Regioselective O-glycosylation of flavonoids by fungi Beauveria bassiana, Absidia coerulea and Absidia glauca

Article abstract of DOI:10.1016/j.bioorg.2019.01.046

In the present study, the species: Beauveria bassiana, Absidia coerulea and Absidia glauca were used in biotransformation of flavones (chrysin, apigenin, luteolin, diosmetin) and flavanones (pinocembrin, naringenin, eriodictyol, hesperetin). The Beauveria bassiana AM 278 strain catalyzed the methylglucose attachment reactions to the flavonoid molecule at positions C7 and C3′. The application of the Absidia genus (A. coerulea AM 93, A. glauca AM 177) as the biocatalyst resulted in the formation of glucosides with a sugar molecule present at C7 and C3′ positions of flavonoids skeleton. Nine of obtained products have not been previously reported in the literature.

Full text of DOI:10.1016/j.bioorg.2019.01.046

BioorganicChemistryxxx(xxxx)xxx–xxx
Contents lists available at ScienceDirect
Bioorganic Chemistry
journal homepage: www.elsevier.com/locate/bioorg
Regioselective O-glycosylation of flavonoids by fungi Beauveria bassiana,
Absidia coerulea and Absidia glauca
Sandra Sordon⁎, Jarosław Popłoński, Tomasz Tronina, Ewa Huszcza
Department of Chemistry, Wrocław University of Environmental and Life Sciences, Norwida 25, 50-375 Wrocław, Poland
A R T I C L E I N F O
A B S T R A C T
InChIKey:
In the present study, the species: Beauveria bassiana, Absidia coerulea and Absidia glauca were used in bio-
transformation of flavones (chrysin, apigenin, luteolin, diosmetin) and flavanones (pinocembrin, naringenin,
eriodictyol, hesperetin). The Beauveria bassiana AM 278 strain catalyzed the methylglucose attachment reactions
to the flavonoid molecule at positions C7 and C3′. The application of the Absidia genus (A. coerulea AM 93, A.
glauca AM 177) as the biocatalyst resulted in the formation of glucosides with a sugar molecule present at C7 and
C3′ positions of flavonoids skeleton. Nine of obtained products have not been previously reported in the lit-
erature.
UAWZDIMXRSZHFO-KBSPUQAJSA-
NKeywords:
Flavanones
Flavones
Biotransformation
Microbial glycosylation
Beauveria bassiana
Absidia coerulea
Absidia glauca
1. Introduction
conditions. From many natural products which can be decorated with
carbohydrates by glycosyltransferases, flavonoids are of special interest
The presence of glycosyl moiety is usually crucial for the biological
activity of many important natural biomolecules such as glycans, lipids,
peptides and small molecules [1].
due to their high biological activities, such as anti-inflammatory, an-
ticancer, anti-obesity, antioxidant and antimicrobial ones [6,7]. Mi-
crobial catalysts are useful tool for production of flavonoid glycosides in
a cheap, simple one-step processes. The most literature reports on this
topic concern the use of filamentous fungi [8,9].
Glycosylation can increase the diversity of structure and function of
natural product, the sugar moieties can improve water-solubility of
natural products, enhance their bioactivity, stability, bioavailability
and decrease their toxicity [2]. From the reasons listed here, a lot of
effort was put into development of efficient production methods of the
glycosylated natural products.
In our previous studies fungal strains belonging to species Beauveria
bassiana, Absidia coerulea and Absidia glauca have been proven to be a
useful glycosylation catalysts toward a isoflavones [10], flavonols [11]
as well as prenylated chalcones, flavanones and aurones [12–16]. The
objective of the present research was to obtain glycosylated derivatives
of four common natural flavones and their four flavanone derivatives,
using the above-mentioned biocatalysts, and to determine the influence
of the structure of flavonoids used on glycosylation regioselectivity and
yield.
Although the extraction from native producers, mainly plants, ap-
pears to be the easiest method to obtain natural glycosides, this ap-
proach has many limitations e.g. low yield as a reason of low con-
centration in a biomass and strict dependence on seasonal vegetation
conditions. Production of specific glycosides by means of the organic
synthesis is generally recognized as a challenging task, uneconomical in
a large scale. It often requires protection of reactive groups in substrates
and application of expensive catalysts, generates toxic wastes and ef-
ficiency is generally low [3–5].
2. Materials and methods
2.1. Compounds
In addition to synthetic methods and isolation from natural sources,
biotransformations are an attractive alternative. Enzymes (or whole
cells as biocatalysts) can be utilized to perform glycosylation reaction,
additionally resulting in specific products and operating under mild
Chrysin (1) and naringenin (6) were purchased from Sigma-Aldrich
(St. Louis, MO, USA), hesperetin (8) from Alfa-Aesar (Thermo Fisher,
Karlsruhe, Germany), apigenin (2), luteolin (3) and diosmetin (4) from
⁎ Corresponding author.
E-mail addresses: sandra.sordon@upwr.edu.pl (S. Sordon), jaroslaw.poplonski@upwr.edu.pl (J. Popłoński), tomasz.tronina@upwr.edu.pl (T. Tronina),
ewa.huszcza@upwr.edu.pl (E. Huszcza).
https://doi.org/10.1016/j.bioorg.2019.01.046
Received 14 December 2018; Received in revised form 11 January 2019; Accepted 18 January 2019
0045-2068/©2019ElsevierInc.Allrightsreserved.
Pleasecitethisarticleas:Sordon,S.,BioorganicChemistry,https://doi.org/10.1016/j.bioorg.2019.01.046

S. Sordon et al.
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Carbosynth (Berkshire, UK).
The purity of obtained biotransformation products were greater
Pinocembrin (5) was obtained by hydrogenation of chrysin (1)
using hydrogen and 10% Pd/C according to the method described by
Popłoński et al. [17]. The mixture of 1 (500 mg, 1.97 mmol) and 10%
Pd/C (100 mg) in methanol (75 mL) was stirred at room temperature,
bubbled with nitrogen for 10 min and then with hydrogen. The progress
of reaction was monitored by HPLC. The reaction was performed for
2 h. After filtration, the solvent was evaporated and the resultant re-
sidue was chromatographed by flash chromatography using an Inter-
chim PF-15SIHP 40 g, 15 µm flash column in isocratic elution program
of a chloroform:ethyl acetate (19:1, v/v) mixture at the flow rate
26 mL/min to afford 139 mg of 5 with 28% yield and purity greater
than 99% (according to HPLC).
than 96% (according to HPLC and NMR).
2.7. Analytical methods
TLC was carried out on Merck silica gel 60, F254 (0.2 mm thick)
plates using chloroform:methanol (7:1, v/v) as eluent. Products were
detected by inspecting plates under UV irradiation.
HPLC analysis were performed on Dionex Ultimate 3000 UHPLC+
instrument system (Thermo Scientific, Waltham, MA, USA) equipped
with C-18 analytical column (ZORBAX Eclipse XDB, 5 µm,
4.6 mm × 250 mm, Agilent, Santa Clara, CA, USA). The mobile-phase
components were: 0.05% formic acid (A) and methanol containing
0.05% formic acid (B). The mobile-phase gradient was as follows:
0–2 min: 50% B, 2–12 min: 50–95% B, 12–14 min: 95% B. Flow rate
was 1 mL/min.
Eriodictyol (7) was obtained according to the same procedure as 5,
using 100 mg of luteolin (3) (0.3 mmol) as a substrate and 45 mg of Pd/
C. The progress of reaction was monitored by HPLC. Reaction was
carried out for 48 h. After purification by flash chromatography using
an Interchim PF-30SIHP 12 g, 30 µm flash column in isocratic elution
program of a hexane:ethyl acetate:formic acid (2:5:0.003, v/v/v) mix-
ture at the flow rate 15 mL/min 41.5 mg of 7 was obtained with the
yield of 41% and purity greater than 99% (according to HPLC).
The NMR spectra were recorded on a DRX 600 MHz Bruker spec-
trometer and measured in DMSO‑d6.
Negative-ion HR-ESIMS spectra were measured on a Bruker ESI-Q-
TOF, maXis impact Mass Spectrometer (Bruker Daltonics). The mass
spectrometer was operated in negative ion mode with the potential
between the spray needle and the orifice 3000 V, nebulizer pressure of
0.4 bar, and a drying gas flow rate of 4 L/min at 200 °C. The sample
flow rate was 3–5 μL/min. Ionization mass spectra were collected at the
ranges m/z 50–1400. The instrument was calibrated with an Agilent
electrospray calibration solution (ESI-L Low Concentration Tunemix
Agilent USA, score = 100%, SD < 1 ppm).
2.2. Microorganisms
The fungal strains used for biotransformation, i.e., Absidia coerulea
AM 93, Absidia glauca AM 177 and Beauveria bassiana AM 278 were
obtained from the collection of the Department of Biology and
Pharmaceutical Botany, Medical University of Wrocław, Poland.
3. Results and discussion
2.3. Cultivation of fungi
3.1. Flavonoids biotransformations
The fungi were maintained on Sabouraud agar slants and grown on
a Sabouraud medium (glucose 3%, peptone 1%). The fungal cultures
were cultivated on rotary shakers (130 rpm, 6.5 amplitude) at 28 °C in
100 mL Erlenmeyer flasks containing 30 mL of the medium in the
screening studies and in 300 mL Erlenmeyer flasks with 100 mL of the
medium in the preparative scale biotransformation.
In this study, selected fungal strains: Beauveria bassiana AM 278,
Absidia coerulea AM 93 and Absidia glauca AM 177 have been tested for
their ability to transform common natural flavones and flavanones. For
this purpose, chrysin (1), apigenin (2), luteolin (3), diosmetin (4), pi-
nocembrin (5), naringenin (6), eriodictyol (7) and hesperetin (8) were
chosen as substrates (Fig. 1). Experiments performed in a preparative
scale allowed to obtain products in amounts necessary to determine its
chemical structures. In the course of our study, we obtained 19 products
of monoglycosylation, 9 of which, to our best knowledge, have not been
reported so far in the literature (Fig. 2). The reaction yields were noted
as isolated yields (Table 1).
2.4. Screening procedure
A substrate (5 mg) was dissolved in 0.5 mL dimethyl sulfoxide
(DMSO) and added to the grown fungal culture. The reactions were
carried out for seven days. Appropriate controls (the substrate in sterile
medium and incubation of fungal strains without a substrate) were run
along with the above experiments.
3.1.1. Biotransformations in Beauveria bassiana AM 278 culture
The fungal strain B. bassiana AM 278 exhibited strict regioselective
glycosylation ability towards flavonoid compounds. In the conducted
studies chrysin (1), apigenin (2), luteolin (3), pinocembrin (5), nar-
ingenin (6) and eriodictyol (7) were converted to 4″-O-methylglucose
derivatives at C7 position (9, 11, 13, 18, 20, 22). Our previous re-
search also indicates that the strain B. bassiana AM 278 is capable of
regioselective glycosylation at C7 position of daidzein, genistein and
biochanin A [10]. The methoxyl group in ring B at C4′ position in
diosmetin (4) and hesperetin (8) resulted in additional glycosylation
products. Biotransformation of both 4 and 8 led to two glycosylated
products containing 4″-O-methylglucose molecule attached at C7 (15,
24) or C3′ position (16, 26). In biotransformation of diosmetin (4)
apart of methylglucose derivatives, the product of conjugation with the
glucose molecule at the C3′ (17) was also isolated. This observation
indicated that glucose methylation occurs after glucosylation, what
corresponds to the discovery of Xie et al. whom indicated in other strain
of B. bassiana that the pair of glycosyltransferase and methyltransferase
are involved in the process [18]. Interestingly, the methoxyl group at
C4′ position in the isoflavone biochanin A did not effect on the glyco-
sylation reaction conducted by the same strain of B. bassiana [10].
The type of flavonoid skeleton has a great importance on efficiency
2.5. Preparative biotransformation
In the preparative biotransformations 60 mg of a substrate was
dissolved in 6 mL of DMSO and distributed between four flasks of 4-
days fungal cultures. The reactions were carried out for ten days.
2.6. Reaction work-up and product analysis
After incubation, the reaction mixtures were acidified with 1 M HCl
to pH about 5 (if necessary) and extracted with organic solvent. In the
screening experiments the cultures were extracted with 15 mL of ethyl
acetate. In preparative biotransformations the cultures were extracted
three times with 25 mL of ethyl acetate. Extracts were dried over an-
hydrous magnesium sulfate. Residues obtained by evaporation of sol-
vent were dissolved in methanol and analyzed by TLC and HPLC. Crude
product mixtures were separated by column chromatography on silica
gel 60 (230–400 mesh, Merck, Darmstadt, Germany) using chlor-
oform:methanol mixture (7:1, v/v) as eluent.
The structures of the obtained products were determined by means
of NMR (1H NMR, 13C NMR, HMBC, HSQC) and HR-ESIMS analysis.
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flavanone, derivative of diosmetin (4) without C2eC3 double bond,
was transformed by both tested strains to hesperetin 7-O-β-D-gluco-
pyranoside (25) and hesperetin 3′-O-β-D-glucopyranoside (27) what
suggests a great importance of the C2eC3 olefin bond in a substrate
recognition. Pinocembrin was converted to pinocembrin 7-O-β-D-glu-
copyranoside by A. coerulea AM 93 and A. glauca AM 177. Additionally,
in the reaction medium of A. coerulea AM 93 the second product,
containing glucose moiety at C5 position was observed, however in
trace amount only. Biotransformation of luteolin (3) and eriodictyol (7)
by A. coerulea AM 93 led to luteolin 3′-O-β-D-glucopyranoside (14) and
eriodictyol 7-O-β-D-glucopyranoside (23) respectively. The NMR
spectra analysis of 23 also confirms traces of luteolin 4′-O-β-D-gluco-
pyranoside. Strain A. glauca AM 177 is not capable of biotransforation
of luteolin (3) and eriodictyol (7).
Presented biotransformations processes performed by filamentous
fungi from the Absidia genus are an attractive method for production of
glucosylated flavonoids. Isolating of these compounds from plant ma-
terial it is not a trivial task. For example, extraction yield of luteolin 3′-
O-glucoside (14) from Verbascum salviifolium is only 0.006% [27]. In
turn, Wang and coworkers isolated diosmetin 3′-O-glucopyranoside
(17) from Saussurea stella with a yield of 0.0003% [28]. There are also
examples of obtaining flavonoid glucosides by chemical synthesis
[29–31]. A disadvantage of chemical glycosylation is a multistep
synthesis and the necessity of selective protection of hydroxyl groups to
avoid side products, what definitively results in a greater effort to ob-
tain a final product. In addition, the catalysts and chemicals used in
synthesis are harmful for the environment [32].
3.2. Spectral data of obtained products
The chemical structures of synthesized substrates (pinocembrin (5)
and eriodictyol (7)) and biotransformation products were determined
by NMR analysis (1H NMR, 13C NMR, COSY, HSQC, HMBC). All spec-
troscopic data (NMR, MS) are available in the Supplementary Materials.
Compounds 5, 7, 9, 10, 12, 14, 17, 19, 21, 23, 25 and 27 are
known. The NMR spectroscopic data for those compounds are con-
sistent with those reported in the literature [22,33–41].
Fig. 1. Flavonoid substrates.
of glycosylation reaction catalyzed by B. bassiana. The lack of a double
bond between the C2 and C3 carbon atoms in the substrate molecule
contributes to an increase in transformation efficiency. The yield of the
reactions catalyzed by the B. bassiana AM 278 enzyme system is sig-
nificantly higher in the reactions in which flavanones were used as
substrates, what might be associated with greater rigidity of a flavanone
skeleton. The biotransformation yield was also influenced by the posi-
tion of the B-ring - in comparison to the biotransformation of flavones,
biotransformations of isoflavones resulted in a slightly higher yield
[10]. It proves that not only state of C ring oxidation, but also B ring
position at flavonoid molecules, have fundamental importance on gly-
cosylation reaction catalyzed by B. bassiana AM 278.
A
glucose or methylglucose molecule, in all obtained bio-
transformation products were confirmed by additional characteristic 6
or 7 carbon signals observed in the region from δ = 59 ppm to
δ = 102 ppm in the 13C NMR spectra, coupled with proton signals be-
tween δ = 3.0–5.2 ppm in the 1H NMR spectra. Exemplary spectra of
aglycon - glucoside - methylglucoside forms for flavone and flavanone
are presented in the Supplementary Materials (Figs. S1 and S2).
The presence of a distinctive doublets at 1H NMR spectra from C1″
carbon atoms with a chemical shift in the δ 4.9–5.2 ppm range and a
coupling constant of 7.7–8.0 Hz clearly indicates that the attached
glucose molecules are β-anomers (Fig. S3, Supplementary Materials).
For compounds: 9, 11, 13, 15, 16, 18, 20, 22, 24, 26 a three-proton
singlets between δ 3.4–3.6 ppm in the 1H NMR spectrum correlated
with glucose C4 carbon signals at 78–79 ppm what indicates the O-
methylation of the sugar hydroxyl group (Fig. S4, Supplementary
Materials).
There are several reports that described the use of filamentous fungi
B. bassiana in flavonoid biotransformation. Attachment of 4″-O-me-
thylglucose is a characteristic reaction for this species [10–16,19–21].
Chrysin 7-O-β-D-4″-O-methylglucopyranoside (9) was previously ob-
tained by Herath and coworkers from chrysin using Beauveria bassiana
strain with the yield of 44.2% [22]. To our best knowledge, other fla-
vonoid derivatives with 4″-methylglucose molecule (11, 13, 15, 16,
18, 20, 22, 24, 26) obtained in our experiments are new compounds.
Interestingly, attachment of 4″-O-methylglucopyranoside to flavonoid
molecules have been also observed in biotransformation conducted by
other entomopathogenic fungi belonging to Isaria genus [23–26].
The position of glucose molecule attachment was determined by
HMBC spectra processing. For the products substituted in the C7 posi-
tion, the correlation of the proton bound to C1″ with the carbon atom
with a chemical shift in the range of 161–165 ppm was observed. In
turn, for products substituted in position C3′ the correlation of the
proton from position C1″ with the carbon atom with a chemical shift in
the range of 146 ppm was observed (Fig. S5, Supplementary Materials).
3.1.2. Biotransformations in Absidia coerulea AM 93 and Absidia glauca
AM 177 culture
Biotransformations of chrysin (1), apigenin (2) and naringenin (6)
by A. coerulea AM 93 and A. glauca AM 177 led to derivatives with the
glucose molecule attached at the C7 position of flavonoid skeleton (10,
12, 21). Reaction of diosmetin (4) – flavone with methoxyl group in
ring B, with Absidia species led to the metabolite containing glucose
molecule only at C3′ position (17). In turn, hesperetin (8) – the
4. Conclusions
A systematic study of the application of fungi A. glauca, A. coerulea
and B. bassiana for the preparation of natural glucosylated flavones and
flavanones have been undertaken.
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Fig. 2. Biotransformation products.
This and our previous studies [10–16] have shown that preferable
many flavonoids of different classes including chalcones, flavanones,
flavones, isoflavones, flavonols and aurones are accepted substrates for
glycosylation. However, yield of glycosylation strongly depends on the
type of flavonoid skeleton and substituents present in aromatic rings,
position of glycosylation catalyzed by mentioned fungal cultures is a
hydroxyl group bound to C7 in a flavonoid molecule. Moreover, low
substrate specificity of enzymes involved in the reaction causes that
4

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Table 1
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Biotransformation products (isolated yield)
B. bassiana AM 278
A. coerulea AM 93
A. glauca AM 177
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Chrysin (1)
Apigenin (2)
Luteolin (3)
Diosmetin (4)
9 (15%)
10 (23%)
12 (8%)
10 (14%)
12 (2%)
–
11 (15%)
13 (23%)
15 (7%)
16 (4%)
17 (7%)
18 (37%)
20 (82%)
22 (36%)
24 (38%)
26 (33%)
14 (18%)
17 (18%)
17 (15%)
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Pinocembrin (5)
Naringenin (6)
Eriodictyol (7)
Hesperetin (8)
19 (45%)
21 (73%)
23 (30%)
25 (36%)
27 (6%)
19 (38%)
21 (35%)
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This work was financed by the (Polish) National Science Centre,
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Supplementary data to this article can be found online at https://
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