Abstract
Polyphenols produced in a wide variety of flowering and fruit-bearing plants have the potential to be valuable fine chemicals for the treatment of an assortment of human maladies. One of the major constituents within this chemical class are flavonoids, among which flavanones, as the precursor to all flavonoid structures, are the most prevalent. We review the current status of flavanone production technology using microorganisms, with focus on heterologous protein expression. Such processes appear as attractive production alternatives for commercial synthesis of these high-value chemicals as traditional chemical, and plant cell cultures have significant drawbacks. Other issues of importance, including fermentation configurations and economics, are also considered.
Similar content being viewed by others
References
Ae Park S, Choi MS, Cho SY, Seo JS, Jung UJ, Kim MJ, Sung MK, Park YB, Lee MK (2006) Genistein and daidzein modulate hepatic glucose and lipid regulating enzyme activities in C57BL/KsJ-db/db mice. Life Sci 79:1207–1213
Allister EM, Borradaile NM, Edwards JY, Huff MW (2005) Inhibition of microsomal triglyceride transfer protein expression and apolipoprotein B100 secretion by the citrus flavonoid naringenin and by insulin involves activation of the mitogen-activated protein kinase pathway in hepatocytes. Diabetes 54:1676–1683
Alper H, Jin YS, Moxley JF, Stephanopoulos G (2005a) Identifying gene targets for the metabolic engineering of lycopene biosynthesis in Escherichia coli. Metab Eng 7:155–164
Alper H, Miyaoku K, Stephanopoulos G (2005b) Construction of lycopene-overproducing E. coli strains by combining systematic and combinatorial gene knockout targets. Nat Biotechnol 23:612–616
An JH, Kim YS (1998) A gene cluster encoding malonyl-CoA decarboxylase (MatA), malonyl-CoA synthetase (MatB) and a putative dicarboxylate carrier protein (MatC) in Rhizobium trifolii—cloning, sequencing, and expression of the enzymes in Escherichia coli. Eur J Biochem 257:395–402
Andersen OM, Markham KR (eds) (2006) Flavonoids: chemistry, biochemistry, and applications. CRC, Boca Raton
Benoit I, Navarro D, Marnet N, Rakotomanomana N, Lesage-Meessen L, Sigoillot JC, Asther M (2006) Feruloyl esterases as a tool for the release of phenolic compounds from agro-industrial by-products. Carbohydr Res 341:1820–1827
Bergbauer M, Eggert C (1994) Degradability of chlorine-free bleachery effluent lignins by two fungi: effects on lignin subunit type and on polymer molecular weight. Can J Microbiol 40:192–197
Birt DF, Hendrich S, Wang W (2001) Dietary agents in cancer prevention: flavonoids and isoflavonoids. Pharmacol Ther 90:157–177
Boerjan W, Ralph J, Baucher M (2003) Lignin biosynthesis. Annu Rev Plant Biol 54:519–546
Caltagirone S, Rossi C, Poggi A, Ranelletti FO, Natali PG, Brunetti M, Aiello FB, Piantelli M (2000) Flavonoids apigenin and quercetin inhibit melanoma growth and metastatic potential. Int J Cancer 87:595–600
Chemler JA, Yan Y, Leonard E, Koffas MA (2007) Combinatorial mutasynthesis of flavonoid analogues from acrylic acids in microorganisms. Org Lett 9:1855–1858
Chemler JA, Fowler ZL, Koffas MA, Leonard E (2009) Trends in microbial synthesis of natural products and biofuels. Adv Enzymol Relat Areas Mol Biol 76:151–217
Davis MS, Solbiati J, Cronan JE Jr (2000) Overproduction of acetyl-CoA carboxylase activity increases the rate of fatty acid biosynthesis in Escherichia coli. J Biol Chem 275:28593–28598
Fong SS, Burgard AP, Herring CD, Knight EM, Blattner FR, Maranas CD, Palsson BO (2005) In silico design and adaptive evolution of Escherichia coli for production of lactic acid. Biotechnol Bioeng 91:643–648
Forkmann G, Martens S (2001) Metabolic engineering and applications of flavonoids. Curr Opin Biotechnol 12:155–160
Fowler ZL, Gikandi WW and Koffas M (2009) Increasing malonyl-CoA biosynthesis by tuning the Escherichia coli metabolic network and its application to flavanone production. Appl Environ Microbiol (in press).
Furlong JJP, Nudelman NS (1985) Mechanism of cyclization of substituted 2'-hydroxychalcones to flavanones. J Chem Soc Perkin Trans 2:633–639
Greenwald P (2004) Clinical trials in cancer prevention: current results and perspectives for the future. J Nutr 134:3507S–3512S
Guglielmetti S, De Noni I, Caracciolo F, Molinari F, Parini C, Mora D (2008) Bacterial cinnamoyl esterase activity screening for the production of a novel functional food product. Appl Environ Microbiol 74:1284–1288
Hall RD, Yeoman MM (1986) Temporal and spatial heterogeneity in the accumulation of anthocyanins in cell-cultures of Catharanthus-roseus (L) Don, G. J Exp Bot 37:48–60
Hanagata N, Ito A, Uehara H, Asari F, Takeuchi T, Karube I (1993) Behavior of cell aggregate of Carthamus-tinctorius L cultured-cells and correlation with red pigment formation. J Biotechnol 30:259–269
Harborne JB, Williams CA (2000) Advances in flavonoid research since 1992. Phytochemistry 55:481–504
Hellwig S, Drossard J, Twyman RM, Fischer R (2004) Plant cell cultures for the production of recombinant proteins. Nat Biotechnol 22:1415–1422
Hou DX, Fujii M, Terahara N, Yoshimoto M (2004) Molecular mechanisms behind the chemopreventive effects of anthocyanidins. J Biomed Biotechnol 5:321–325
Hsu CL, Yen GC (2006) Induction of cell apoptosis in 3T3–L1 pre-adipocytes by flavonoids is associated with their antioxidant activity. Mol Nutr Food Res 50:1072–1079
Hwang EI, Kaneko M, Ohnishi Y, Horinouchi S (2003) Production of plant-specific flavanones by Escherichia coli containing an artificial gene cluster. Appl Environ Microbiol 69:2699–2706
Jiang H, Wood KV, Morgan JA (2005) Metabolic engineering of the phenylpropanoid pathway in Saccharomyces cerevisiae. Appl Environ Microbiol 71:2962–2969
Kaneko M, Hwang EI, Ohnishi Y, Horinouchi S (2003a) Heterologous production of flavanones in Escherichia coli: potential for combinatorial biosynthesis of flavonoids in bacteria. J Ind Microbiol Biotechnol 30:456–461
Kaneko M, Ohnishi Y, Horinouchi S (2003b) Cinnamate:coenzyme A ligase from the filamentous bacterium streptomyces coelicolor A3(2). J Bacteriol 185:20–27
Katsuyama Y, Funa N, Horinouchi S (2007) Precursor-directed biosynthesis of stilbene methyl ethers in Escherichia coli. Biotechnol J 2:1286–1293
Kim JS, Kwon CS, Son KH (2000) Inhibition of alpha-glucosidase and amylase by luteolin, a flavonoid. Biosci Biotechnol Biochem 64:2458–2461
Kinghorn AD, Su BN, Jang DS, Chang LC, Lee D, Gu JQ, Carcache-Blanco EJ, Pawlus AD, Lee SK, Park EJ, Cuendet M, Gills JJ, Bhat K, Park HS, Mata-Greenwood E, Song LL, Jang M, Pezzuto JM (2004) Natural inhibitors of carcinogenesis. Planta Med 70:691–705
Kobayashi Y, Akita M, Sakamoto K, Liu HF, Shigeoka T, Koyano T, Kawamura M, Furuya T (1993) Large-scale production of anthocyanin by Aralia-cordata cell-suspension cultures. Appl Microbiol Biotechnol 40:215–218
Kontogiorgis C, Mantzanidou M, Hadjipavlou-Litina D (2008) Chalcones and their potential role in inflammation. Mini Rev Med Chem 8:1224–1242
Kumar A, Katiyar SB, Agarwal A, Chauhan PM (2003) Perspective in antimalarial chemotherapy. Curr Med Chem 10:1137–1150
Kumazawa T, Kimura T, Matsuba S, Sato S, Onodera J (2001) Synthesis of 8-C-glucosylflavones. Carbohydr Res 334:183–193
Kwon O, Eck P, Chen S, Corpe CP, Lee JH, Kruhlak M, Levine M (2007) Inhibition of the intestinal glucose transporter GLUT2 by flavonoids. FASEB J 21:366–377
Latha GM, Srinivas P, Muralikrishna G (2007) Purification and characterization of ferulic acid esterase from malted finger millet (Eleusine coracana, Indaf-15). J Agric Food Chem 55:9704–9712
Lee JS (2006) Effects of soy protein and genistein on blood glucose, antioxidant enzyme activities, and lipid profile in streptozotocin-induced diabetic rats. Life Sci 79:1578–1584
Leonard E, Koffas MA (2007) Engineering of artificial plant cytochrome P450 enzymes for synthesis of isoflavones by Escherichia coli. Appl Environ Microbiol 73:7246–7251
Leonard E, Yan Y, Lim KH, Koffas MA (2005) Investigation of two distinct flavone synthases for plant-specific flavone biosynthesis in Saccharomyces cerevisiae. Appl Environ Microbiol 71:8241–8248
Leonard E, Chemler J, Lim KH, Koffas MA (2006) Expression of a soluble flavone synthase allows the biosynthesis of phytoestrogen derivatives in Escherichia coli. Appl Microbiol Biotechnol 70:85–91
Leonard E, Lim KH, Saw PN, Koffas MA (2007) Engineering central metabolic pathways for high-level flavonoid production in Escherichia coli. Appl Environ Microbiol 73:3877–3886
Leonard E, Yan Y, Fowler ZL, Li Z, Lim CG, Lim KH, Koffas MA (2008) Strain improvement of recombinant Escherichia coli for efficient production of plant flavonoids. Mol Pharm 5:257–265
Leonowicz A, Cho NS, Luterek J, Wilkolazka A, Wojtas-Wasilewska M, Matuszewska A, Hofrichter M, Wesenberg D, Rogalski J (2001) Fungal laccase: properties and activity on lignin. J Basic Microbiol 41:185–227
Li F, Jin Z, Qu W, Zhao D, Ma F (2006) Cloning of a cDNA encoding the Saussurea medusa chalcone isomerase and its expression in transgenic tobacco. Plant Physiol Biochem 44:455–461
Lim SS, Jung SH, Ji J, Shin KH, Keum SR (2001) Synthesis of flavonoids and their effects on aldose reductase and sorbitol accumulation in streptozotocin-induced diabetic rat tissues. J Pharm Pharmacol 53:653–668
Martone PT, Estevez JM, Lu F, Ruel K, Denny MW, Somerville C, Ralph J (2009) Discovery of lignin in seaweed reveals convergent evolution of cell-wall architecture. Curr Biol 19:169–175
McDougall GJ, Shpiro F, Dobson P, Smith P, Blake A, Stewart D (2005) Different polyphenolic components of soft fruits inhibit alpha-amylase and alpha-glucosidase. J Agric Food Chem 53:2760–2766
Meyer JE, Pepin MF, Smith MA (2002) Anthocyanin production from Vaccinium pahalae: limitations of the physical microenvironment. J Biotechnol 93:45–57
Miranda CL, Stevens JF, Ivanov V, McCall M, Frei B, Deinzer ML, Buhler DR (2000) Antioxidant and prooxidant actions of prenylated and nonprenylated chalcones and flavanones in vitro. J Agric Food Chem 48:3876–3884
Miyahisa I, Kaneko M, Funa N, Kawasaki H, Kojima H, Ohnishi Y, Horinouchi S (2005) Efficient production of (2S)-flavanones by Escherichia coli containing an artificial biosynthetic gene cluster. Appl Microbiol Biotechnol 68:498–504
Mojzis J, Varinska L, Mojzisova G, Kostova I, Mirossay L (2008) Antiangiogenic effects of flavonoids and chalcones. Pharmacol Res 57:259–265
Moore BS, Hopke JN (2001) Discovery of a new bacterial polyketide biosynthetic pathway. Chembiochem 2:35–38
Nakai M, Fukui Y, Asami S, Toyoda-Ono Y, Iwashita T, Shibata H, Mitsunaga T, Hashimoto F, Kiso Y (2005) Inhibitory effects of oolong tea polyphenols on pancreatic lipase in vitro. J Agric Food Chem 53:4593–4598
Park JB, Levine M (2000) Intracellular accumulation of ascorbic acid is inhibited by flavonoids via blocking of dehydroascorbic acid and ascorbic acid uptakes in HL-60, U937 and Jurkat cells. J Nutr 130:1297–1302
Popiolkiewicz J, Polkowski K, Skierski JS, Mazurek AP (2005) In vitro toxicity evaluation in the development of new anticancer drugs—genistein glycosides. Cancer Lett 229:67–75
Potter SM, Baum JA, Teng HY, Stillman RJ, Shay NF, Erdman JW (1998) Soy protein and isoflavones: their effects on blood lipids and bone density in postmenopausal women. Am J Clin Nutr 68:1375S–1379S
Pouget C, Lauthier F, Simon A, Fagnere C, Basly JP, Delage C, Chulia AJ (2001) Flavonoids: Structural requirements for antiproliferative activity on breast cancer cells. Bioorg Med Chem Lett 11:3095–3097
Ro DK, Douglas CJ (2004) Reconstitution of the entry point of plant phenylpropanoid metabolism in yeast (Saccharomyces cerevisiae): implications for control of metabolic flux into the phenylpropanoid pathway. J Biol Chem 279:2600–2607
Shi HC, Huang QY, Yamaji R, Inui H, Fujita T, Miyatake K, Nakano Y, Tada T, Nishimura K (1998) Suppression by water extracts of Sophora plants of sucrose-induced hyperglycemia in rats and inhibition of intestinal disaccharidases in vitro. Biosci Biotechnol Biochem 62:1225–1227
Smith MAL, Spomer LA (1995) Vessels, gels, liquid media, and support systems. In: Aitken-Christie J, Kozai T, Smith MAL (eds) Automation and environmental control in plant tissue culture. Kluwer Academic, Dordrecht, pp 371–404
Song J, Kwon O, Chen SL, Daruwala R, Eck P, Park JB, Levine M (2002) Flavonoid inhibition of sodium-dependent vitamin C transporter 1 (SVCT1) and glucose transporter isoform 2 (GLUT2), intestinal transporters for vitamin C and glucose. J Biol Chem 277:15252–15260
Sternberg Z, Chadha K, Lieberman A, Hojnacki D, Drake A, Zamboni P, Rocco P, Grazioli E, Weinstock-Guttman B, Munschauer F (2008) Quercetin and interferon-beta modulate immune response(s) in peripheral blood mononuclear cells isolated from multiple sclerosis patients. J Neuroimmunol 205:142–147
Tanaka H, Stohlmeyer MM, Wandless TJ, Taylor LP (2000) Synthesis of flavonol derivatives as probes of biological processes. Tetrahedron Lett 41:9735–9739
Tanaka H, Miyoshi H, Chuang YC, Ando Y, Takahashi T (2007) Solid-phase synthesis of epigallocatechin gallate derivatives. Angew Chem Int Ed Engl 46:5934–5937
Tokimitsu I (2004) Effects of tea catechins on lipid metabolism and body fat accumulation. Biofactors 22:141–143
Tsuda T (2008) Regulation of adipocyte function by anthocyanins; possibility of preventing the metabolic syndrome. J Agric Food Chem 56:642–646
Ueda K, Kim KM, Beppu T, Horinouchi S (1995) Overexpression of a gene cluster encoding a chalcone synthase-like protein confers redbrown pigment production in Streptomyces griseus. J Antibiot (Tokyo) 48:638–646
Wan SB, Chan TH (2004) Enantioselective synthesis of afzelechin and epiafzelechin. Tetrahedron 60:8207–8211
Watts KT, Lee PC, Schmidt-Dannert C (2004) Exploring recombinant flavonoid biosynthesis in metabolically engineered Escherichia coli. Chembiochem 5:500–507
Wellmann E (1975) UV dose-dependent induction of enzymes related to flavonoid biosynthesis in cell suspension cultures of parsley. FEBS Lett 51:105–107
Wolfram S, Raederstorff D, Preller M, Wang Y, Teixeira SR, Riegger C, Weber P (2006) Epigallocatechin gallate supplementation alleviates diabetes in rodents. J Nutr 136:2512–2518
Yan YJ, Kohli A, Koffas MAG (2005) Biosynthesis of natural flavanones in Saccharomyces cerevisiae. Appl Environ Microbiol 71:5610–5613
Yu O, Jung W, Shi J, Croes RA, Fader GM, McGonigle B, Odell JT (2000) Production of the isoflavones genistein and daidzein in non-legume dicot and monocot tissues. Plant Physiol 124:781–794
Yu O, Shi J, Hession AO, Maxwell CA, McGonigle B, Odell JT (2003) Metabolic engineering to increase isoflavone biosynthesis in soybean seed. Phytochemistry 63:753–763
Zava DT, Duwe G (1997) Estrogenic and antiproliferative properties of genistein and other flavonoids in human breast cancer cells in vitro. Nutr Cancer 27:31–40
Zhong JJ, Seki T, Kinoshita S, Yoshida T (1991) Effect of light irradiation on anthocyanin production by suspended culture of Perilla-frutescens. Biotechnol Bioeng 38:653–658
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Fowler, Z.L., Koffas, M.A.G. Biosynthesis and biotechnological production of flavanones: current state and perspectives. Appl Microbiol Biotechnol 83, 799–808 (2009). https://doi.org/10.1007/s00253-009-2039-z
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00253-009-2039-z