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Microbial Biotransformation of Natural Products

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Natural Products Chemistry".

Deadline for manuscript submissions: closed (28 February 2022) | Viewed by 38981

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Prof. Dr. Ik-Soo Lee

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Guest Editor

College of Pharmacy and Research Institute of Pharmaceutical Sciences, Chonnam National University, Gwangju 61186, Korea
Interests: microbial transformation of bioactive natural products; spectroscopic identification of organic small molecules of natural origin; natural product drug discovery

Prof. Dr. Hyun Jung Kim

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Guest Editor

College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam 58554, Korea
Interests: bioactive natural products; structure elucidation; biotransformation; traditional medicine

Special Issue Information

Dear Colleagues,

Since the concept of “microbial models of mammalian drug metabolism” was first formalized in the 1970s, biotransformation strategies using microbes have been extensively applied as in vitro models to predict the metabolic fates of xenobiotics and drug molecules. In parallel, microbial transformation has long been proven to be a highly influential tool for providing more feasible and useful ways to yield a considerable amount of structurally unknown derivatives for pharmacological and toxicological studies.

The Special Issue “Microbial Biotransformation of Natural Products” aims to collect and publish original research or review articles concerning chemical, biological, and toxicological progress and advances associated with transformation or metabolism studies of natural product-based substrates on microbial whole cell enzyme systems.

Prof. Ik-Soo Lee
Prof. Hyun Jung Kim
Guest Editors

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Keywords

natural products
natural product-derived xenobiotics
microbial transformation
microbial model of mammalian metabolism
biotransformation
biocatalysis
metabolic fate prediction
structural modification
structural diversity
drug lead discovery

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Published Papers (10 papers)

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Research

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13 pages, 1026 KiB

Open AccessArticle

Microbial Transformation and Biological Activities of the Prenylated Aromatic Compounds from Broussonetia kazinoki

by EunA Choi, Fubo Han, Jisu Park and Ik-Soo Lee

Molecules 2022, 27(6), 1879; https://doi.org/10.3390/molecules27061879 - 14 Mar 2022

Cited by 2 | Viewed by 2416

Abstract

Broussonetia kazinoki has been used as a traditional medicine for the treatment of burns and acne, and its extracts have been found to show tyrosinase inhibitory and anticancer activities. In this study, the tyrosinase inhibitory and cytotoxic activities of B. kazinoki were explored, leading to the isolation of kazinol C (1), kazinol E (2), kazinol F (3), broussonol N (4), and kazinol X (5), of which the compounds 4 and 5 have not been previously reported. Microbial transformation has been recognized as an efficient tool to generate more active metabolites. Microbial transformation of the major compounds 1 and 3 was conducted with Mucor hiemalis, where four glucosylated metabolites (6–9) were produced from 1, while one hydroxylated (10) and one glucosylated (11) metabolites were obtained from 3. Structures of the isolated metabolites were determined by extensive spectroscopic analyses. All compounds were evaluated for their tyrosinase inhibitory and cytotoxic activities. Compound 3 and its metabolites, kazinol Y (10) and kazinol F-4″-O-β-d-glucopyranoside (11), exhibited the most potent tyrosinase inhibitory activities with the IC₅₀ values ranging from 0.71 to 3.36 µM. Meanwhile, none of the metabolites, except for kazinol C-2′,3″-di-O-β-d-glucopyranoside (7), showed moderate cytotoxic activities (IC₅₀ 17.80 to 24.22 µM) against A375P, B16F10 and B16F1 cell lines. Full article

(This article belongs to the Special Issue Microbial Biotransformation of Natural Products)

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12 pages, 1385 KiB

Open AccessArticle

Biotransformation of (−)-α-Bisabolol by Absidia coerulea

by Jisu Park, Fubo Han and Ik-Soo Lee

Molecules 2022, 27(3), 881; https://doi.org/10.3390/molecules27030881 - 27 Jan 2022

Cited by 7 | Viewed by 3875

Abstract

(−)-α-Bisabolol, a bioactive monocyclic sesquiterpene alcohol, has been used in pharmaceutical and cosmetic products with anti-inflammatory, antibacterial and skin-caring properties. However, the poor water solubility of (−)-α-bisabolol limits its pharmaceutical applications. It has been recognized that microbial transformation is a very useful approach to generate more polar metabolites. Fifteen microorganisms were screened for their ability to metabolize (−)-α-bisabolol in order to obtain its more polar derivatives, and the filamentous fungus Absidia coerulea was selected for scale-up fermentation. Seven new and four known metabolites were obtained from biotransformation of (−)-α-bisabolol (1), and all the metabolites exhibited higher aqueous solubility than that of the parent compound 1. The structures of newly formed metabolites were established as (1R,5R,7S)- and (1R,5S,7S)-5-hydroxy-α-bisabolol (2 and 3), (1R,5R,7S,10S)-5-hydroxybisabolol oxide B (4), (1R,7S,10S)-1-hydroxybisabolol oxide B (5), 12-hydroxy-α-bisabolol (7), (1S,3R,4S,7S)- and (1S,3S,4S,7S)-3,4-dihydroxy-α-bisabolol (8 and 10) on the basis of spectroscopic analyses. These compounds could also be used as reference standards for the detection and identification of the metabolic products of 1 in the mammalian system. Full article

(This article belongs to the Special Issue Microbial Biotransformation of Natural Products)

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13 pages, 4530 KiB

Open AccessArticle

The Donor-Dependent and Colon-Region-Dependent Metabolism of (+)-Catechin by Colonic Microbiota in the Simulator of the Human Intestinal Microbial Ecosystem

by Qiqiong Li, Florence Van Herreweghen, Marjan De Mey, Geert Goeminne and Tom Van de Wiele

Molecules 2022, 27(1), 73; https://doi.org/10.3390/molecules27010073 - 23 Dec 2021

Cited by 13 | Viewed by 3781

Abstract

The intestinal absorption of dietary catechins is quite low, resulting in most of them being metabolized by gut microbiota in the colon. It has been hypothesized that microbiota-derived metabolites may be partly responsible for the association between catechin consumption and beneficial cardiometabolic effects. Given the profound differences in gut microbiota composition and microbial load between individuals and across different colon regions, this study examined how microbial (+)-catechin metabolite profiles differ between colon regions and individuals. Batch exploration of the interindividual variability in (+)-catechin microbial metabolism resulted in a stratification based on metabolic efficiency: from the 12 tested donor microbiota, we identified a fast- and a slow-converting microbiota that was subsequently inoculated to SHIME, a dynamic model of the human gut. Monitoring of microbial (+)-catechin metabolites from proximal and distal colon compartments with UHPLC-MS and UPLC-IMS-Q-TOF-MS revealed profound donor-dependent and colon-region-dependent metabolite profiles with 5-(3′,4′-dihydroxyphenyl)-γ-valerolactone being the largest contributor to differences between the fast- and slow-converting microbiota and the distal colon being a more important region for (+)-catechin metabolism than the proximal colon. Our findings may contribute to further understanding the role of the gut microbiota as a determinant of interindividual variation in pharmacokinetics upon (+)-catechin ingestion. Full article

(This article belongs to the Special Issue Microbial Biotransformation of Natural Products)

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10 pages, 1551 KiB

Open AccessArticle

Enzymatic Synthesis of Novel Vitexin Glucosides

by Jiumn-Yih Wu, Tzi-Yuan Wang, Hsiou-Yu Ding, Yun-Rong Zhang, Shu-Yuan Lin and Te-Sheng Chang

Molecules 2021, 26(20), 6274; https://doi.org/10.3390/molecules26206274 - 16 Oct 2021

Cited by 14 | Viewed by 3759

Abstract

Vitexin is a C-glucoside flavone that exhibits a wide range of pharmaceutical activities. However, the poor solubility of vitexin limits its applications. To resolve this limitation, two glycoside hydrolases (GHs) and four glycosyltransferases (GTs) were assayed for glycosylation activity toward vitexin. The results showed that BtGT_16345 from the Bacillus thuringiensis GA A07 strain possessed the highest glycosylation activity, catalyzing the conversion of vitexin into new compounds, vitexin-4′-O-β-glucoside (1) and vitexin-5-O-β-glucoside (2), which showed greater aqueous solubility than vitexin. To our knowledge, this is the first report of vitexin glycosylation. Based on the multiple bioactivities of vitexin, the two highly soluble vitexin derivatives might have high potential for pharmacological usage in the future. Full article

(This article belongs to the Special Issue Microbial Biotransformation of Natural Products)

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16 pages, 2378 KiB

Open AccessArticle

A Promiscuous Halogenase for the Derivatization of Flavonoids

by Dominik Kolling, Marc Stierhof, Constanze Lasch, Maksym Myronovskyi and Andriy Luzhetskyy

Molecules 2021, 26(20), 6220; https://doi.org/10.3390/molecules26206220 - 14 Oct 2021

Cited by 4 | Viewed by 3420

Abstract

Halogenation often improves the bioactive properties of natural products and is used in pharmaceutical research for the generation of new potential drug leads. High regio- and stereospecificity, simple reaction conditions and straightforward downstream processing are the main advantages of halogenation using enzymatic biocatalysts compared to chemical synthetic approaches. The identification of new promiscuous halogenases for the modification of various natural products is of great interest in modern drug discovery. In this paper, we report the identification of a new promiscuous FAD-dependent halogenase, DklH, from Frankia alni ACN14a. The identified halogenase readily modifies various flavonoid compounds, including those with well-studied biological activities. This halogenase has been demonstrated to modify not only flavones and isoflavones, but also flavonols, flavanones and flavanonols. The structural requirements for DklH substrate recognition were determined using a feeding approach. The homology model of DklH and the mechanism of substrate recognition are also proposed in this paper. Full article

(This article belongs to the Special Issue Microbial Biotransformation of Natural Products)

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14 pages, 5043 KiB

Open AccessArticle

Production of Minor Ginsenosides C-K and C-Y from Naturally Occurring Major Ginsenosides Using Crude β-Glucosidase Preparation from Submerged Culture of Fomitella fraxinea

by Dae-Woon Kim, Won-Jae Lee, Yoseph Asmelash Gebru, Jitendra Upadhyaya, Sung-Ryong Ko, Young-Hoi Kim and Myung-Kon Kim

Molecules 2021, 26(16), 4820; https://doi.org/10.3390/molecules26164820 - 9 Aug 2021

Cited by 14 | Viewed by 3057

Abstract

Minor ginsenosides, such as compounds (C)-K and C-Y, possess relatively better bioactivity than those of naturally occurring major ginsenosides. Therefore, this study focused on the biotransformation of major ginsenosides into minor ginsenosides using crude β-glucosidase preparation isolated from submerged liquid culture of Fomitella fraxinea (FFEP). FFEP was prepared by ammonium sulfate (30–80%) precipitation from submerged culture of F. fraxinea. FFEP was used to prepare minor ginsenosides from protopanaxadiol (PPD)-type ginsenoside (PPDG-F) or total ginsenoside fraction (TG-F). In addition, biotransformation of major ginsenosides into minor ginsenosides as affected by reaction time and pH were investigated by TLC and HPLC analyses, and the metabolites were also identified by UPLC/negative-ESI-Q-TOF-MS analysis. FFEP biotransformed ginsenosides Rb1 and Rc into C-K via the following pathways: Rd → F2 → C-K for Rb1 and both Rd → F2→ C-K and C-Mc1 → C-Mc → C-K for Rc, respectively, while C-Y is formed from Rb2 via C-O. FFEP can be applied to produce minor ginsenosides C-K and C-Y from PPDG-F or TG-F. To the best of our knowledge, this study is the first to report the production of C-K and C-Y from major ginsenosides by basidiomycete F. fraxinea. Full article

(This article belongs to the Special Issue Microbial Biotransformation of Natural Products)

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14 pages, 1860 KiB

Open AccessArticle

Biotransformation of Timosaponin BII into Seven Characteristic Metabolites by the Gut Microbiota

by Guo-Ming Dong, Hang Yu, Li-Bin Pan, Shu-Rong Ma, Hui Xu, Zheng-Wei Zhang, Pei Han, Jie Fu, Xin-Yu Yang, Adili Keranmu, Hai-Tao Niu, Jian-Dong Jiang and Yan Wang

Molecules 2021, 26(13), 3861; https://doi.org/10.3390/molecules26133861 - 24 Jun 2021

Cited by 14 | Viewed by 3278

Abstract

Timosaponin BII is one of the most abundant Anemarrhena saponins and is in a phase II clinical trial for the treatment of dementia. However, the pharmacological activity of timosaponin BII does not match its low bioavailability. In this study, we aimed to determine the effects of gut microbiota on timosaponin BII metabolism. We found that intestinal flora had a strong metabolic effect on timosaponin BII by HPLC-MS/MS. At the same time, seven potential metabolites (M1-M7) produced by rat intestinal flora were identified using HPLC/MS-Q-TOF. Among them, three structures identified are reported in gut microbiota for the first time. A comparison of rat liver homogenate and a rat liver microsome incubation system revealed that the metabolic behavior of timosaponin BII was unique to the gut microbiota system. Finally, a quantitative method for the three representative metabolites was established by HPLC-MS/MS, and the temporal relationship among the metabolites was initially clarified. In summary, it is suggested that the metabolic characteristics of gut microbiota may be an important indicator of the pharmacological activity of timosaponin BII, which can be applied to guide its application and clinical use in the future. Full article

(This article belongs to the Special Issue Microbial Biotransformation of Natural Products)

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14 pages, 1327 KiB

Open AccessArticle

Biotransformation of Cortisone with Rhodococcus rhodnii: Synthesis of New Steroids

by Federico Zappaterra, Stefania Costa, Daniela Summa, Valerio Bertolasi, Bruno Semeraro, Paola Pedrini, Raissa Buzzi and Silvia Vertuani

Molecules 2021, 26(5), 1352; https://doi.org/10.3390/molecules26051352 - 3 Mar 2021

Cited by 13 | Viewed by 3755

Abstract

Cortisone is a steroid widely used as an anti-inflammatory drug able to suppress the immune system, thus reducing inflammation and attendant pain and swelling at the site of an injury. Due to its numerous side effects, especially in prolonged and high-dose therapies, the development of the pharmaceutical industry is currently aimed at finding new compounds with similar activities but with minor or no side effects. Biotransformations are an important methodology towards more sustainable industrial processes, according to the principles of “green chemistry”. In this work, the biotransformation of cortisone with Rhodococcus rhodnii DSM 43960 to give two new steroids, i.e., 1,9β,17,21-tetrahydoxy-4-methyl-19-nor-9β-pregna-1,3,5(10)-trien-11,20-dione and 1,9β,17,20β,21-pentahydoxy-4-methyl-19-nor-9β-pregna-1,3,5(10)-trien-11-one, is reported. These new steroids have been fully characterized. Full article

(This article belongs to the Special Issue Microbial Biotransformation of Natural Products)

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18 pages, 7549 KiB

Open AccessArticle

Biotechnological Transformation of Hydrocortisone into 16α-Hydroxyprednisolone by Coupling Arthrobacter simplex and Streptomyces roseochromogenes

by Odile Francesca Restaino, Simona Barbuto Ferraiuolo, Addolorata Perna, Marcella Cammarota, Maria Giovanna Borzacchiello, Antonio Fiorentino and Chiara Schiraldi

Molecules 2020, 25(21), 4912; https://doi.org/10.3390/molecules25214912 - 23 Oct 2020

Cited by 12 | Viewed by 3598

Abstract

16α-Hydroxyprednisolone, an anti-inflammatory drug, could be potentially obtained from hydrocortisone bioconversion by combining a 1,2-dehydrogenation reaction performed by Arthrobacter simplexATCC31652 with a 16α-hydroxylation reaction by Streptomyces roseochromogenes ATCC13400. In this study we tested, for the first time, potential approaches to couple the two reactions using similar pH and temperature conditions for hydrocortisone bioconversion by the two strains. The A. simplex capability to 1,2-dehydrogenate the 16α-hydroxyhydrocortisone, the product of S. roseochromogenes transformation of hydrocortisone, and vice versa the capability of S. roseochromogenes to 16α-hydroxylate the prednisolone were assessed. Bioconversions were studied in shake flasks and strain morphology changes were observed by SEM. Whole cell experiments were set up to perform the two reactions in a sequential mode in alternate order or contemporarily at diverse temperature conditions. A. simplex catalyzed either the dehydrogenation of hydrocortisone into prednisolone efficiently or of 16α-hydroxyhydrocortisone into 16α-hydroxyprednisolone in 24 h (up to 93.9%). Surprisingly S. roseochromogenes partially converted prednisolone back to hydrocortisone. A 68.8% maximum of 16α-hydroxyprednisolone was obtained in 120-h bioconversion by coupling whole cells of the two strains at pH 6.0 and 26 °C. High bioconversion of hydrocortisone into 16α-hydroxyprednisolone was obtained for the first time by coupling A. simplex and S. roseochromogenes. Full article

(This article belongs to the Special Issue Microbial Biotransformation of Natural Products)

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Review

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24 pages, 3582 KiB

Open AccessReview

Transformations of Monoterpenes with the p-Menthane Skeleton in the Enzymatic System of Bacteria, Fungi and Insects

by Małgorzata Grabarczyk, Wanda Mączka, Anna K. Żołnierczyk and Katarzyna Wińska

Molecules 2020, 25(20), 4840; https://doi.org/10.3390/molecules25204840 - 20 Oct 2020

Cited by 10 | Viewed by 6022

Abstract

The main objective of this article was to present the possibilities of using the enzymatic system of microorganisms and insects to transform small molecules, such as monoterpenes. The most important advantage of this type of reaction is the possibility of obtaining derivatives that are not possible to obtain with standard methods of organic synthesis or are very expensive to obtain. The interest of industrial centers focuses mainly on obtaining particles of high optical purity, which have the desired biological properties. The cost of obtaining such a compound and the elimination of toxic or undesirable chemical waste is important. Enzymatic reactions based on enzymes alone or whole microorganisms enable obtaining products with a specific structure and purity in accordance with the rules of Green Chemistry. Full article

(This article belongs to the Special Issue Microbial Biotransformation of Natural Products)

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