Synthesis of Unnatural 2-Substituted Quinolones and 1,3-Diketones by a Member of Type III Polyketide Synthases from Huperzia serrata

Article abstract of DOI:10.1021/acs.orglett.6b01501

A curcuminoids, benzalacetone-, and quinolone-producing type III polyketide synthase (HsPKS3) from Huperzia serrata uniquely catalyzes the formation of unnatural 2-substituted quinolones and 1,3-diketones via head-to-head condensation of two completely different substrates. The broad range of substrate tolerance of HsPKS3 facilitates accessing structurally diverse 2-substituted quinolones and 1,3-diketones.

Full text of DOI:10.1021/acs.orglett.6b01501

Letter
pubs.acs.org/OrgLett
Synthesis of Unnatural 2‑Substituted Quinolones and 1,3-Diketones
by a Member of Type III Polyketide Synthases from Huperzia serrata
Juan Wang,†,‡ Xiao-Hui Wang,† Xiao Liu,† Jun Li,† Xiao-Ping Shi,†,‡ Yue-Lin Song,† Ke-Wu Zeng,§
Le Zhang,†,‡ Peng-Fei Tu,*,† and She-Po Shi*,†
†Modern Research Center for Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
‡School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, China
§State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China
S
* Supporting Information
ABSTRACT: A curcuminoids, benzalacetone-, and quinolone-
producing type III polyketide synthase (HsPKS3) from
Huperzia serrata uniquely catalyzes the formation of unnatural
2-substituted quinolones and 1,3-diketones via head-to-head
condensation of two completely different substrates. The broad
range of substrate tolerance of HsPKS3 facilitates accessing
structurally diverse 2-substituted quinolones and 1,3-diketones.
residues lining the active-site cavity could dramatically change
the catalytic functions.1,3 Therefore, screening novel type III
PKSs from plants and probing their catalytic potentials would
be not only advantageous to understand the biosynthesis of
plant metabolites but also instructive to enzymatically or
biomimetically synthesize structurally diverse and chemically
complex unnatural natural products.
ype III polyketide synthases (PKSs) are a class of
Tarchitecturally simple homodimeric proteins that catalyze
iteratively decarboxylative condensations of a starter coenzyme
A (CoA) thioester and C2 units derived from malonyl-CoA to
produce a dazzling array of secondary metabolites contributing
to plant defense and human health.1 A representative example
is that chalcone synthase (CHS) catalyzes sequential
condensations of p-coumaroyl-CoA with three molecules of
malonyl-CoA to produce naringenin chalcone (Scheme 1A).2
Despite the fact that type III PKSs share a common three-
dimensional overall fold and utilize an identical catalytic triad of
Cys-His-Asn, the catalytic functions of type III PKSs are
extremely divergent, and a subtle variation of the amino acid
2-Substituted quinolones and 1,3-diketones are two classes of
natural products with a broad spectrum of biological activities,
such as antibacterial, antitumor, and antioxidative activities.4 In
addition, 1,3-diketones are synthetically useful intermediates in
heterocyclic chemistry. The high reactivity of the electrophilic
carbonyl carbons and the nucleophilic methylene facilitates
accessing a variety of pharmaceutically important heterocyclic
compounds such as isoxazoles, pyrazoles, and pyrimidines.5
Although chemical syntheses of 2-substituted quinolones and
1,3-diketones have been extensively reported,6 enzymatic
syntheses of these two kinds of scaffolds are currently confined
to a handful of compounds such as curcuminoids. Regarding
the enzymatic synthesis of curcuminoids, a two-step reaction
mechanism involving two type III PKSs, diketide-CoA synthase
(DCS) and curcumin synthase (CURS) from Curcuma longa
(Scheme 1B),7 and a one-pot reaction mechanism involving a
single type III PKS (CUS) from Oryza sativa have been
reported.8
Scheme 1. Formation of (A) Naringenin Chalcone by CHS
and (B) Curcumin by DCS and CURS
Herein, we report a new type III PKS (HsPKS3) from
Huperzia serrata and enzymatic synthesis of a variety of
unnatural 2-substituted quinolones and 1,3-diketones by
HsPKS3 (Figure 1A).
Received: May 24, 2016
© XXXX American Chemical Society
A
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Figure 1. Products and substrates. (A) Representative products enzymatically synthesized by HsPKS3. Compounds P01−P06, P1a, P12, and P15
were identified using authentic compounds (Supporting Information, Figures S3−S9); compounds P07−P11, P13, P14, and P16−P18 were
elucidated on the basis of their HRESIMS and NMR data (Supporting Information, Tables S1−S3, Figures S10−S50). (B) Synthesized starters. (C)
Synthesized extenders. The numbers in parentheses represent the yield of each enzymatic product. Note: 1,3-Diketones produced by HsPKS3 are
presented as a relatively stable enol form.
Using a homologous cloning strategy, a new type III PKS
(HsPKS3) was successfully cloned from the leaves of H. serrata.
The full-length cDNA of HsPKS3 contained a 1239 bp ORF
encoding a protein with 413 amino acids including the Cys-His-
Asn catalytic triad conserved in all known plant type III PKSs.
Sequence alignment revealed that HsPKS3 shared 60.53%
amino acid identity with HsPKS1 from H. serrata,9 44.36% with
CUS from O. sativa,8 47.94% with BAS from R. palmatum,10
47.46% with CURS from C. longa,7 50.61% with QNS from
A. marmelos,11 and 56.42% with CHS from M. sativa,2
respectively. Phylogenetic analysis revealed that HsPKS3 was
grouped into nonchalcone synthases.
Incubation of p-coumaroyl-CoA (S01), malonyl-CoA, and
the recombinant enzyme HsPKS3 resulted in the production of
a diarylheptanoid scaffold of bisdemethoxycurcumin (P01),
accompanying the formation of a C6−C3 scaffold of p-
HsPKS3 from (A) p-hydroxyphenylpropinoyl-CoA, N-methylanthra-
Figure 2. HPLC chromatograms of the reaction products produced by
hydroxybenzalacetone (P1a). Further investigations revealed
that HsPKS3 could also catalyze the formation of various
diarylheptanoids (P02−P05) from cinnamoyl-CoA analogues
(S02−S05). Interestingly, HsPKS3 accepts nitrogen-contain-
ing, bulky N-methylanthraniloyl-CoA (S06) as a starter to
produce quinolone alkaloid P06. To the best of our knowledge,
HsPKS3 is the first type III PKS with the multifunctions
producing benzalacetone, curcuminoids, and a quinolone
alkaloid.
When p-hydroxyphenylpropinoyl-CoA (S05) was incubated
with N-methylanthraniloyl-CoA (S06) and malonyl-CoA, the
enzyme reaction generated an unknown product (P07) (Figure
2A). The HRESIMS spectrum of P07 showed the presence of a
protonated ion at m/z 280.1336 ([M + H]+), consistent with
an empirical molecular formula of C18H17NO2. Analysis of the
1D- and 2D-NMR spectra allowed establishing the structure of
P07 as 2-(4-hydroxyphenethyl)-1-methylquinolin-4(1H)-one.
Considering that HsPKS3 could not produce a head-to-head
condensation product from two molecules of N-methylan-
niloyl-CoA, and malonyl-CoA; (B) N-methylanthraniloyl-CoA and 3-
oxodecanoic acid; (C) p-hydroxyphenylpropinoyl-CoA, benzoyl-CoA,
and malonyl-CoA; (D) salicyloyl-CoA and 3-oxo-5-phenylpentanoic
acid. SA represents the abbreviation of salicylic acid.
thraniloyl-CoA (S06) and malonyl-CoA, the mechanism of the
quinolone alkaloid (P07) formation was proposed as follows:
HsPKS3 first catalyzed the condensation of p-hydroxyphenyl-
propinoyl-CoA and malonyl-CoA to produce a β-keto acid
intermediate (Scheme 2A), and then, the β-keto acid
intermediate serves as the second extender, performing the
ongoing head-to-head condensation with N-methylanthraniloyl-
CoA to form a 1,3-diketone intermediate, followed by
nucleophilic attack of a carbonyl carbon by a nitrogen atom
to produce the final product (Scheme 2B). Further co-
incubation of cinnamoyl-CoA analogues (S01−S04) with N-
methylanthraniloyl-CoA and malonyl-CoA yielded quinolone
alkaloids (P08−P11). However, when octanoyl-CoA (S07) was
incubated with N-methylanthraniloyl-CoA (S06) and malonyl-
B
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(Figure 1B), including aromatic-CoAs (S01−S05, S09, S10,
and S17), aliphatic-CoAs (S07, S14, and S19), heteroaromatic-
CoAs (S11, S15, S16, and S18), and bulky anthraniloyl-CoA
analogues (S06, S08, S12, S13, and S20), were prepared and
co-incubated with 3-oxodecanoic acid (E01), and the reaction
mixtures were analyzed by LC-MS (Supporting Information,
Figures S52−S71). The results revealed that HsPKS3 could
efficiently catalyze head-to-head condensations of 3-oxodeca-
noic acid with all the synthesized starters to produce
structurally diverse 1,3-diketones. However, when S10 and
S20 were used as starters, only trace amounts of 2-
heptylchromone- and 2-heptylquinolone-type products could
be detected by LC-MS. Unexpectedly, incubation of 3-
oxodecanoic acid (E01) with 2-carbamoylbenzoyl-CoA (S12)
produced (Z)-2-(3-hydroxydec-2-enoyl)benzonitrile (P18), the
structure of which was confirmed by co-incubation of E01 with
designedly synthesized 2-cyanobenzoyl-CoA (S13). Consider-
ing that S12 was poorly accepted by HsPKS3 and slowly
changed into 2-cyanobenzoic acid in the reaction medium, it
was tentatively proposed that the dehydration might sponta-
neously occur in the reaction buffer. For the purpose of further
confirmation of the enzymatic products, P18 from 2-
carbamoylbenzoyl-CoA (S12), the long-chain alphatic 1,3-
diketone (P16) from octanoyl-CoA, and nitrogen-containing 1-
(1H-indol-2-yl) decane-1,3-dione (P17) from indole-2-carbon-
yl-CoA (S11) were prepared by large-scale reactions, and their
structures were unambiguously elucidated on the basis of their
HRESIMS and NMR data. In order to probe the extender
tolerance of HsPKS3, β-keto acids (E01−E04) and β-keto acid
thioesters of N-acetyl cysteamine (NAC) (E05 and E06) were
synthesized and incubated with feruloyl-CoA (S02) (Support-
ing Information, Figures S72−S76). HsPKS3 could accept
various extenders including 3-oxo-4-phenylbutanoic acid (E04),
very long chain 3-oxooctadecanoic acid (E02), and structurally
stable β-keto acid thioesters of NAC (E05 and E06) to produce
1,3-diketones. For example, head-to-head condensation of 3-
oxo-4-phenylbutanoic acid and feruloyl-CoA (S02) could
produce a diarylhexanoid scaffold.
Scheme 2. HsPKS3 Catalyzed the Formation of β-Keto Acid
Intermediate (A), 2-Substituted Quinolones (B and C),
Diarylpentanoid (D), and 2-(2-Phenylethyl)chromone (E)
CoA, only an LC-MS-detectable quinolone alkaloid was
produced, which was presumably caused by the poor capability
of forming a β-keto acid intermediate from the condensation of
octanoyl-CoA and malonyl-CoA. Accordingly, 3-oxodecanoic
acid (E01) was chemically synthesized and incubated with N-
methylanthraniloyl-CoA (S06). Expectedly, a single product, 2-
heptyl-N-methylquinolin-4(1H)-one (P12), was obtained with
respectable yield (Figure 2B, Scheme 2C). By replacement of
N-methylanthraniloyl-CoA (S06) with anthraniloyl-CoA (S08),
2-heptyl-quinolin-4(1H)-one could be synthesized by HsPKS3.
Moreover, HsPKS3 could also catalyze a head-to-head
condensation of very long chain 3-oxooctadecanoic acid
(E02) and N-methylanthraniloyl-CoA to produce quinolone
alkaloids (Supporting Information, Figure S51), suggesting the
great potential of HsPKS3 in enzymatic synthesis of 2-
substituted quinolones with flexible variation of the alkyl
chain length.
HsPKS3 catalyzing the formation of 2-substituted quinolone
from two completely different starters motivated us to explore
the potential of HsPKS3 in the synthesis of unnatural 1,3-
diketone scaffolds. Considering that curcumin-like diary-
lpentanoids possess diverse biological activities such as anti-
inflammatory, antioxidant, and antityrosinase activities,12 syn-
thesis of a diarylpentanoid scaffold using HsPKS3 was tested.
Expectedly, a diarylpentanoid (P13) were produced from the
condensation of benzoyl-CoA (S09), p-hydroxyphenylpropi-
noyl-CoA (S05), and malonyl-CoA (Figure 2C, Scheme 2A
and D). Likewise, (E)-5-(4-hydroxyphenyl)-1-phenylpent-4-
ene-1,3-dione (P14) could also be synthesized from p-
coumaroyl-CoA. Interestingly, co-incubation of HsPKS3 with
salicyloyl-CoA (S10) and 3-oxo-5-phenylpentanoic acid (E03)
led to the formation of a small amount of 2-(2-phenylethyl)-
chromone (P15) (Figure 2D, Scheme 2E).
Compounds P07−P11, P13, P14, and P16−P18 were
evaluated for their inhibitory activities against LPS-activated
NO production in BV-2 microglial cells. Compounds P08, P13,
P17, and P18 showed inhibitory activity against NO
production with IC50 values in the range 15.7−29.8 μM
(Supporting Information, Table S4).
Despite the fact that both CURS from Curcuma and CUS
from O. sativa could catalyze the formation of 1,3-diketone
scaffolds via head-to-head condensation, these two enzymes
reportedly utilize cinnamoyl-CoA analogues as starters, and the
products are, accordingly, confined to curcuminoids and
gingerol analogues.7,8 Distinguished from the stepwise synthesis
of curcumin by DCS and CURS,7 HsPKS3 catalyzing the one-
pot formation of curcuminoids seems much like rice CUS.8
However, production of p-hydroxybenzalacetone and quino-
lone by CUS has never been reported. Irrespective of the
divergent functions producing benzalacetone, curcuminoids,
and quinolone, HsPKS3 reported here has a broad range of
substrate tolerance, which facilitates synthesizing a vast array of
structurally diverse 1,3-diketones. Remarkably, HsPKS3 un-
precedentedly catalyzes the formation of 2-substituted
quinolones from a 1,3-diketone intermediate via intramolecular
cyclization, greatly expanding the structural diversity and
chemical complexity of the enzymatic products. On the other
hand, 2-substituted quinolones extensively occurred in
In order to further probe the extremely promiscuous catalytic
potential of HsPKS3, structurally varied starters (S01−S20)
C
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Rutaceae plants and Pseudomonas bacteria.13 In Pseudomonas
bacteria, the biosynthesis of 2-substituted quinolones requires
the PqsABCD enzymes coded by the pqsABCD operon.14
Enzymes in plants responsible for the biosynthesis of 2-
substituted quinolones are currently little understood. Despite
that 1,3-diketones and quinolones synthesized here have not
been reported from H. serrata, and HsPKS3 catalyzing the
formation of 2-substituted quinolones and 1,3-diketones would
be instructive to understand the biosynthesis of these two kinds
of natural products and irradiative to biomimetic synthesis of
structurally diverse unnatural 2-substituted quinolones and 1,3-
diketones.
In summary, we have identified a unique type III PKS with
multifunctions producing curcuminoids, benzalacetone, and
quinolone. Probing the catalytic promiscuity of HsPKS3 with
synthesized starters led to the synthesis of various 2-substituted
quinolones and 1,3-diketones. The broad range of substrate
tolerance of HsPKS3 facilitates accessing structurally diverse 2-
substituted quinolones and 1,3-diketones.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01501.
Experimental section (general experimental procedures,
cDNA cloning, expression of cDNA, enzyme purification,
enzyme reaction, and anti-inflammatory assay), phyloge-
netic analysis, alignment of amino acid sequence, full
spectroscopic data (NMR, HRESIMS) for P07−P11,
P13, P14, and P16−P18, and LC-MS data for enzymatic
reactions (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
(8) (a) Katsuyama, Y.; Matsuzawa, M.; Funa, N.; Horinouchi, S. J.
Biol. Chem. 2007, 282, 37702. (b) Morita, H.; Wanibuchi, K.; Nii, H.;
Kato, R.; Sugio, S.; Abe, I. Proc. Natl. Acad. Sci. U. S. A. 2010, 107,
19778.
*E-mail: pengfeitu@163.com.
*E-mail: shishepo@163.com. Tel/Fax: +86-10-64286350.
Notes
(9) Wanibuchi, K.; Zhang, P.; Abe, T.; Morita, H.; Kohno, T.; Chen,
G.; Noguchi, H.; Abe, I. FEBS J. 2007, 274, 1073.
The authors declare no competing financial interest.
(10) Abe, I.; Takahashi, Y.; Morita, H.; Noguchi, H. Eur. J. Biochem.
2001, 268, 3354.
(11) Resmi, M. S.; Verma, P.; Gokhale, R. S.; Soniya, E. V. J. Biol.
Chem. 2013, 288, 7271.
(12) Lee, K.-H.; Ab Aziz, F. H.; Syahida, A.; Abas, F.; Shaari, K.; Israf,
D. A.; Lajis, N. H. Eur. J. Med. Chem. 2009, 44, 3195.
ACKNOWLEDGMENTS
■
This work was financially supported by the National Natural
Science Foundation of China (Grant No. 81573312), Beijing
Natural Science Foundation (No. 5132022), and Graduate
Independent Project in Beijing University of Chinese Medicine
(No. 2015-JYB-XS059).
(13) da Silva, M. F. G. F.; Soares, M. S.; Fernandes, J. B.; Vieria, P. C.
Alkaloids Chem. Biol. 2007, 64, 139.
(14) Dulcey, C. E.; Dekimpe, V.; Fauvelle, D.-A.; Milot, S.; Groleau,
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