Prenylated flavonoids, promising nutraceuticals with impressive biological activitiesReview
Prenylated
Jianga, Jiali Yanga,b, Jirui Hea,b, Jian Sunc, Feng Chend, Mingwei
Zhange and Bao Yanga,* aKey Laboratory of Plant Resources Conservation and
Sustainable Utilization, Guangdong Provincial Key
Laboratory of Applied Botany, South China Botanical
Garden, Chinese Academy of Sciences, Guangzhou
510650, China (Tel.: D86 20 37083042; fax: D86 20 37252960; e-mail: yangbao@scbg.ac.cn)
bUniversity of Chinese Academy of Sciences, Beijing
100039, China cInstitute of Agro-food Science & Technology, Guangxi
Academy of Agricultural Sciences, Nanning 530007,
China dDepartment of Food Science and Human Nutrition,
Clemson University, Clemson, SC 29634, USA eSericultural & Agri-Food Research Institute,
Guangdong Academy of Agricultural Sciences/Key
Laboratory of Functional Foods, Ministry of
Agriculture/Guangdong Key Laboratory of Agricultural
Products Processing, Guangzhou 510610, China
Prenylated flavonoids have attracted much attention as a novel
type of nutraceuticals in late years. The main structural charac-
teristics and biological activities of prenylated flavonoids are
reviewed in this paper. Usually prenylated flavonoids have a
low abundance in nature and are complicated to be
chemically synthesized, which limits the applications in die-
tary supplements and medicines. Biotransformation is a prom-
ising alternative to solve this problem due to the advantages of
high specificity, easy manipulation and good productivity. The
key to this technique is to find an effective flavonoid prenyl-
transferase. Detailed information regarding biotransformation
and flavonoid prenyltransferase is reviewed in this paper.
Introduction Prenylated flavonoids are a sub-class of flavonoids, which combine a flavonoid skeleton with a lipophilic prenyl side-chain. Flavonoids are quite abundant in nature, while prenylated flavonoids are much less common. To date, pre- nylated flavonoids have been identified in 37 of plant genera. Prenylation usually renders flavonoids with improved bioactivities. The mechanism of action is preny- lation increases the lipophilicity of flavonoids, which re- sults in a higher affinity to biological membranes and a better interaction with target proteins (Xu et al., 2012). De- pending on the length of prenyl side-chain and flavonoid skeletons, prenylated flavonoids have diverse structures. Flavonoids, including chalcones, flavones, flavanones and flavonols, have been found to be prenylated in plant sec- ondary metabolites.
In planta prenylated flavonoids are considered as phyto- alexins (Botta, Vitali, Menendez, Misiti, & Monache, 2005), which play a key role in physiological processes when defending against pathogenic microorganisms. As a class of bioactive compounds, prenylated flavonoids possess a wide variety of bioactivities, such as estrogenic activity, antioxidant activity, immunomodulatory activity and anticancer activity (Bruno Botta, Vitali et al., 2005; Cerqueira et al., 2003). However, the natural abundance of prenylated flavonoids is pretty low, which limits the application of these bioactive compounds in pharmaceuti- cals. In vitro synthesis is a good way to solve this problem, and chemical synthesis is the first thought coming to a re- searcher’s mind. However, in most cases chemical synthesis is quite complicated, has low efficiency and is time- consuming for synthesis of specific prenylated flavonoids. Harsh synthesis conditions and occurrence of many byprod- ucts make chemical synthesis difficult to be applied in large scale production. The development of cost-effective biotransformation techniques in recent years, which use fla- vonoids prenyltransferase as a catalysis agent, makes
Fig. 2. Prenylation patterns occurred on flavonoids.
94 X. Yang et al. / Trends in Food Science & Technology 44 (2015) 93e104
specific synthesis of prenylated flavonoids possible. The key is to find an efficient and stable flavonoid prenyltrans- ferase. In this article, recent information regarding struc- tural characteristics, in vitro bioactivities and synthesis of prenylated flavonoids is reviewed.
Structural characteristics of prenylated flavonoids Prenylation has been detected on most of flavonoids,
including chalcones, flavanones, flavones, flavonols and iso- flavones (Barron & Ibrahim, 1996). Approximately 1000 prenylated flavonoids have been identified from plants. Ac- cording to the number of prenylated flavonoids reported before, prenylated flavonones is the most common sub- class and prenylated flavanols is the rarest sub-class. In gen- eral, C-prenylation on flavonoids is much more popular than O-prenylation (Barron & Ibrahim, 1996), which is usually synthesized by substitution of hydroxyl group on flavonoid skeleton (Fig. 1). The first reported O-prenylated flavonoids were 40,5-dihydroxy-7-isopentenyloxyflavanone and 5- hydroxy-7-isopentenyloxyflavanone from Helichrysum athrixiifolium (Bohlmann&G€oren, 1984).C-prenylation oc- curs frequently on ring A at C-6/C-8 and ring B at C-30 and C-50, which is usually ortho to a phenolic hydroxyl.C-preny- lation at ring C is relatively rare in natural prenylated flavo- noids. Fig. 2 shows the prenylation patterns at flavonoids skeleton. Among numerous prenylation groups, 3,3- dimethylallyl group is the most common pattern presented. Geranyl and farnesyl flavonoids are also well known in nat- ural prenylated flavonoids. Further oxidation, cyclization,
O
O
O
O
O
O
O
O
A
B
C
Fig. 1. Flavonoid skeletons.
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dehydration and reduction can lead to more modifications of terpenoid chains. It is worthy to mention that cyclization of isopentenyl with ortho-phenolic hydroxyl to form a six- membered pyran derivative is often found in plants, such as Artocarpus heterophyllus (Zheng et al., 2009).
The plant resources of prenylated flavonoids Even though natural prenylated flavonoids have been de-
tected to have diversely structural characteristics, they have a narrow distribution in plants, which are different to the parent flavonoids as they are present almost in all plants. Most of prenylated flavonoids are found in the following families, including Cannabaceae, Guttiferae, Leguminosae, Moraceae, Rutaceae and Umbelliferae. Due to widely consumed as vegetables and fruits, Leguminosae and Mor- aceae are the most frequently investigated families and many novel prenylated flavonoids have been explored. Hu- mulus lupulus of the Cannabaceae is famous for the pres- ence of 8-prenylnaringenin and xanthohumol, which play an important role in the health benefits of beer (Henderson, Miranda, Stevens, Deinzer, & Buhler, 2000). The levels of xanthohumol and 8-prenylnaringenin are 70.8 and 27.5 mg/L, respectively (Stevens, Taylor, & Deinzer, 1999). They are characterized as broad-spectrum cancer chemopreventive agent and antioxidant (Stevens & Page, 2004).
The present literatures available indicate that Moraceae family has the largest number of prenylated flavonoids. Mulberry is the well-known delicious fruit of Morus alba, which is the most common species of the genus Morus. This plant species has been recognized as natural functional fruit due to abundant multiprenylated flavones, like sange- non J and 30-geranyl-3-dimethylallyl-20,40,5,7- tetrahydroxyflavone (Butt, Nazir, Sultan, & Schroen, 2008; Nguyen Tien et al., 2010). Artocarpus heterophyllus is widely distributed in tropical and subtropical regions, and its fruit (jackfruit) is widely accepted by consumers. Many flavones with diverse prenyl substitutions have been iso- lated from this species (Baliga, Shivashankara, Haniadka, Dsouza, & Bhat, 2011).
Isoflavonoids are predominantly found in legumes. In consistent with this phenomenon, the prenylated isoflavo- noids identified are alsomainly from this family. As a species of Leguminosae, licorice extract is usually used as dietary supplements and traditional folk medicines. The presence of glabridin, glabrene, glabrone, hispaglabridin A and B make Glycyrrhiza a rich source of prenylated isoflavonoids (Simons, Vincken, Mol et al., 2011; Simons, Vincken, Roidos et al., 2011).Moreover, this genus produces dimethy- lallyl chalcones and farnesylated flavonols. All these chem- icals contribute much to the biological activities of this plant (Zeng, Fukai, Nomura, Zhang, & Lou, 1992). Prenylated iso- flavones have been identified from soybean. Yellow lupin has been detected to have prenylated isoflavones and flavanones (Tahara, Katagiri, Ingham, &Mizutani, 1994). Interestingly, synthesis of prenylated isoflavonoids can be apparently
induced under biotic or abiotic stress in leguminous seed sprouts. This induction is amenable to up-scaling as malting of soybean can accumulate ca. 2 mg/g of prenylated isoflavo- noids (Simons, Vincken, Mol et al., 2011; Simons, Vincken, Roidos et al., 2011).
Besides the above plant families, there are still some other plant species producing prenylated flavonoids as sec- ondary metabolites. The Epimedium genus of Berberida- ceae is a good resource for nutraceuticals and herbal medicines. It is also an enriched source of 8-dimethylallyl flavonol glycosides, which have a large amount of epime- dins A and C (Sofi et al., 2014). Natural prenylated flava- nols are very limited when comparing with other prenylated flavonoids. Illicium anisatum (Magnoliaceae) is the only plant species that has been identified to have 8-dimethylallylcatechin and 6-dimethylallylcatechin (Morimoto, Tanabe, Nonaka, & Nishioka, 1988). Some pre- nylated flavanes have been isolated from Marshallia grami- nifolia ssp. tenuifolia (Compositae) (Jukupovic, Paredes, Bohlmann, & Watson, 1988).
Extraction and quantitation of prenylated flavonoids Extraction of prenylated flavonoids
The extraction technique is highly depended on the sam- ple type and the physicochemical properties of target pre- nylated flavonoids. The procedures should allow quantitative recovery of prenylated flavonoids, and avoid any chemical modification or degradation (Cuyckens & Claeys, 2004). Similar to the flavonoid precursors, solvent extraction by methanol or ethanol is the most common technique used for preparation of prenylated flavonoids from plant resources. Homogenization, filtration, centrifu- gation, concentration or lyophilization are also required to obtain the product (Yang, Jiang, Shi, Chen, & Ashraf, 2011). Temperature, time and solvent type have consider- able effects on the amount and number of prenylated flavo- noids. For liquid samples, after filtration and centrifugation, liquideliquid extraction is often used for analyte isolation (de Rijke et al., 2006). New extraction techniques, such as high pressure extraction, ultrasound-assisted extraction, supercritical fluid extraction, microwave-assisted extrac- tion, are good alternatives for prenylated flavonoid prepara- tion. They can reduce solvent consumption, and are of time-saving and highly efficient. Moreover, such new tech- niques can minimize the possibility of modification and degradation of prenylated flavonoids.
Quantitation and quantification of prenylated flavonoids by liquid chromatography-tandem mass spectrometry (LC-MS/MS)
Prenylated flavonoids are extracted from plant resources as a complex mixture, which require a purification proce- dure for precise quantitation and quantification. Though gas chromatography-mass spectrometry has been applied for quantification of prenylated flavonoids (Tekel, de Keukeleire, Rong, Daeseleire, & van Peteghem, 1999), it
96 X. Yang et al. / Trends in Food Science & Technology 44 (2015) 93e104
shows limited potential due to the poor volatility of preny- lated flavonoids. Liquid chromatography-nuclear magnetic resonnance spectroscopy (LC-NMR) is a novel technique for natural product analysis (de Rijke et al., 2006). It has high information content, and can differentiate isomers and substitution patterns. However, the low sensitivity, expensive instrumentation and long operation time limit the application. At present, LC-MS/MS is the most popular technique for online quantification and quantitation of pre- nylated flavonoids. It can conduct structural characteriza- tion of unknown prenylated flavonoids depending the fragments and give further quantitative analysis.
Prenylated flavonoids have been investigated with elec- trospray ionization and atmospheric pressure chemical ioni- zation in nagative and positive ion modes. Negative ion mode is considered to be more sensitive and selective. Due to the nucleophilic nature of the prenyl group degrada- tion is unfavourable, there is no fragmentation of prenyl group in negative ion mode (Simons, Vincken, Bakx, Verbruggen, & Gruppen, 2009). A proposed fragmentation pathway of a prenylisoflavane, hispaglabridin A, is shown in Scheme 1. The fragments at 28 u (CO) and 44 u (CO2) are detected due to the degradation of C ring. 1,3B and 2,3A are the most abundant ions when compared with other fragments. In positive ion mode, the prenyl group at A or B ring will go through DielseAlder fission. [MHeC4H8]
þ and [A1HeC4H8] þ are the leading fragment
ions (Stevens, Ivancic, Hsu, & Deinzer, 1997).
Scheme 1. Proposed fragmentation pathway of hispaglabridi
Bioactivities of prenylated flavonoids The previous literatures have indicated that prenylation
is expected to enhance some bioactivities of flavonoids, such as antifungal activity and anticancer activity (Adesanya, O’Neill, & Roberts, 1986; Lane et al., 1985). The possible mechanism of action is that the prenyl moiety increases the lipophilicity, which changes the affinity of prenylated flavonoids to cell membrane and makes them easier contact to targets. Prenylation can improve the up- take of flavonoids into the epithelial cells of digestive tract and the bioaccumulation in muscle and liver tissues. How- ever, the bioavailability of prenylated flavonoids is usually lower than the parent flavonoids. The efflux from epithelial cells to the blood circulation may be hindered by prenyla- tion (Terao & Mukai, 2014).
Estrogenic activity Estrogens are critical regulators in various target tissues,
including human reproductive system, bone tissues, cardio- vascular and central nervous systems (Cos et al., 2003). Es- trogenic activity of natural products in plants is described as binding to human estrogen receptors and acting through signal conduction in the cells. The estrogenic activity of hops extract, which has abundant amount of prenylated flavo- noids, has been documented by in vivo assay (Chadwick, Pauli, & Farnsworth, 2006). 8-Prenylnaringenin is the repre- sentative nutraceutical, which are naturally occurred in hops and beer. 8-Prenylnaringenin can compete stronglywith 17b-
n A in negative ionization mode (Simons et al., 2009).
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estradiol for binding to a and b estrogen receptors when the dose is as low as 10 mM. Moreover, its binding affinity is higher than the most active isoflavonoids coumestrol and genistein (Milligan et al., 2000). Prenylation at C8 is very important, and 6-prenylnaringenin has been proved to have very low estrogenic activity (Milligan et al., 2000).
The estrogenic activities of prenylated flavonoids in lic- orice root (Glycyrrhiza glabra) were investigated by Simons, Gruppen, Bovee, Verbruggen, and Vincken (2012). Most fractions containing prenylated flavonoids showed estrogenic activity on both ERa and ERb, indi- cating the presence of phytoestrogens. Prenylated flavo- noids from plants are usually served as selective estrogen receptor modulators (phytoSERMs) (Simons et al., 2012). Glabridin (a prenylated isoflavane) at 3 mM is similar to 17b-estradiol in stimulation of the specific activity of crea- tine kinase in both pre- and post-menopausal cells (Somjen et al., 2004). Research on the estrogenic activity of preny- lated flavonoids in vivo or in vitro showed that prenylated flavonoids could be used in food and medicine industry as estrogen receptor modulators (Simons et al., 2012).
Immunosuppressive activity Immunosuppression is performed to prevent the body
from organ transplant or the treatment of autoimmune inflammation diseases. Xanthohumol exhibits good immu- nosuppressive effects on T cell proliferation, development of IL-2 activated killer cells, T lymphocytes and production of Th1 cytokines (Gao et al., 2009). These effects are partially due to the inhibition of nuclear factor NF-kB tran- scription factor through suppression of IkBa phosphoryla- tion. Prenylated flavonoids from Sophora flavescens show significant anti-allergic activity with inhibition of the b- hexosaminidase release (Quan et al., 2008). Artelastin, ar- telastochromene, artelasticin and artocarpesin are preny- lated flavones from Artocarpus elasticus. They shows a strong inhibition of the classical pathway of the human complement system with a dose-dependent behavior. Furthermore, artocarpesin also exhibits an inhibitory effect on the alternative pathway (Nascimento, Cidade, Pinto, & Kijjoa, 1997). Fifteen prenylated or geranylated flavonoids have been isolated from the roots of Campylotropis hirtella. Their immunosuppressive activities on mitogen-induced splenocytes proliferation have been tested. The IC50 values of these compounds are in the range of 1.49e61.23 mM for T lymphocyte suppression and 1.16e73.07 mM for B lymphocyte suppression. The low IC50 values indicate that some of them can be good candidates for immunosup- pressive agents (Shou, Fu, Tan, & Shen, 2009).
Anticancer activity Prenylated flavonoids have been reported to inhibit
various cancer cells, including HeLa and MCF-7 carcinoma cells (Dat et al., 2010). The anti-proliferative activity of 8- prenylnaringenin and 6-prenylnaringenin from hops on hu- man prostate cancer cells PC-3 and DU145 have been
reported. Both show good inhibitory effects on the growth of prostate cancer cells (Delmulle et al., 2006). The mech- anism of action is that 8-prenylnaringenin and 6- prenylnaringenin can induce a caspase-independent form of cell death (Delmulle, Vanden Berghe, Keukeleire, & Vandenabeele, 2008). Ten prenylated and geranylated fla- vonoids have been isolated from Morus alba. The cytotox- icities of these compounds to HeLa, MCF-7 and Hep-3B cells have been evaluated. The results show that their IC50 values are in the range of 0.64e3.69 mM against HeLa cells, 3.21e7.88 mM against MCF-7 cells, 3.09e9.21 mM against Hep-3B cells, repectively, which are much lower than kaempferol (Dat et al., 2010). Lavan- duly side-chain has been proved to be essential for the ac- tivity of flavonoids isolated from Sophora flavesecns, which can be used as cancer chemotherapeutic and chemopreven- tive agents (Ko et al., 2000). Neves et al. (2011) have stud- ied the effects of structure of prenylated derivatives of baicalein and 3,7-dihydroxyflavone on tumor cell lines growth, cell cycle and apoptosis. They have found that ger- anyl group is associated with a remarkable increase in the inhibitory activity in vitro. In this study, the effect of preny- lated flavonoids on inhibiting three human cell lines, MCF- 7 (breast adenocarcinoma), NCIeH460 (non-small cell lung cancer) and A375-C5 (melanoma) have been evalu- ated. Baicalein is demonstrated to inhibit MCF-7 and NCIeH450 with GI50 (50% cell growth inhibition) concen- trations of 32.8 2.2 and 26.7 2.9 mM, while its O-pre- nylated derivatives are more potent with GI50 concentrations of 9.1 0.6 and 6.8 0.8 mM. The facts suggest that prenylation of flavones generates derivatives with stronger inhibitory activity (Neves et al., 2011).
The prenylated flavonoids can inhibit cancer cells at all stages of carcinogenesis, including initiation, promotion and pregression phases (Botta, Delle Monache, Menendez, & Boffi, 2005). Cancer cell resistance to chemotherapy is usually regulated by P-glycoprotein, a plasma membrane ATP-binding cassette transporter (Di Pietro et al., 2002). It can extrude anticancer drugs at the expense of ATP hydroly- sis. The mechanism of flavonoid family has been docu- mented in four aspects: (1) direct binding to recombinant cytosolic nucleotide-binding domain and/or full-length transporter; (2) inhibition of ATP hydrolysis and energy- dependent drug interaction with transporter-enriched mem- branes; (3) inhibition of cell transporter activity; and (4) cell growth. The facts indicate that prenylated flavonoids bind with high affinity, and significantly inhibit the drug interaction and nucleotide hydrolysis (Di Pietro et al., 2002).
Anti-inflammatory activity Inflammation is part of the complex biological response
of vascular tissues to harmful stimuli, such as pathogens, damaged cells or irritants. There are five anti- inflammation mechanisms for prenylated flavonoids (Garca-Lafuente, Guillamon, Villares, Rostagno, & Martnez, 2009), including (1) antioxidant and radical
98 X. Yang et al. / Trends in Food Science & Technology 44 (2015) 93e104
scavenging activities; (2) regulation of inflammation- related cells’ activities; (3) modulation of the activities of arachidonic acid metabolism enzymes (phospholipase A2, cyclooxygenase, lipoxygenase) and nitric oxide synthase; (4) modulation of the production of other proinflammatory molecules; (5) modulation of proinflammatory gene expres- sion. Zhao and his colleagues have examined the inhibitory activity of ethyl acetate-soluble fraction of hops (Humulus lupulus) on the production of nitric oxide (NO) induced by a combination of lipopolysaccharides and IFN-g in macro- phage RAW 264.7 cells. The IC50 values of lupulones A and B are 20 and 14 mM, respectively (Zhao et al., 2005).
Antioxidant activity Reactive oxygen species play a key role in the pathogen-
esis of human diseases, such as cancer and inflammation (Yang et al., 2012). Therefore, it is important to quench the reactive oxygen species before attacking the human body. Antioxidants are such chemicals that can eliminate reactive oxygen species and defend against oxidative impairment. It is well known that flavonoids are good anti- oxidants, which can scavenge DPPH radicals, superoxide anion radicals and hydroxyl radicals with low IC50 values (Wen et al., 2014). Due to the high reactivity of the hydrox- yl group in B or C ring of flavonoids, they can readily donate a hydrogen atom to radicals and form a more stable and less reactive phenoxy radical. 2,3-double bond at C ring are highly associated with high radical-scavenging ac- tivity. Monohydroxy-substitution at B ring acts better against radicals than o-dihydroxy-substitution. Hydroxy- substitution at A ring contributes the mininum to the anti- oxidation behaviour (Tsimogiannis & Oreopoulou, 2006). Flavonoids can directly scavenge reactive oxygen species. Some of them can inhibit xanthine oxidase and interfere the inducible NO synthase activity for in vivo antioxidation behaviour (Nijveldt, et al., 2001). Prenylation leads to in- crease or decrease of antioxidant activity of flavonoids, de- pending on the assay and prenylation pattern. In the carotene antioxidation assay, 1’-geranylated and 5’-gerany- lated eriodictyols are better than eriodictyol. However, 6- geranylated eriodictyol has a lower antioxidant activity (Kumazawa et al., 2007). It indicates that prenyl location is important for the antioxidation behaviour. Prenylated and geranylated chalcones are more effective than chalcone on inhibition of microsomal lipid peroxidation induced by Fe2þ/ascorbate (Rodriguez, Miranda, Stevens, Deinzer, & Buhler, 2001). However, In vitro DPPH radical assay, pre- nylated flavonoids usually show a lower scavenging activity than the parent flavonoids. The IC50 value of kaempferol is 28 mM, which is lower than its prenylated derivative (35 mM) (Thongnest, Lhinhatrakool, Wetprasit, Sutthivaiyakit, & Sutthivaiyakit, 2013).
Other activities In addition to the activities listed above, prenylated flavo-
noids have been identified to have activities in other aspects.
Icariin derivatives and sophoflavescenol showed significant inhibition of cyclic guanosine monophosphate-specific phosphodiesterase-5 (Dell’Agli et al., 2008; Shin et al., 2002). The prenylated flavonoids from stem bark of Artocar- pus styracifolius have antiplasmodial, antitrypanosomal ac- tivities (Bourjot et al., 2010). Tyrosinase inhibitory activity has been confirmed for prenylated flavonoids from S. flaves- cens (Kim, Son, Chang, Kang, & Kim, 2003). By comparing the effects of 8-prenylnaringenin and naringenin on the ac- tivity and apoptosis of osteoclasts cultured in vitro, 8- prenylnaringenin is much more active than naringenin in in- hibiting the resorption of osteoclasts and inducing their apo- tosis. Therefore, C8-prenyl substitution is able to enhance the anti-bone resorption activity of naringenin (Lv et al., 2013). All these evidences indicate the great potential of prenylated flavonoids in nutraceuticals and medicines.
Safety Secondary metabolites from plants have been proved to
be important sources of novel medicines and nutraceuticals candidates. To be an applicable candidate, the chemical should be not only active and specific against target diseases with effective dose in nanomolar range, but also non-toxic to normal cells. A chemical with IC50 value of anti-cell prolif- eration activity at a dose less than 10 mM is designated as “cytotoxic” (Suffness & Douros, 1982). Flavonoids, espe- cially prenylated flavonoids, are usually being considered as non-toxic, which are a good choice of drug and nutraceu- tical candidates. They are usually found in plants not recog- nized as poisonous, but rather as medicinal plants, even as dietary plants in some cases. Prenylated isoflavone pomi- ferin and geranylated flavanone 30-O-methyl-50-hydroxydi- placone show low toxicities to native macrophages and good NO-balancing activities to lipopolysaccharide- induced rat macrophages (Nesuta et al., 2011). The preny- lated isoflavonoids from Bituminaria morisiana have been tested for cytotoxic potential against immune-associated cells, and no significant cytotoxicities are detected below 75 mM (Cottiglia et al., 2005). Artelastin is a triprenylated flavone, which acts as a strong immunosuppressant against different mitogen-stimulated splenic lymphocytes. Howev- er, it gives no effects on the basal levels of CD69 (marker of lymphocyte activation) in non-stimulated splenocytes and apoptosis of splenocytes (Cerqueira et al., 2003). Above evidences indicate that prenylated flavonoids are usually safe to human body.
Synthesis of prenylated flavonoids Chemical synthesis
Due to the limited distribution of prenylated flavonoids in nature, chemical synthesis is a natural choice for re- searchers interested on such compounds. Various chemical syntheses have been attempted to prenylation of flavonoids, especially to 8-prenylnaringenin due to strong estrogenic activity. An efficient synthesis of 8-prenylnaringenin by europium(III)-catalyzed Claisen rearrangement has been
99X. Yang et al. / Trends in Food Science & Technology 44 (2015) 93e104
reported, which includes four-step programme from racemic naringenin to 8-prenylnaringenin in ca. 20% yield via a domino ClaiseneCope rearrangement (Gester, Metz, Zierau, & Vollmer, 2001). The synthesis route is shown in Scheme 2. The previsous study has designed a route
Scheme 2. Pathway for synthesis of 8-prenylnaringenin, 6-(1,1-dimethylallyl) wise in dry pyridine at room temperature; b, 3-methyl-2-buten-1-ol, tripheny under argon to a solution of diethyl azodicarboxylate in dry THF; c, sample in anol and a drop of water. K2CO3 is addedwith stirring for 1 h at 40 C; e, allyl a f, Eu(fod)3, CHCl3, 70
C; g, isobutylene, benzene, room temperature; h, m
for 6-prenylnaringenin, which used allyl alcohol instead of 3-methyl-2-buten-1-ol. The product was further Claisen rearranged and dimethylated to obtain the final product 6- prenylnaringenin with a yield of 33% (Tischer & Metz, 2007). Kawamura, Hayashi, Mukai, Terao, and Nemoto
naringenin and 6-prenylnaringenin. a, acetic anhydride is added drop- lphosphine in dry THF cooled to 0 C is added drop wise over 45 min dry CHCl3 is treated with Eu(fod)3 at 40
C for 6 h; d, treated with meth- lcohol, PPh3, diethyl azodicarboxylate, THF, 0 C to room temperature; ethanol, K2CO3, 40
C. (Gester et al., 2001; Tischer & Metz, 2007).
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(2012) designed a five-step route to synthesize C-8 preny- lation of flavonols and flavanones. Acetylation is the first step to protect hydroxyl group, then C7 O-deacetylation is carried out by thiophenol and imidazole in N-methylpyr- rolidone under mild basic conditions. After C7eO-prenyla- tion, C8-regioselective Claisen rearrangement in acetic anhydride and deacetylation afforded 8-prenylated flavo- nols and flavanones. 8-Prenylated chalcone is detected as minor product. Little has been reported about the synthesis of 8-prenylflavanol. There are other protocols preparing C- prenylated flavonoids on A- or B-ring by a condensation re- action between a prenylated aromatic ring and another aro- matic ring (Neves et al., 2012). But these protocols usually have a poor selectivity and a low yield for C-prenylated fla- vonoids (nearly 1%). However, the yield for O-prenylated flavonoids is high (44%e77%).
Biological synthesis Though chemical synthesis can obtain expected preny-
lated flavonoids, there are some apparent disadvantages, such as expensive reagents and harsh conditions required, non-environment-friendly practices, and tedious operations. Biotransformation by metabolic engineering is a good alter- native to solve this problem. Before using this technique,
Table 1. Flavonoid prenyltransferase genes characterized from plants.
Prenyltransferases Source Structure of coding protein Localization
SfN8DT-1 Sophora flavescens
410 AAs, 9 transmenbrane a-helices, conserved motifs NQLCDIEID and KDIPDMEGD
Plastid
407 AAs, 9 transmenbrane a-helices, conserved motifs NQLCDIEID and KDIPDMEGD
Plastid
410 AAs, 9 transmenbrane a-helices, conserved motifs NQLCDIEID and KDIPDMEGD
Plastid
391 AAs, 7 transmenbrane a-helices, conserved motifs NELCDVELD and KDIPDIEGD
Plastid
407 AAs, 7 transmenbrane a-helices, conserved motifs NQLCDIEID and KDIPDTEGD.
Plastid
408 AAs, 7 transmenbrane a-helices, conserved motifs NQLCDLEID and KDIPDMEGD.
Plastid
411 AAs, 8 transmenbrane a-helices, conserved motifs NQIFDMDID and KDLSDINGD
Plastid
409 AAs, 9 transmembrane a-helices, conserved motifs NQLYDLEID and KDIPDVEGD
Plastid
the key is to find an effective flavonoid prenyltransferase that can catalyze directly O- or C-prenylation of flavonoids at certain locations of rings A, B or C. As most of preny- lated flavonoids are found from plant resources, these plants are obviously the source of flavonoid prenyltrans- ferases. However, it is possible that prenylation might take place before the flavonoid biosynthesis step in planta. Fortunately, some prenyltransferases with desired function of catalyzing flavonoids to generate prenylated flavonoids have been identified (Yazaki, Sasaki, & Tsurumaru, 2009).
Naringenin 8-dimethylallytransferase (SfN8DT-1) is the first flavonoid prenyltransferase identified from S. flaves- cens by Sasaki, Tsurumaru, and Yazaki (2009). Sasaki and his co-workers studied the prenylation of naringenin by biotransformation of yeast overexpressing SfN8DT-1. Results of LC-ESI-MS analysis show that 8- dimethylallylnaringenin is existed in the culture medium. It indicates that the prenyl substrate (dimethylallyl pyro- phosphate) can be provided by transgenic yeast in vivo, and the recombinant SfN8DT-1 converts naringenin to pre- nylated naringenin. Only 8 flavonoid prenyltransferases have been isolated and identified from plants with definite catalytic characteristics (Table 1). These prenyltransferases show more strict substrate specificity than those from
Enzymatic characterization Reference
(Sasaki, Mito, Ohara, Yamamoto, & Yazaki, 2008)
Same to SfN8DT-1 (Sasaki et al., 2008)
Flavonoids substrates: naringenin; Prenyl donor: DMAPP; Cofactor: Mg2þ
(Sasaki, Tsurumaru, Yamamoto, & Yazaki, 2011)
Flavonoids substrate: pterocarpan; Prenyl substrate: DMAPP, GPP, FPP, GGPP; Mg2þ
(Sasaki et al., 2011)
(Sasaki et al., 2011)
(Shen et al., 2012)
(Tsurumaru et al., 2010)
Flavonoids substrate: pterocarpan; Prenyl donor: DMAPP; Cofactor: Mg2þ>Mn2þ>Co2þ
(Akashi, Sasaki, Aoki, Ayabe, & Yazaki, 2009)
101X. Yang et al. / Trends in Food Science & Technology 44 (2015) 93e104
microorganisms. Flavanones, isoflavones and chalcones are the preferred flavonoids substrates. Dimethylallyl diphos- phate is the main prenyl donor accepted by these enzymes. Some of them also accept geranyl diphosphate and farnesyl diphosphate as donors. Plant flavonoid prenyltransferases have a signal peptides located to plastid at N-terminus and several transmembrane a-helices. They shares common conserved aspartate-rich motifs NQxxDxxxD and KDxxDxxGD, while the former is involved in binding prenyl donor and the latter is involved in binding flavonoid substrates (Stec & Li, 2012).
Besides above plant flavonoid prenyltransferases, there is an ABBA family of aromatic prenyltransferases, which are mainly from bacteria and fungi. This type of prenyl- transferase can catalyze the prenylation of flavonoids. How- ever, they are not involved in prenylated flavonoid synthesis in vivo. The ABBA aromatic prenyltransferase family in- cludes two sub-families, the DMATS/CymD family (indole prenyltransferases) and CloQ/NphB family (phenol/phena- zine prenyltransferases) (Bonitz, Alva, Saleh, Lupas, & Heide, 2011). They are soluble biocatalysts that can be easily overexpressed in E. coli. Antiparallel beta/alpha bar- rel (PT-barrel) consisted of repetitive aabb elements is pre- sent in such enzymes, and b-strands arrange in an antiparallel fashion to form a central b-barrel constructing the active center while a-helices form a solvent-exposed ring around the barrel. ABBA aromatic prenyltransferases have no Asp-enriched conserved motif and some of them are active in the absence or presence of Mg2þ or other diva- lent cations (Kuzuyama, Noel, & Richard, 2005). They have a broad substrate specificity to prenyl donor and flavo- noids, and can produce multiple products including C- and O-prenylated flavonoids in one reaction (Heide, 2009; Kumano, Tomita, Nishiyama, & Kuzuyama, 2010).
As cDNA of flavonoid prenyltransferases have been identified, establishment of prenylated flavonoids produc- tion system in heterologous organism is possible. When SfN8DT-1 is ectopically expressed in Arabidopsis thaliana, it can accumulate 8-prenylnaringenin, 8-prenylkaempferol, 8-prenylapigenin and 8-prenylquercetin, which are not found in wild type (Sasaki et al., 2009). Five prenyltransfer- ase genes, NphB, SCO7190, NovQ (from Streptomyces) and N8DT, G6DT (from S. flavescens) have been overex- pressed in Lotus japonicus. Prenylated flavonoids are unde- tectable in these plants. However, exogenous addition of flavonoid substrate leads to production of prenylated flavo- noids, such as 7-O-geranylgenistein and 6- dimethylallylnaringenin. These work demonstrate the po- tential of prenylated flavonoid production by using meta- bolic engineering technique (Sugiyama et al., 2011). Moreover, biotransformation in transgenic microbes is a more promising way to produce prenylated flavonoids, as it is easy to conduct gene manipulation and grows faster. Yeast transformants expressing SfN8DT-1 can produce 8- prenylnaringenin when adding naringenin to the medium. Exogenous gene transformed into E. coli expression system
usually has a higher expression level than in the yeast sys- tem. Thus, it is generally preferred to produce prenylated flavonoids through biotransformation by E. coli. Plant- derived flavonoid prenyltransferases cannot be actively ex- pressed in E. coli, but can be actively expressed in Sophora cerevisiae (Yazaki et al., 2009). However, bacteria- or fungi-derived flavonoid prenyltransferases can be active when expressed in E. coli, and it is a promising way to uti- lize such prenyltransferases for synthesis of prenylated flavonoids.
Conclusions and perspectives Prenylation significantly enhance some bioactivities of
flavonoids, especially the estrogenic activity and anticancer activity. The good bioactivities and safety make prenylated flavonoids very potential to be used as nutraceuticals or drugs. Furthermore, the bioavailability of flavonoids is decreased and the bioaccumulation in muscle and liver tis- sues is increased by prenyl group. However, due to the diverse structures, it is important to reveal the safety con- cerns when applying as nutraceuticals. To overcome the limits of low-abundance distribution in nature, biotransfor- mation by E. coli or yeast is a good technique to solve this problem. Up to now, the gene information about prenyl- transferases that are capable of catalyzing the synthesis of prenylated flavonoids is very limited. It is required to discover more flavonoid prenyltransferases from natural resources.
Acknowledgments We are grateful for the financial support from National
Natural Science Foundation of China (No. U1301211), Guangdong Natural Science Fund for Distinguished Young Scholar (No. S2013050014131), Youth Innovation Promo- tion Association of Chinese Academy of Sciences, Pearl River Science and Technology New Star Fund of Guangz- hou (No. 2014J2200081) and International Foundation for Science (No. F/4451-2).
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Introduction
The plant resources of prenylated flavonoids
Extraction and quantitation of prenylated flavonoids
Extraction of prenylated flavonoids
Bioactivities of prenylated flavonoids