acid (Synth), CaCl2·2H2O (Synth), KCl (Synth), NaCl (LS Chemicals), MgCl2·6H2O (Synth), NaH2PO4 (Merck), Na2SO4 (Synth), NaHCO3 (Synth), KBr (Synth), SrCl2. 6H2O (J.T. Backer), H3BO4 (Synth), phosphomolybdic acid (Qhemis), silica gel
Molecular structures of steroids progesterone, testosterone and testololactone
Fig. 1A and B show the numeric type assignment for carbon and hydrogen atoms for progesterone, testosterone, and testololactone according to International Union of Biochemistry and Molecular Biology (IUBMB) and International Union of Pure and Applied Chemistry (IUPAC) (Hill et al., 1991). The rings of molecular structures were named according to this convention as gonane nucleus.
Biotransformation of progesterone using mycelia from A. sydowii CBMAI 935
After using the mycelia from marine derived-fungus A. sydowii CBMAI 935 for the biotransformation reaction of
Conclusion
The mycelia of marine-derived fungus A. sydowii CBMAI 935 was able to catalyze the biotransformation of progesterone to produce testololactone as a major product; the culture broth yielded both testosterone and testololactone. These products obtained by Baeyer-Villiger oxidation reactions of progesterone showed that important enzymes are present in A. sydowii CBMAI 935 that assist the biotransformation of steroids disposed into the environment. In summary, steroid nuclei undergo enzymatic
Acknowledgments
SFCP thanks to Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) for scholarship. This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) – Finance Code 001 and Fundação de Amparo a Pesquisa do Estado de São Paulo – FAPESP (Brazil) Proc. Number 2016/20155-7. The author thank Prof. Roberto Gomes de Souza Berlinck (IQSC-USP) and Mirna Helena Regali Seleghim (DBE-UFSCar) for providing marine fungus.
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