Enzymatic O-Prenylation of Diverse Phenolic Compounds by a Permissive O-Prenyltransferase from the Medicinal Mushroom Antrodia camphorata

Article abstract of DOI:10.1002/adsc.201901396

Prenylated compounds are pharmacologically attractive natural products that are widely distributed in nature. Prenyltransferases (PTs) could catalyze the transfer of prenyl moieties to aromatic acceptors and increase the structural diversity and biological activity of natural products. In this work, a permissive O-prenyltransferase AcaPT was discovered from Antrodia camphorata, a precious medicinal mushroom in Taiwan. AcaPT exhibited robust O-prenylation capability toward structurally diverse drug-like phenolic compounds, including antrodins, flavonoids, and coumarins. In total, 23 O-prenylated products were obtained by scaled-up enzymatic synthesis. AcaPT could be used as an efficient biocatalyst to synthesize O-prenylated derivatives for drug discovery. (Figure presented.).

Full text of DOI:10.1002/adsc.201901396

Title: Enzymatic <i>O</i>-Prenylation of Diverse Phenolic Compounds
by a Permissive<i> O</i>-Prenyltransferase from the Medicinal
Mushroom <i>Antrodia camphorata</i>
Authors: Junbin He, Zhimin Hu, Zeyuan Dong, Bin Li, Kuan Chen,
Zhanpeng Shang, Meng Zhang, Xue Qiao, and Min Ye
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201901396
Link to VoR: http://dx.doi.org/10.1002/adsc.201901396

10.1002/adsc.201901396
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Enzymatic O-Prenylation of Diverse Phenolic Compounds by a
Permissive O-Prenyltransferase from the Medicinal Mushroom
Antrodia camphorata
Junbin Hea,†, Zhimin Hua,†, Zeyuan Donga, Bin Lia, Kuan Chena, Zhanpeng Shanga,
Meng Zhanga, Xue Qiaoa,* and Min Yea,*
a
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38
Xueyuan Road, Beijing 100191, China.
E-mail: qiaoxue@bjmu.edu.cn, yemin@bjmu.edu.cn
These authors contributed equally to this work.
†
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
nidulans catalyzed the O-prenylation of 1,7-
Abstract. Prenylated compounds are pharmacologically
attractive natural products that are widely distributed in dihydroxy-6-methyl-8-hydroxymethylxanthone and
analogues.[11] CnqPT1, a membrane-bound PT from
nature. Prenyltransferases (PTs) could catalyze the transfer
of prenyl moieties to aromatic acceptors and increase the
structural diversity and biological activity of natural
products. In this work, a permissive O-prenyltransferase
AcaPT was discovered from Antrodia camphorata, a
precious medicinal mushroom in Taiwan. AcaPT exhibited
robust O-prenylation capability toward structurally diverse
drug-like phenolic compounds, including antrodins,
flavonoids, and coumarins. In total, 23 O-prenylated
products were obtained by scaled-up enzymatic synthesis.
AcaPT could be used as an efficient biocatalyst to
synthesize O-prenylated derivatives for drug discovery.
Streptomyces sp. CNQ-509, catalyzed the O-
prenylation of phenazines.[12] PAPT from Phomopsis
amygdali catalyzed O-prenylation of the glucose 6'-
hydroxy group in the biosynthesis of fusicoccin A.[13]
Moreover, NovQ,[14] CdpNPT,[15] 7-DMATS,[15]
AstPT,[16] CdpC7PT,[17] AtaPT,[18] and AnaPT[15]
could respectively catalyze the O-prenylation of
aromatic substrates, such as phenylpropanoids,
flavonoids
(flavanone
and
isoflavone),
hydroxynaphthalenes, hydroxyxanthones, dipeptides,
stilbenes (resveratrol), acylphloroglucinols, and 4,4'-
dihydroxybenzophenone. However, majority of the
known PTs exhibit relatively narrow substrate spectra
in O-prenylation, and few of them have been applied
as biocatalysts to synthesize diverse O-prenylated
Keywords: Antrodia camphorata; enzyme catalysis;
prenylation; prenyltransferase; O-prenylation
derivatives. Herein, we report
a
new O-
prenyltransferase AcaPT (Antrodia camphorata
aromatic prenyltransferase) from A. camphorata,
which exhibited robust O-prenylation for various
types of aromatic acceptors and showed high catalytic
activities.
A. camphorata, known as “Niu-Chang-Chih” in
Chinese, is an endemic fungal species in Taiwan.[19] It
is a rare and expensive medicinal mushroom.[19,20]
Antrodins, including antrodin A, B (1a), and C, are
its characteristic metabolites.[3a,3b,21] The main
skeleton of antrodins is composed of butanedioic or
butenedioic anhydride with an isobutyl moiety and a
Prenylation is
a
ubiquitous reaction in the
biosynthesis of bioactive natural products in plants,
bacteria, and fungi.[1] The introduction of prenyl
moieties may increase the lipophilicity of natural
products and thus enhance their affinity to biological
membranes.[1a,2] In particular, the modification with
an O-prenyl group could significantly increase the
bioactivity.[1c,3] However, chemical synthesis of O-
prenylated compounds remains difficult due to poor
selectivity, and the protection and deprotection steps
of functional groups.[4]
Prenyltransferases (PTs) catalyze the transfer of
prenyl moieties to aromatic acceptors and increase
the structural diversity and biological activity of
natural products.[5] Recently, a number of O-PTs have
been identified to catalyze O-prenylation reactions.
For example, SirD,[6] TyrPT,[7] FtmPT3,[8] PgaF,[9]
and LynF[10] could catalyze the O-prenylation of
indole compounds including tyrosine and its
derivatives. The xanthone PT XptB from Aspergillus
Fig. 1 Structures of antrodin A, B (1a), and C.
1
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10.1002/adsc.201901396
Advanced Synthesis & Catalysis
para-substituted (O-prenylated or hydroxylated)
phenyl ring (Figure 1), which indicate the presence of
O-prenyltransferases. In this work, we analyzed the
genome sequence (GenBank assembly accession:
GCA_003413585.1)
and
transcriptome
data
(SRR1258114, SRR1258115, and SRR1258116) of A.
camphorata to mine the O-prenyltransferase genes.
Bioinformatics analysis on the antiSMASH 4.0
platform[22] combined with transcriptome analysis
identified a putative antrodin (ant) biosynthetic gene
cluster with 19 coding sequences (Table S1).
Intriguingly, a putative core gene antM, tentatively
named AcaPT, was annotated as an aromatic
prenyltransferase (aPTase). The coding region of
AcaPT (GenBank accession No. MN577949)
contains an open reading frame (ORF, 1350 bp)
encoding 449 amino acids (theoretical molecular
weight 50.6 kDa). Further sequence analysis
indicated that AcaPT shares high sequence identity
(76%) with
a
predicted O-prenyltransferase
(GenBank accession number GBE88132) from
Sparassis crispa.[23] Also, AcaPT shares 33% and
27% sequence identity with SirD[6] and TyrPT,[7]
respectively. Phylogenetic relationship analysis
demonstrated that AcaPT belonged to the
dimethylallyltryptophan synthase (DMATS) family
and was grouped together with the O-
prenyltransferase SirD (Figure S1 and Table S2).
These evidences indicated that AcaPT may be an O-
prenyltransferase.
To confirm the above speculations, we cloned the
AcaPT gene from A. camphorata by RT-PCR (Table
S3). Recombinant AcaPT was expressed in
Escherichia coli and subsequently purified by His-tag
affinity chromatography (purity above 95% by SDS-
PAGE, Figure S2).
Figure 2. O-prenylation of 1 catalyzed by recombinant
AcaPT. (A) The catalytic reaction. (B) HPLC
chromatograms of 1 and the enzymatic product 1a. (C) (+)-
ESI-MS/MS spectrum of 1a. (D) HMBC spectrum of 1a
1
(CDCl3, 400 MHz). The HPLC conditions and the H and
13C NMR spectroscopic data of 1a are given in the
Supporting Information (Table S4, Figures S23–S25).
Although AcaPT could prenylate 1 to form 1a, the
conversion rate was approximately 28% (Figure S3).
We also tested 34 (the putative precursor of antrodin
A) as the prenyl acceptor, and the conversion rate
was around 2% (Figure S4). While antrodins had
been detected in the mycelia and fruiting bodies of A.
camphorata, none of them were detected in this
study,[24] probably due to different cultivation
conditions. These limited our exploration of the
catalytic function of AcaPT in vivo.
To identify the O-prenylation activity of AcaPT in
vitro, compound 1, the proposed biosynthetic
precursor, was used as the prenyl acceptor, and
dimethylallyl diphosphate (DMAPP) was used as the
donor. The reaction mixture (50 mM Tris-HCl buffer
(pH 7.0), 0.2 mM 1, 0.4 mM DMAPP, and 100 μg of
purified AcaPT; 37 C, 12 h) was analyzed by liquid
chromatography coupled with mass spectrometry
(LC/MS). Heat-inactivated AcaPT (boiled at 100 °C
for 15 min) was used as the negative control.
Convincingly, one product (1a) with lower polarity
was observed in the enzymatic reaction catalyzed by
AcaPT (Figure 2). Compound 1a showed an [M+H]+
ion at m/z 314, 68 amu greater than 1, indicating
mono-prenylation of 1. The product was subsequently
To further explore the substrate promiscuity and
probe the synthetic utility of AcaPT in O-prenylation,
96 structurally diverse aromatics (Figure 3, Figures
S5–S148) were tested as acceptors, and DMAPP as
the donor. LC/MS analysis revealed that AcaPT
could catalyze the prenylation of 53 substrates (1–53)
(Tables S4 and S5). Particularly, AcaPT exhibited
robust substrate promiscuity towards various drug-
like natural products, including maleic and succinic
acid derivatives (1 and 34), flavonoids and glycosides
(2–23, 35–43), coumarins (24, 25, 44–46), curcumins
(26–28), amino acids (29, 48, 49, 51), stilbenes (30
prepared via
a
preparative-scale reaction for
structural characterization. The HMBC correlation
from H-1''' (δH 4.56) to C-4'' (δC 160.2) indicated the
dimethylallyl group was linked to C-4''. The NMR
and 31), benzophenones (32, 52, 53),
a
spectroscopic data of 1a were in good agreement with
[3a,3b,21]
hydroxynaphthalene (33), and an indole alkaloid (50).
For 9 substrates (9, 10, 13, 20, 21, 23, 28, 30, 33), the
total conversion rates were >75%. Particularly,
AcaPT showed high catalytic capabilities toward
isoflavones (9 and 10) and isoflavans (20 and 21).
previously reported results,
and thus 1a was
identified as antrodin B. These results unambiguously
established AcaPT as an O-prenyltransferase that
catalyzes the O-prenylation reaction to synthesize
antrodins in vitro. To our knowledge, AcaPT is the
first identified PT from Antrodia genus.
2
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10.1002/adsc.201901396
Advanced Synthesis & Catalysis
Figure 3. Substrate promiscuity of AcaPT. (A) Conversion rates of different substrates. Experiments were performed in
triplicate. DMAPP was used as the prenyl donor. The colors in the bar graphs represent conversion ratios of different
prenylated products. Tested substrates with low conversions (<5%) are shown in Figure S5. (B) Structures of the substrates
used as prenyl acceptors. Tested substrates with no conversions are shown in Figure S6. * indicates the prenylated
products were isolated and their structures were characterized by MS and NMR analyses. ∆ represents new compounds.
Moreover, AcaPT could prenylate some substrates (9,
10, 16, 20, 21, 25, 27, 33) at different sites, and the
diprenylated products were obtained for 9 and 10.
To fully identify structures of the prenylated
products, we conducted preparative-scale reactions
and purified the enzymatic products. In total, we
obtained 26 prenylated products (1a, 3a, 6a, 7a, 9a–
9c, 10a–10c, 13a, 20a–20c, 23a, 24a, 26a, 27a, 27b,
29a, 30a–32a, and 33a–33c), 12 of which are new
compounds. Their structures were identified by HR-
ESI-MS, 1D and 2D NMR analyses (Figures S23–
S148). All the compounds are O-prenylated products
except that 20c, 29a, and 33c are C-prenylated
products. It should be noted that AcaPT could
catalyze the prenylation of L-tryptophan at C-7,
which is similar to the O-PTs SirD[6b,6c] and TyrPT.[7]
The above results cumulatively demonstrated that
AcaPT is a permissive O-prenyltransferase, which
exhibited unexpected O-prenylation capability toward
drug-like aromatics. To the best of our knowledge,
AcaPT is the first PT to synthesize O-prenylated
flavones, flavonols, chalcones, isoflavans, flavonoid
glycosides, curcumins, and umbelliferone with
DMAPP as the donor. It has remarkably broader
This finding indicated AcaPT as a powerful
enzymatic tool for the synthesis of O-prenylated
derivatives.
To demonstrate the donor selectivity of AcaPT,
five other prenyl donors including isopentenyl
pyrophosphate (IPP), geranyl diphosphate (GPP),
farnesyl
diphosphate
(FPP),
geranylgeranyl
diphosphate (GGPP), and phytyl diphosphate (PPP)
were individually tested using representative
substrates (1, 10, 24, 26, 29, 30, 33 and 34) as
acceptors. LC/MS analysis revealed that no
prenylated products were observed (Figure S149).
This result demonstrated that only DMAPP could be
recognized by AcaPT.
We further determined the biochemical properties
and kinetic parameters of AcaPT. It exhibited its
maximum activity at pH 7.0 and 37 °C, and was
independent of divalent cations (Figure S150).
Notably, Co2+, Fe2+, Sn2+, Ni2+, and Zn2+ could
significantly inhibit the enzyme activity. Kinetic
studies demonstrated that AcaPT exhibited Km values
of 128.5 μM and 27.3 μM for 1 and DMAPP,
respectively. The Km values for 29 and DMAPP were
respectively 188.3 μM and 222.9 μM (Figure S151),
substrate promiscuity than previously reported O-PTs. which were slightly higher than that for 1. The results
3
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10.1002/adsc.201901396
Advanced Synthesis & Catalysis
grade methanol and acetonitrile were purchased from
Damao Chemical Reagent Factory (Tianjin, China).
indicated that AcaPT showed relatively higher
affinity to 1 (O-prenylated substrate) than 29 (C-
prenylated substrate). Also, the Km value for 29 (L-
tryptophan) in the presence of DMAPP was lower
than the reported O-PTs SirD (Km=230 μM)[6a] and
TyrPT (Km=190 μM),[7] but higher than 7-DMATS
(Km=140 μM).[15]
We further tested the biotransformation of selected
substrates (1, 10, 26, 29, and 30) by whole E. coli
cells harboring AcaPT. The results revealed that the
conversion rates for 10, 26, and 30 by AcaPT in vivo
were identical to that of the purified enzyme, whereas
the conversion rates for 1 (3.1%) and 29 (16.8%)
were significantly lower than that of the purified
enzyme (Figure S152). The difference may be due to
different reaction microenvironments around proteins
and the substrate solubility between in vitro and in
vivo.
We have also tried to elucidate the catalytic
mechanism of AcaPT by homology modelling and
molecular docking. We used two homologous PTs
FgaPT2 (PDB: 3I4X) and AnaPT (PDB: 4LD7) as
the templates. Unfortunately, we failed to obtain
satisfactory protein model. Further work will be
conducted to determine the protein structure to
provide insights into the molecular basis of AcaPT.
In summary, AcaPT represents the first identified
PT from Antrodia genus. It exhibited unprecedented
O-prenylation capability and high catalytic efficiency
toward different types of drug-like natural and
unnatural products. A total of 23 O-prenylated
products including 11 new compounds were obtained.
AcaPT could be an efficient biocatalyst to synthesize
O-prenylated derivatives through either enzymatic
reactions or whole cell biotransformations.
Methods
AcaPT was amplified by PCR, and the gene fragment was
then inserted into plasmid pET-28a(+) (Invitrogen, USA).
The recombinant plasmid was then transformed into
Escherichia coli BL21 (DE3) (TransGen Biotech, China)
for heterologous expression. Recombinant AcaPT was
purified using His-tag affinity chromatography. The
prenylated products were analyzed by HPLC on an Agilent
1290 instrument equipped with a diode-array detector
(DAD) (Agilent Technologies, Waldbronn, Germany).
LC/MS analyses were performed on an LCQ Advantage
ion-trap mass spectrometer (Thermo Fisher, CA, USA)
equipped with an electrospray ionization (ESI) source. The
prenylated products were isolated and purified by semi-
preparative HPLC on an Agilent 1200 instrument (Agilent).
HR-ESI-MS spectra were obtained on a Thermo Scientific
Q-Exactive Focus spectrometer. NMR spectra were
recorded on a Bruker AVANCE III-400 instrument at 400
1
MHz for H and 100 MHz for 13C, or a Bruker AVANCE
1
III-600 instrument operating at 600 MHz for H and 150
MHz for 13C in CDCl3 or DMSO-d6, using TMS as
reference. The detailed experimental procedures, including
gene mining, gene cloning, protein expression and
purification, SDS-PAGE analysis, biochemical properties
of
AcaPT,
LC/MS,
HR-ESI-MS,
and
NMR
characterization data and spectra of prenylated products as
well as analytical protocols can be found in the Supporting
Information.
Acknowledgements
This work was supported by National Natural Science
Foundation of China (81725023, 81891010/81891011,
81921001), Beijing Natural Science Foundation (JQ18027), and
Young Elite Scientists Sponsorship Program by China
Association for Science and Technology (2016QNRC001).
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10.1002/adsc.201901396
Advanced Synthesis & Catalysis
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