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Enzymatic Synthesis of Anabolic Steroid Glycosides by Glucosyltransferase from Terribacillus sp. PAMC 23288.

ABSTRACT: The application of steroids has steadily increased thanks to their therapeutic effects. However, alternatives are required due their severe side effects; thus, studies on the activities of steroid derivatives are underway. Sugar derivatives of nandrolone, which is used to treat breast cancer, as well as cortisone and prednisone, which reduce inflammation, pain, and edema, are unknown. We linked O-glucose to nandrolone and testosterone using UDP-glucosyltransferase (UGT-1) and, then, tested their bioactivities in vitro. Analysis by NMR showed that the derivatives were 17β-nandrolone β-D-glucose and 17β-testosterone β-D-glucose, respectively. The viability was higher and cytotoxicity was evident in PC12 cells incubated with rotenone and, testosterone derivatives, compared to the controls. SH-SY5Y cells incubated with H₂O₂ and nandrolone derivatives remained viable and cytotoxicity was attenuated. Both derivatives enhanced neuronal protective effects and increased the amounts of cellular ATP.

SUBMITTER: Yu EJ

PROVIDER: S-EPMC9728329 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Enzymatic Synthesis of Anabolic Steroid Glycosides by Glucosyltransferase from <i>Terribacillus</i> sp. PAMC 23288.

Yu Eun-Ji EJ Yamaguchi Tokutaro T Lee Joo-Ho JH Lim A-Rang AR Lee Jun Hyuck JH Park Hyun H Oh Tae-Jin TJ

Journal of microbiology and biotechnology 20200401 4

The application of steroids has steadily increased thanks to their therapeutic effects. However, alternatives are required due their severe side effects; thus, studies on the activities of steroid derivatives are underway. Sugar derivatives of nandrolone, which is used to treat breast cancer, as well as cortisone and prednisone, which reduce inflammation, pain, and edema, are unknown. We linked O-glucose to nandrolone and testosterone using UDP-glucosyltransferase (UGT-1) and, then, tested their ...[more]

PMID: 31893610

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Project description:BackgroundBiotransformation of organic compounds by using microbial whole cells provides an efficient approach to obtain novel analogues which are often difficult to synthesize chemically. In this manuscript, we report for the first time the microbial transformation of a synthetic anabolic steroidal drug, oxymetholone, by fungal cell cultures.ResultsIncubation of oxymetholone (1) with Macrophomina phaseolina, Aspergillus niger, Rhizopus stolonifer, and Fusarium lini produced 17?-hydroxy-2-(hydroxy-methyl)-17?-methyl-5?-androstan-1-en-3-one (2), 2?,17?-di(hydroxyl-methyl)-5?-androstan-3?,17?-diol (3), 17?-methyl-5?-androstan-2?,3?,17?-triol (4), 17?-hydroxy-2-(hydroxymethyl)-17?-methyl-androst-1,4-dien-3-one (5), 17?-hydroxy-2?-(hydroxy-methyl)-17?-methyl-5?-androstan-3-one (6), and 2?-(hydroxymethyl)-17?-methyl-5?-androstan-3?-17?-diol (7). Their structures were deduced by spectral analyses, as well as single-crystal X-ray diffraction studies. Compounds 2-5 were identified as the new metabolites of 1. The immunomodulatory, and anti-inflammatory activities and cytotoxicity of compounds 1-7 were evaluated by observing their effects on T-cell proliferation, reactive oxygen species (ROS) production, and normal cell growth in MTT assays, respectively. These compounds showed immunosuppressant effect in the T-cell proliferation assay with IC50 values between 31.2 to 2.7 ?g/mL, while the IC50 values for ROS inhibition, representing anti-inflammatory effect, were in the range of 25.6 to 2.0 ?g/mL. All the compounds were found to be non-toxic in a cell-based cytotoxicity assay.ConclusionMicrobial transformation of oxymetholone (1) provides an efficient method for structural transformation of 1. The transformed products were obtained as a result of de novo stereoselective reduction of the enone system, isomerization of double bond, insertion of double bond and hydroxylation. The transformed products, which showed significant immunosuppressant and anti-inflammatory activities, can be further studied for their potential as novel drugs.

Dataset Information

Enzymatic Synthesis of Anabolic Steroid Glycosides by Glucosyltransferase from Terribacillus sp. PAMC 23288.

Publications

Enzymatic Synthesis of Anabolic Steroid Glycosides by Glucosyltransferase from <i>Terribacillus</i> sp. PAMC 23288.

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