|
|
Recent Advances in Microbial Production of Phloretin and Its Glycosides |
LIU Jin-cong1,LIU Xue1,YU Hong-jian2,ZHAO Guang-rong1,**() |
1 School of Chemical Engineering and Technology, Tianjin University, Frontier Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education), Tianjin 300072, China 2 Ubasio Biotech Go.,Ltd., Tianjin 300450, China |
|
|
Abstract Phloretin and its glycosides are natural dihydrochalcones with various physiological activities, such as antioxidant, anti-inflammatory and anti-bacterial activities, and have potential application in food, pharmaceutical, and cosmetics industries. At present, phloretin and its glycosides are mainly extracted from plants. However, the low content and complex components make it difficult to prepare products with high efficiency and low cost. With the development of metabolic engineering and synthetic biology, microbial production of phloretin and its glycosides has become an alternative approach. This article reviews the identification of key genes, the reconstruction of synthetic pathways and optimization strategies for the biosynthesis of phloretin and its glycosides. Finally, the potential strategies to solve existing problems as unspecific enzymes and the formation of multiple byproducts were proposed.
|
Received: 31 May 2020
Published: 10 November 2020
|
|
Corresponding Authors:
Guang-rong ZHAO
E-mail: grzhao@tju.edu.cn
|
|
|
[1] |
Mariadoss A V A, Vinyagam R, Rajamanickam V, et al. Pharmacological aspects and potential use of phloretin: a systemic review. Mini Reviews in Medicinal Chemistry, 2019,19(13):1060-1067.
doi: 10.2174/1389557519666190311154425
pmid: 30864525
|
|
|
[2] |
Zheng W, Chen C, Zhang C, et al. The protective effect of phloretin in osteoarthritis: an in vitro and in vivo study. Food & Function, 2018,9(1):263-278.
pmid: 29168867
|
|
|
[3] |
冯甜, 王力彬, 周楠, 等. 根皮素的研究进展. 转化医学杂志, 2017,6(1):42-46.
|
|
|
[3] |
Feng T, Wang L, Zhou N, et al. Advance in studies on phloretin. Translational Medicine Journal, 2017,6(1):42-46.
|
|
|
[4] |
Bays H. Sodium glucose co-transporter type 2 (sglt2) inhibitors: targeting the kidney to improve glycemic control in diabetes mellitus. Diabetes Therapy, 2013,4(2):195-220.
doi: 10.1007/s13300-013-0042-y
pmid: 24142577
|
|
|
[5] |
Lei L, Huang B, Liu A, et al. Enzymatic production of natural sweetener trilobatin from citrus flavanone naringin using immobilised α-l-rhamnosidase as the catalyst. International Journal of Food Science & Technology, 2018,53(9):2097-2103.
|
|
|
[6] |
Yang S, Lee C, Lee B S, et al. Renal protective effects of aspalathin and nothofagin from rooibos (Aspalathus linearis) in a mouse model of sepsis. Pharmacological Reports, 2018,70(6):1195-1201.
doi: 10.1016/j.pharep.2018.07.004
pmid: 30340097
|
|
|
[7] |
崔树梅, 曹孟岑, 杨雪晨, 等. 根皮素在化妆品中的应用. 日用化学工业, 2018,48(2):113-118.
|
|
|
[7] |
Cui S M, Cao M C, Yang X C, et al. Applications of phloretin in cosmetics. China Surfactant Detergent & Cosmetics, 2018,48(2):113-118.
|
|
|
[8] |
Cravens A, Payne J, Smolke C D. Synthetic biology strategies for microbial biosynthesis of plant natural products. Nature Communications, 2019,10(1):2142.
doi: 10.1038/s41467-019-09848-w
pmid: 31086174
|
|
|
[9] |
Yang D, Park S Y, Park Y S, et al. Metabolic engineering of Escherichia coli for natural product biosynthesis. Trends in Biotechnology, 2020,38(7):745-765.
doi: 10.1016/j.tibtech.2019.11.007
pmid: 31924345
|
|
|
[10] |
Avadhani P N, Towers G H. Fate of phenylalanine-C14 and cinnamic acid-C14 in Malus in relation to phloridzin synthesis. Canadian Journal of Biochemistry and Physiology, 1961,39(10):1605-1616.
|
|
|
[11] |
Gosch C, Halbwirth H, Kuhn J, et al. Biosynthesis of phloridzin in apple (Malus domestica Borkh). Plant Science, 2009,176(2):223-231.
|
|
|
[12] |
Dare A P, Tomes S, Cooney J M, et al. The role of enoyl reductase genes in phloridzin biosynthesis in apple. Plant Physiology & Biochemistry, 2013,72:54-61.
pmid: 23510577
|
|
|
[13] |
Ibdah M, Berim A, Martens S, et al. Identification and cloning of an NADPH-dependent hydroxycinnamoyl-CoA double bond reductase involved in dihydrochalcone formation in Malus x domestica Borkh. Phytochemistry, 2014,107:24-31.
doi: 10.1016/j.phytochem.2014.07.027
pmid: 25152451
|
|
|
[14] |
Yahyaa M, Ali S, Davidovich-Rikanati R, et al. Characterization of three chalcone synthase-like genes from apple (Malus x domestica Borkh). Phytochemistry, 2017,140:125-133.
doi: 10.1016/j.phytochem.2017.04.022
pmid: 28482241
|
|
|
[15] |
Jiang H, Wood K V, Morgan J A. Metabolic engineering of the phenylpropanoid pathway in Saccharomyces cerevisiae. Applied and Environmental Microbiology, 2005,71(6):2962-2969.
doi: 10.1128/AEM.71.6.2962-2969.2005
pmid: 15932991
|
|
|
[16] |
Lehka B J, Eichenberger M, Bjorn-Yoshimoto W E, et al. Improving heterologous production of phenylpropanoids in Saccharomyces cerevisiae by tackling an unwanted side reaction of Tsc13, an endogenous double bond reductase. FEMS Yeast Reserach, 2017, 17(1): fox004.
|
|
|
[17] |
Eichenberger M, Lehka B J, Folly C, et al. Metabolic engineering of Saccharomyces cerevisiae for de novo production of dihydrochalcones with known antioxidant, antidiabetic, and sweet tasting properties. Metabolic Engineering, 2017,39:80-89.
doi: 10.1016/j.ymben.2016.10.019
pmid: 27810393
|
|
|
[18] |
Werner S R, Chen H, Jiang H, et al, 2010. Synthesis of non-natural flavanones and dihydrochalcones in metabolically engineered yeast. Journal of Molecular Catalysis B Enzymatic, 2010,66(3):257-263.
|
|
|
[19] |
Jiang C, Liu X, Chen X, et al. Raising the production of phloretin by alleviation of by-product of chalcone synthase in the engineered yeast. Science China Life Sciences, 2020, doi: 10.1007/s11427-019-1634-8.
doi: 10.1007/s11427-019-1634-8
pmid: 32975722
|
|
|
[20] |
Watts K T, Lee P C, Schmidt-Dannert C. Exploring recombinant flavonoid biosynthesis in metabolically engineered Escherichia coli. ChemBioChem, 2004,5(4):500-507.
doi: 10.1002/cbic.200300783
pmid: 15185374
|
|
|
[21] |
Yu H N, Liu X Y, Gao S, et al. Structural and biochemical characterization of the plant type III polyketide synthases of the liverwort, Marchantia paleacea. Plant Physiology and Biochemistry, 2018,125:95-105.
doi: 10.1016/j.plaphy.2018.01.030
pmid: 29428820
|
|
|
[22] |
Elejalde-Palmett C, Billet K, Lanoue A, et al. Genome-wide identification and biochemical characterization of the UGT88F subfamily in Malus x domestica Borkh. Phytochemistry, 2019,157:135-144.
doi: 10.1016/j.phytochem.2018.10.019
pmid: 30399496
|
|
|
[23] |
Gosch C, Halbwirth H, Schneider B, et al. Cloning and heterologous expression of glycosyltransferases from Malus x domestica and Pyrus communis, which convert phloretin to phloretin 2'-O-glucoside (phloridzin). Plant Science, 2009,178(3):299-306.
|
|
|
[24] |
Gosch C, Flachowsky H, Halbwirth H, et al. Substrate specificity and contribution of the glycosyltransferase UGT71A15 to phloridzin biosynthesis. Trees-Structure and Function, 2012,26(1):259-271.
|
|
|
[25] |
Jugdé H, Nguy D, Moller I, et al. Isolation and characterization of a novel glycosyltransferase that converts phloretin to phlorizin, a potent antioxidant in apple. FEBS Journal, 2008,275(15):3804-3814.
doi: 10.1111/j.1742-4658.2008.06526.x
pmid: 18573104
|
|
|
[26] |
Zhang T, Liang J, Wang P, et al. Purification and characterization of a novel phloretin-2'-O-glycosyltransferase favoring phloridzin biosynthesis. Scientific Reports, 2016,6:35274.
doi: 10.1038/srep35274
pmid: 27731384
|
|
|
[27] |
Yahyaa M, Davidovich-Rikanati R, Eyal Y, et al. Identification and characterization of UDP-glucose: Phloretin 4'-O glycosyltransferase from Malus x domestica Borkh. Phytochemistry, 2016,130:47-55.
doi: 10.1016/j.phytochem.2016.06.004
pmid: 27316677
|
|
|
[28] |
Pandey R P, Li T F, Kim E H, et al. Enzymatic synthesis of novel phloretin glucosides. Applied & Environmental Microbiology, 2013,79(11):3516-3521.
doi: 10.1128/AEM.00409-13
pmid: 23542617
|
|
|
[29] |
Bungaruang L, Gutmann A, Nidetzky B. Leloir glycosyltransferases and natural product glycosylation: Biocatalytic synthesis of the C-glucoside nothofagin, a major antioxidant of redbush herbal tea. Advanced Synthesis & Catalysis, 2013,355(14-15):2757-2763.
doi: 10.1002/adsc.201300251
pmid: 24415961
|
|
|
[30] |
Nagatomo Y, Usui S, Ito T, et al. Purification, molecular cloning and functional characterization of flavonoid C-glucosyltransferases from Fagopyrum esculentum M. (buckwheat) cotyledon. The Plant Journal, 2014,80(3):437-448.
doi: 10.1111/tpj.12645
pmid: 25142187
|
|
|
[31] |
Ito T, Fujimoto S, Suito F, et al. C-glycosyltransferases catalyzing the formation of di-C-glucosyl flavonoids in citrus plants. Plant Journal, 2017,91(2):187-198.
doi: 10.1111/tpj.13555
pmid: 28370711
|
|
|
[32] |
Zhang M, Li F D, Li K, et al. Functional characterization and structural basis of an efficient di-C-glycosyltransferase from Glycyrrhiza glabra. Journal of the American Chemical Society, 2020,142(7):3506-3512.
pmid: 31986016
|
|
|
[33] |
Chen D, Sun L, Chen R, et al. Enzymatic synthesis of acylphloroglucinol 3-C-glucosides from 2-O-glucosides using a C-glycosyltransferase from Mangifera indica. Chemistry A European Journal, 2016,22(17):5873-5877.
doi: 10.1002/chem.201600411
|
|
|
[34] |
Ban Z, Qin H, Mitchell A J, et al. Noncatalytic chalcone isomerase-fold proteins in Humulus lupulus are auxiliary components in prenylated flavonoid biosynthesis. Proceedings of the National Academy of Sciences of the United States of America, 2018,115(22):E5223-E5232.
|
|
|
[35] |
Medema M H, Osbourn A. Computational genomic identification and functional reconstitution of plant natural product biosynthetic pathways. Nature Product Reports, 2016,33(8):951-962.
|
|
|
[36] |
Santamaría L, Reverón I, López de Felipe F, et al. Unravelling the reduction pathway as an alternative metabolic route to hydroxycinnamate decarboxylation in Lactobacillus plantarum. Applied & Environmental Microbiology, 2018,84(15):e01123-18.
doi: 10.1128/AEM.01123-18
pmid: 29776925
|
|
|
[37] |
Stompor M, Kałuzny M, Zarowaka B. Biotechnological methods for chalcone reduction using whole cells of Lactobacillus, Rhodococcus and Rhodotorula strains as a way to produce new derivatives. Applied Microbiology and Biotechnology, 2016,100(19):8371-8384.
doi: 10.1007/s00253-016-7607-4
pmid: 27209040
|
|
|
[38] |
Zyszka B, Anioł M, Lipok J. Highly effective, regiospecific reduction of chalcone by cyanobacteria leads to the formation of dihydrochalcone: two steps towards natural sweetness. Microbial Cell Factories, 2017,16(1):136-151.
doi: 10.1186/s12934-017-0752-3
pmid: 28778165
|
|
|
[39] |
Xiong D, Lu S, Wu J, et al. Improving key enzyme activity in phenylpropanoid pathway with a designed biosensor. Metabolic Engineering, 2017,40:115-123.
doi: 10.1016/j.ymben.2017.01.006
pmid: 28111248
|
|
|
[40] |
Morita H, Wong C P, Abe I. How structural subtleties lead to molecular diversity for the type III polyketide synthases. Journal of Biological Chemistry, 2019,294(41):15121-15136.
doi: 10.1074/jbc.REV119.006129
pmid: 31471316
|
|
|
[41] |
Camacho-Zaragoza J M, Hernández-Chávez G, Moreno-Avitia F, et al. Engineering of a microbial coculture of Escherichia coli strains for the biosynthesis of resveratrol. Microbial Cell Factories, 2016,15(1):163.
doi: 10.1186/s12934-016-0562-z
pmid: 27680538
|
|
|
[42] |
Fang Z, Jones J A, Zhou J, et al. Engineering Escherichia coli co-cultures for production of curcuminoids from glucose. Biotechnology Journal, 2018,13(5):1700576.
|
|
|
[44] |
Akdemir H, Silva A, Zha J, et al. Production of pyranoanthocyanins using Escherichia coli co-cultures. Metabolic Engineering, 2019,55:290-298.
doi: 10.1016/j.ymben.2019.05.008
pmid: 31125607
|
|
|
[44] |
Liu X, Li X B, Jiang J, et al. Convergent engineering of syntrophic Escherichia coli coculture for efficient production of glycosides. Metabolic Engineering, 2018,47:243-253.
|
|
|
[45] |
Liu X, Li L, Liu J, et al. Metabolic engineering Escherichia coli for efficient production of icariside D2. Biotechnology for Biofuels, 2019,12:261.
doi: 10.1186/s13068-019-1601-x
pmid: 31709010
|
|
|
|
Viewed |
|
|
|
Full text
|
|
|
|
|
Abstract
|
|
|
|
|
Cited |
|
|
|
|
|
Shared |
|
|
|
|
|
Discussed |
|
|
|
|