Open access peer-reviewed chapter

Biosynthesis of Diverse Class Flavonoids via Shikimate and Phenylpropanoid Pathway

Written By

Mohd Rehan

Submitted: 12 November 2020 Reviewed: 08 February 2021 Published: 18 May 2021

DOI: 10.5772/intechopen.96512

From the Edited Volume

Bioactive Compounds

Edited by Leila Queiroz Zepka, Tatiele Casagrande do Nascimento and Eduardo Jacob-Lopes

Chapter metrics overview

674 Chapter Downloads

View Full Metrics


Flavonoids are natural products, which are useful in the protection of various types of human diseases. Several bioactive flavonoids as chalcones, flavonols, flavanol, flavones, flavanone, flavan, isoflavonoids, and proanthocyanidin, are found in parts as leaves, root, bark, stem, flowers, weed, fruits of plant species. Flavonoids are synthesized in higher plant species via the shikimate pathway, phenylpropanoid and polyketide pathway. The chalcones and flavanones are central intermediates of the pathway, which give several diverse classes of flavonoids. Central intermediates pathway (chalcones and flavanones pathway) depends on plants species and group of enzymes such as hydroxylases, reductases and isomerases to give different classes of flavonoids skeleton. The anthocyanins, isoflavonoids and condensed tannin (proanthocyanidins) are an important class of flavonoids, which synthesized by flavanones. Mostly, biosynthesis of flavonoids start from phenylpropanoid pathway. The phenylpropanoid pathway starts from shikimate pathway. The shikimate pathway starts from phosphoenol pyruvate and erythrose 4-phosphate.


  • flavonoids
  • biosynthesis
  • shikimate pathway
  • phenylpropanoid pathway
  • tannins

1. Introduction

Flavonoids, are the largest class of secondary metabolites, having polyphenolic structure, which widely distributed in several parts as leaves, root, stem, bark, fruit, flower, weed, of diverse plant species [1]. The flavonoids play a key role to provide pigments in plant as dark blue and red color of berries, yellow and orange color of citrus fruits. These flavonoids play similar role as vitamins in the human body [2]. The flavonoids are constituted by 15 carbon atoms, which are arranged in C6-C3-C6 backbone skeleton rings, in which ring A and ring B are linked by three carbon ring C [3]. The skeleton of ring represented in Figure 1.

Figure 1.

Basic skeleton C6-C3-C6 of ring A, B, and C in flavonoids.

On the basis of substitution pattern, flavonoids can be classified into major subgroups as chalcone, flavanone, dihydroflavonol, flavanol, flavones, isoflavone, flavonol, leucoanthocyanidin, proanthocyanidin (condensed tannins), anthocyanin [4]. The nature of these flavonoids depends on the basis of degree of hydroxylation, structural class, conjugations, substitutions and degree of polymerization [5]. Approximately, 9000 diverse type flavonoids have been reported and sure this number will be increased [6]. The diverse type flavonoids show diverse biological function as protection from UV radiation, apoptosis, treatment of psoriasis [7, 8]. The diverse class of flavonoids have been isolated from several plant species as quercetin and apigenin from Cymbopogon citratus [9], pinostrobin and cardamonin chalcone from rhizomes of Boesenbergia rotunda [10], 6-aldehydo-isoophiopogonanone A, 6-aldehydo-isoophiopogonanone B, methylophiopogonanone A and methylophiopogonanone B from fibrous roots of Ophiopogon japonicus [11]. The diverse type flavonoids were synthesized in plant species via shikimate and phenylpropanoid pathway. Several types enzyme as DAHP synthase, DHQ synthase, SA kinase, PAT, ADT, 4CL, CHS, CHI, F3H, DFR play key role in the biosynthesis of flavonoids [12, 13].


2. Shikimate pathway

Shikimate pathway plays high potential role in the biosynthesis of flavonoids. Several key enzymes are involved in this pathway for biosynthesis of shikimic acid. This pathway starts with the aldol condensation reaction of phosphoenol pyruvate (PEP) and D-erythrose 4-phosphate (E4P) to generate seven carbon keto acid, 3-deoxy-D-arabino-heptulosonate −7-phosphate (DAHP). This reaction catalyzes by 3-deoxy-D-arabino-heptulosonate −7-phosphate synthase (DAHPS) enzyme. The DAHPS is a highly potential enzyme of the shikimate pathway. Two DAHPS genes as DHS1 and DHS2 are found in Arabidopsis thaliana plants [14]. From literature, it is identified that DHS1 is more produced by infiltration or by physical wounding with pathogen in both tomato and Arabidopsis [15]. The DAHP is transformed to 3-dehydroquinic acid (DHQ) by intramolecular cyclization reaction in presence of DHQ synthase enzymes.

In most bacteria, DHQS is monofunctional and in some organism, it behaves multifunctional enzyme, which catalyze 2, 3, 4, and 5 steps of the shikimate pathway. The DHQS is a small part of larger AROM protein, which is pentafunctional peptide containing enzyme [16, 17]. The Neurospora crassa and Aspergillus nidulans DHQS enzyme found in nature as part of the AROM protein [18]. The DHQ converts into 3-dehydroshikimic acid (DHS) by losing a water molecule.

In the fourth step, DHS is transformed into shikimic acid by removing water molecule. The phosphorylation of shikimic acid is done by activating of shikimate kinase enzyme in the fifth step reaction. The shikimic acid with ATP is phosphorylated at the 5-OH group of shikimic acid converts into shikimic acid 3-phosphate (S3P). The shikimate kinase enzyme is not found in the human cell, but is an essential enzyme of many bacterial pathogens [19, 20]. The shikimic acid 3-phosphate converts into 3-enolpyruvyl shikimate −5-P (EPSP) by EPSP synthase enzymes.

The EPSPS is activating of shikimic acid 3-phosphate in the sixth step reaction of the shikimate pathway. According to intrinsic glyphosate sensitivity, it enzyme has been classified as a class I EPSP synthases and class II EPSP synthases [21, 22]. The class I EPSP synthases are found in plant and some bacteria as Escherichia coli and Salmonella typhimurium. The class II EPSP synthases is found several bacteria species as Streptococcus pneumonia, Streptococcus aureus. The EPSP converts into chorismic acid (CHA) by eliminating of the pi group at C-3.

The end product of shikimate pathway is chorismic acid, which found in plants, fungi, bacteria and some parasites [23]. The chorismate synthases (CS) is divided within one of two functional groups as fungal type bifunctional CS and plant, bacterial type monofunctional CS [24, 25].

The chorismate mutase (CM) is a first step enzyme of the tyrosine and phenylalanine biosynthesis. It activates of chorismic acid, which converts into prephenic acid by claisen rearrangement [26]. On the basis functional and structural, multiple form of this enzyme exists. Some monofunctional example from Serratia rubidaea, Bacillus subtilis [27], Aspergillus nidulans [28]. In presence of this enzyme, chorismic acid change into prephenic acid.

The prephenate aminotransferase (PAT) play a key role in phenylalanine biosynthesis. It catalyzes first step product (prephenic acid) into arogenic acid [29]. The arogenate dehydratase (ADT) is a last step enzyme of phenylalanine biosynthesis, which catalyzes of arogenic acid into amino acid phenylalanine [30]. In the arabidopsis genome, six ADT genes as ADT1-ADT6 are found, whereas ADT4 and ADT5 were dominant in roots and stems [31]. The shikimate pathway with enzyme activity is summarized in Figure 2.

Figure 2.

Shikimate pathway in biosynthesis of flavonoids.


3. Phenylpropanoid pathway

The shikimate pathway plays the main role in the biosynthesis of flavonoids, which provides amino acid phenylalanine. The phenylalanine ammonia lyase (PAL) is an enzyme of first step reaction in phenylpropanoid pathway. The presence of this enzyme has been reported in different types of plant species [32] as certain fungi [33], few prokaryotic organisms, including Streptomyces [34, 35], algae, including Dunaliella marina [36] and detected in several species representing gymnosperms, ferns, lycopods, monocots, and dicots [37]. This enzyme converts phenylalanine into cinnamic acid and remove the ammonium ion.

The cinnamate −4-hydroxylase (C4H) plays a crucial role in conversion of trans-cinnamic acid in 4-coumaric acid. This acid, yielding 4-coumaroyl-CoA by catalyzing of 4-coumaroyl-CoA-ligase (4CL). The 4-coumaroyl-CoA-ligase (4CL) plays a pivotal role in phenylpropanoid biosynthesis pathway and produced coumarin skeleton. Mostly, a multiple isoform of 4CL are found in higher plants. These isoforms have distinct catalytic properties and expression profiles in plant tissue [38].

The initial step of flavonoids biosynthesis is the condensation reaction of one molecule 4-coumaroyl-CoA with three molecules of malonyl-CoA to yielding chalcone (2′,4′,6′,4-tetrahydroxy chalcone) by catalyzing the chalcone synthase (CHS) enzyme [39]. chalcone synthase (CHS) enzyme plays key role in the biosynthesis of flavonoids and isoflavonoids. The plant polyketide synthase is a big family called superfamily, CHS is a member of this family [40]. The chalcone isomerized into flavanone by activating of chalcone flavanone isomerase (CHI) enzyme. The flavanone is the intermediate pathway of flavonoids, which divided into many different flavonoids classes [41, 42]. The modification of flavanone into the basic skeleton of flavonoids, depends on the species and a group of enzymes as hydroxylases, reductases, isomerases [43]. The phenylpropanoid pathway in the biosynthesis of flavonoids summarized in Figure 3.

Figure 3.

Phenylpropanoid pathway in biosynthesis of flavonoids.


4. Flavonoids pathway

The shikimate and phenylpropanoid pathway play important role in biosynthesis of flavonoids. After this pathway flavonoids pathway starts, which produce various diverse type flavonoids in presence of several enzymes. The isoflavonoid synthase (IFS) is a main enzyme, which converts a flavanone into isoflavone. In soybean, two isoform of IFS genes as IFS-1 and IFS-2 are found, which play a crucial role in the isoflavones biosynthesis [44, 45]. The role of this enzyme summarized in Figure 4.

Figure 4.

The essential role of enzyme in flavonoids pathway.

The flavonol synthase (F3H) is a key enzyme of the biosynthesis in the central flavonoid pathway. It plays a pivotal role in the conversion of flavanone into dihydroflavonol. It has been isolated from various plant species (more than 50 plants) [46, 47]. The flavonol synthase (FLS) is a highly activating enzyme, which converts of dihydroflavonol into flavonol. The first FLS gene was known from P. hybrida [48] and other FLS gene were known from various plant species as A. thaliana [49], E. grandiflorum [50] etc.

The dihydroflavonol reductase (DFR) is a essential enzyme, which catalyzes dihydroflavonol into leucoanthocyanidin and are precursors of anthocyanidins and proanthocyanidins [51]. The DFR genes have been cloned in several plant species as Lotus japonicas [52], Ginkgo biloba [53], Brassica rapa [54]. The DFR can overexpression in apple and tobacco, which increase anthocyanin production [55, 56].

The proanthocyanidins is known condensed tannins (polymers), which produced by condensation of flavan-3-ol monomeric units as epicatechin and catechin. It catalyzes in the presence of two enzymes as leucoanthocyanidin reductase (LAR) and anthocyanidin reductase (ANR). The LAR is the main enzyme of anthocyanin biosynthesis pathway, which converts leucoanthocyanidin into catechin, while ANR converts anthocyanidin into epicatechin [57, 58, 59]. The CsLAR gene is found in tobacco, which accumulation of higher level of epicatechin than catechin while ANR in tea and grapevine is involved in biosynthesis of mixture of catechin and epicatechin from anthocyanidin [60, 61]. The proanthocyanidins have been reported from various plant species [62, 63]. The catalyzing properties of these enzymes are showed inFigure 5.

Figure 5.

Biosynthesis of tannins and anthocyanin in flavonoids pathway.

4.1 Chalcones

Chalcone synthase plays potential role in the biosynthesis of flavonoids/isoflavonoids pathway. The CHS is a member of the polyketide synthase family, which play a key role flowering plant as providing floral pigment, insect repellents, UV Protectants and antibiotics [64]. The chalcones are called open chain flavonoids, which have 15 carbon structure and arranged in C6-C3-C6 skeleton. The modification of chalcones can be done by methylation, condensation, and hydroxylation. These chalcones can be distributed in many parts of plants as fruits, seed, bark, stem, flowers [65].

Various diverse type chalcones have been reported from many plant species such as 2,4-dihydroxy-30-methoxy-40-ethoxychalcone from Caragana pruinosa [66], two chalcones, sappanchalcone and 3-deoxysappanchalcone from Haematoxylum campechianum [67], 4,2′,4′-trihydroxy-chalcone 4,2′-dihydroxy-4′- methoxy-chalcone, 4-hydroxylonchocarpin, crotmadine chalcones Codonopsis cordifolioidea root [68], and crotaramin chalcone from Crotalaria ramosissima plant [69]. These chalcones are showed in Figure 6.

Figure 6.

Various types chalcones isolated from several plants.

4.2 Flavan and Flavan-3-ol

Many different flavan and flavan-3-ol are summarized in Figure 7, which have been isolated from many plants as afzelechin from steam bark of Pinus halepensis [70], oncoglabrinol C from Oncocalyx glabratus [71], epicatechin, and 3,5,7,4′-tetrahydroxy flavan from stem bark of Embelia schimperi [72], three flavan-3-ol derivatives as (+)-afzelechin, (+)-afzelechin-7-O-α-L-arabinofuranoside and (+)-afzelechin-7-O-β-D-apiofuranoside from Polypodium vulgare L. rhizomes [73].

Figure 7.

Diverse type of flavan and flavan-3-ol reported from parts of plants.

4.3 Flavone-flavanone

Many different structures of flavones and flavanone are synthesized via shikimate and flavonoids pathway. These structures of these are showed in Figure 8. Several type of flavones and flavanone were isolated such as apigenin 7-O-β-D-glucopyranoside, dimethylchrysin, trimethylapigenin, 5,7,3′,4′-tetrahydroxyflavone (Luteolin) from Sterculia foetida leaves [74], three new flavan-flavanones as friesodielsones A, friesodielsones B, friesodielsones, from Friesodielsia desmoides leaves [75], and flavonoids (flavones) as apigenin-7,4′-dimethylether, genkwanin from Aquilaria sinensis leaves [76].

Figure 8.

Structural diversity of flavones and flavanone.

4.4 Isoflavonoids

The diverse type structure of isoflavonoids was synthesized from flavanone, which have been reported several plants as corylifol A, neobavaisoflavone, and irisflorentin from Cytisus striatus [77], formoninetin and biochanin A from Hylastinus obscurus [78]. One new leptoisoflavone A (a rare 5-membered dihydrofuran ring) from Limonium leptophyllum [79], 2,2′-trimethoxy-6,8-dihydroxy-isoflavone from the ethanol extract of Thespesia populnea bark [80] and isoflavones, genistein and daidzein from Hericium erinaceum (Figure 9) [81].

Figure 9.

Diverse structure of isoflavonoids from plants species.

4.5 Flavonol

Several type of flavonol were reported from parts of plants as myricetin 3-O-(2″,4″-di-O-acetyl)-α-L-rhamnopyranoside from Myrsine Africana [82], flavonoid glycoside named as 3’-O-methyl quercetin-3-glucose-6-gallic acid from Cordia oblique leaves [83], 2-(3, 4-dihydroxyphenyl)-3, 5, 7-trihydroxy-4H-chromen-4-one from aerial parts of Chenopodium album [84], amurensin and cosmosiin from Trigonella foenum graecum [85], rhamnosides flavonol, kaempferol-3-O-rhamnoside and quercetin-3-O-rhamnoside from leaves of Pometia pinnata [86] and a new flavonol glycoside, sabiapside A from Sabia parviflora [87] (Figure 10).

Figure 10.

Several different structures of flavonol isolated from parts of plant species.


5. Conclusions

Flavonoids are a large class of natural compounds, which isolated from various of plants as seed, root, bark, flower, leaves, fruit etc. and prevent from various diseases. The biosynthesis of flavonoids is highly complicated because a group of enzyme (DHAP synthase, SA kinase, EPSP synthase, PAL, 4CL, CHS, CHI, F3H, DFR) plays a key role in the pathway of flavonoids biosynthesis. These enzymes play a potential role in modification of flavonoids via isomerases, hydroxylases, reductases, and polymerises reaction. The proanthocynidins are interested natural compounds, which formed via polymerization reaction of flavonoids. The flavonoids are synthesized in various plant species via shikimate and phenylpropanoid pathway.



Author thanks to UGC, New Delhi, India for institutional fellowship. The author is also thankful to the Chairman, Department of Chemistry, AMU, Aligarh, for providing research facilities.


Conflict of interest

The author declares no conflicts of interest.


  1. 1. Wang T-Y, Li Q, Bi K-S. Bioactive flavonoids in medicinal plants: Structure, activity and biological fate. Asian Journal of Pharmaceutical Sciences. 2018;13:12-23. doi:
  2. 2. Brodowska KM. Natural Flavonoids: Classification, Potential Role, and Application of Flavonoid Analogues. European Journal of Biological Research. 2017;7:108-123. doi:
  3. 3. Isoda H, Motojima H, Onaga S, et al. Analysis of the erythroid differentiation effect of flavonoid apigenin on K562 human chronic leukemia cells. Chem Biol Interact. 2014;220:269-277. doi:
  4. 4. Winkel BSJ. The Biosynthesis of Flavonoids. In: Grotewold E. (eds) The Science of Flavonoids. Springer, New York, NY; 2006. doi:
  5. 5. Heim KE, Tagliaferro AR, Bobilya DJ. Flavonoid antioxidants: chemistry, metabolism and structure-activity relationships. J Nutr Biochem. 2002;13(10):572-584. doi:
  6. 6. Wang Y, Chen S, Yu O. Metabolic engineering of flavonoids in plants and microorganisms. Appl Microbiol Biotechnol. 2011;91:949-956. doi:
  7. 7. Park CH, Han SE, Nam-Goong IS, Kim YI, Kim ES. Combined Effects of Baicalein and Docetaxel on Apoptosis in 8505c Anaplastic Thyroid Cancer Cells via Downregulation of the ERK and Akt/mTOR Pathways. Endocrinol Metab (Seoul). 2018;33(1):121-132. doi:
  8. 8. Chamcheu JC, Esnault S, Adhami VM, Noll AL, Banang-Mbeumi S, Roy T, Singh SS, Huang S, Kousoulas KG, Mukhtar H. Fisetin, a 3,7,3′,4’-Tetrahydroxyflavone Inhibits the PI3K/Akt/mTOR and MAPK Pathways and Ameliorates Psoriasis Pathology in 2D and 3D Organotypic Human Inflammatory Skin Models. Cells. 2019;8:1089. doi: 10.3390/cells8091089
  9. 9. Ahmed NZ, Ibrahim SR, Omar A. Ahmed-Farid OA. Quercetin and Apigenin of Cymbopogon citratus mediate inhibition of HCT-116 and PC-3 cell cycle progression and ameliorate Doxorubicin-induced testicular dysfunction in male rats. Biomedical Research and Therapy 2018;5(7):2466-2479. doi:
  10. 10. Mohammed IA, Akhtar MN, Biau FJ, Tor YS, Zareen S, Shahabudin SB, AbdHamid HB, Haq ZU, Khalil R, Khalaf RM. Isolation of Cardamonin and Pinostrobin Chalcone from the Rhizomes of Boesenbergia rotunda (L.) Mansf. and their Cytotoxic Effects on H-29 and MDA-MB-231 Cancer Cell Lines. The Natural Products Journal. 2019;9:341. doi:
  11. 11. Zhou Y, Wang L, Liu T, Mao Z, Ge Q, Mao J. Isolation of Homoisoflavonoids from the Fibrous Roots of Ophiopogon japonicus by Recycling High-Speed Counter-Current Chromatography and Online Antioxidant Activity Assay. Acta Chromatographica. 2019;31(4):272-279. doi:
  12. 12. Díaz Quiroz DC, Carmona SB, Bolívar F, Escalante A. Current perspectives on applications of shikimic and aminoshikimic acids in pharmaceutical chemistry. Research and Reports in Medicinal Chemistry. 2014;4:35-46. doi:
  13. 13. Tohge T, Watanabe M, Hoefgen R, Fernie AR. Shikimate and phenylalanine biosynthesis in the green lineage. Frontiers in plant science. 2013;4:62. doi:
  14. 14. Keith B, Dong XN, Ausubel FM, Fink GR. Differential induction of 3-deoxy-D-arabino-heptulosonate 7-phosphate synthase genes in Arabidopsis thaliana by wounding and pathogenic attack. Proceedings of the national Academy of Science, USA. 1991;88:8821-8825. doi:
  15. 15. Gorlach J, Schmid J, Amrhein N. Differential expression of tomato (Lycopersicon esculentum L.) genes encoding shikimate pathway isoenzymes. II. Chorismate synthase. Plant Molecular Biology. 1993;23:707-716. doi:
  16. 16. Bentley R, Haslam E. The shikimate pathway-a metabolic tree with many branches. Critical Reviews in Biochemistry and Molecular Biology. 1990;25(5):307-384. doi:
  17. 17. Hawkins AR, Moore JD, Adeokun AM. Characterization of the 3-dehydroquinase domain of the pentafunctional AROM protein, and the quinate dehydrogenase from Aspergillus nidulans, and the overproduction of the type II 3-dehydroquinase from Neurospora crassa. Biochemical Journal. 1993;296(2):451-457. doi:
  18. 18. Moore JD, Coggins JR, Virden R, Hawkins AR. Efficient independent activity of a monomeric, monofunctional dehydrogenate synthase derived from the N-terminus of the pentafunctional AROM protein of Aspergillus nidulans. Biochemical Journal. 1994;301(1):297-304. doi:
  19. 19. Coracini JD, Azevedo WF. Shikimate kinase, a protein target for drug design. Current Medicinal Chemistry. 2014;21:592-604. doi:
  20. 20. Blanco B, Prado V, Lence E, Otero JM, García-Doval C, van Raaij MJ, et al. Mycobacterium tuberculosis shikimate kinase inhibitors: Design and simulation studies of the catalytic turnover. Journal of the American Chemical Society. 2013;135:12366-12376. doi:
  21. 21. Funke T, Han H, Healy-Fried ML, Fischer M, Schonbrunn E (2006) Molecular basis for the herbicide resistance of Roundup Ready crops. Proc. Natl. Acad, Sci. USA, 103, 13010-13015. doi:
  22. 22. Franz JE, Mao MK, Sikorski JA. Glyphosate A Unique Global Herbicide. Washington Americal Chemical Society. 1997
  23. 23. He Z, Stigers Lavoie KD, Bartlett PA, Toney MD. Conservation of mechanism in three chorismate-utilizing enzymes. J Am Chem Soc. 2004;126(8):2378-2385. doi:
  24. 24. Schaller A, Vanafferden M, Wind-hofer V, Bulow S, Abel G, Schmid J, et al. Purification and characterization of chorismate synthase from Euglena gracilis comparison with chorismate synthases of plant and microbial origin. Plant Physiol. 1991;97:1271-1279. doi:
  25. 25. Maeda H, Dudareva N. The shikimate pathway and aromatic Amino acid biosynthesis in plants. Annu Rev Plant Biol. 2012;63:73-105. doi:
  26. 26. Andrews PR, Cain EN, Rizzardo E, Smith GD. Rearrangement of chorismate to prephenate. Use of chorismate mutase inhibitors to define the transition state structure. Biochemistry. 1977;22:4848-4852. doi:
  27. 27. Gray JV, Golinelli-Pimpaneau B, Knowles JR. Monofunctional chorismate mutase from Bacillus subtilis: purification of the protein, molecular cloning of the gene, and overexpression of the gene product in Escherichia coli. Biochemistry. 1990;29:376-383. doi:
  28. 28. KrappmannS,HelmstaedtK,GerstbergerT,EckertS,HoffmannB,HoppertM,SchnappaufG,BrausGH. The aroC gene of Aspergillus nidulans codes for a monofunctional, allosterically regulated chorismate mutase. J Biol Chem. 1999;274:22275-22282. doi:
  29. 29. Holland CK, Berkovich DA, Kohn ML, Maeda H, Jez JM. Structural basis for substrate recognition and inhibition of prephenate aminotransferase from Arabidopsis. Plant J. 2018;94(2):304-314. doi:
  30. 30. Bross CD, Howes TR, Abolhassani Rad S, Kljakic O, Kohalmi SE. Subcellular localization of Arabidopsis arogenate dehydratases suggests novel and non-enzymatic roles. J Exp Bot. 2017;68(7):1425-1440. doi:
  31. 31. Cho MH, Corea OR, Yang H, Bedgar DL, Laskar DD, Anterola AM, Moog-Anterola FA, Hood RL, Kohalmi SE, Bernards MA, et al. Phenylalanine biosynthesis in Arabidopsis thaliana. Identification and characterization of arogenate dehydratases. J Biol Chem. 2007;282:30827-30835. doi:
  32. 32. Jorrín J, López-Valbuena R, Tena M. Purification and properties of phenylalanine ammonia-lyase from sunflower (Helianthus annuus L.) hypocotyls. Biochim Biophys Acta. 1988;964:73-82. doi:
  33. 33. Bandoni RJ, Moore K, Subba Rao PV, Towers GH. Phenylalanine and tyrosine ammonia-lyase activity in some Basidiomycetes. Phytochemistry. 1968;7:205-207. doi:
  34. 34. Xiang L, Moore BS. Inactivation, complementation, and heterologous expression of encP, a novel bacterial phenylalanine ammonia-lyase gene. J Biol Chem. 2002;277:32505-32509. doi:
  35. 35. Emes AV, Vining LC. Partial purification and properties of L-phenylalanine ammonia-lyase from Streptomyces verticillatus. Can J Biochem. 1970;48:613-622. doi:
  36. 36. Czichi U, Kindl H. Formation of p-coumaric acid and o-coumaric acid from L-phenylalanine by microsomal membrane fractions from potato: evidence of membrane-bound enzyme complexes. Planta. 1975;125:115-125. doi:
  37. 37. Young MR, Towers GH, Neish AC. Taxonomic distribution of ammonia-lyases for L-phenylalanine and L-tyrosine in relation to lignification. Can J Bot. 1966;44:341-349. doi:
  38. 38. Liu T, Yao R, Zhao Y, Xu S, Huang C, Luo J, Kong L. Cloning, Functional Characterization and Site-Directed Mutagenesis of 4-Coumarate: Coenzyme A Ligase (4CL) Involved in Coumarin Biosynthesis in Peucedanum praeruptorum Dunn. Front. Plant Sci. 2017;8:4. doi:
  39. 39. Brenda Winkel-Shirley. Flavonoid Biosynthesis. A Colorful Model for Genetics, Biochemistry, Cell Biology, and Biotechnology. Plant Physiology Jun 2001, 126 (2) 485-493. doi:
  40. 40. Sanchez IJF. Polyketide synthase in Cannabis sativa L. PhD thesis, Leiden University, Leiden, The Netherlands; 2008
  41. 41. Mierziak J, Kostyn K, Kulma A. Flavonoids as important molecules of plant interactions with the environment. Molecules. 2014;19:16240-16265. doi:
  42. 42. Koes RE, Quattrocchio F, Mol JNM. The flavonoid biosynthetic pathway in plants: function and evolution. BioEssays. 1994;16:123-132. doi:
  43. 43. Martens S, Preuss A, Matern U. Multifunctional flavonoid dioxygenases: flavonols and anthocyanin biosynthesis in Arabidopsis thaliana L. Phytochemistry. 2010;71:1040-1049. doi:
  44. 44. SteeleCL,GijzenM,QutobD,DixonRA. Molecular characterization of the enzyme catalyzing the aryl migration reaction of isoflavonoid biosynthesis in soybean. Arch Biochem Biophys. 1999;367:146-150. doi:
  45. 45. YuO,JungW,ShiJ,CroesRA,FaderGM,McGonigleB,OdellJT. Production of the isoflavones genistein and daidzein in non-legume dicot and monocot tissues. Plant Physiol. 2000;124:781-794. doi:
  46. 46. Meng C, Zhang S, Deng Y-S, Wang G-D, Kong F-Y. Overexpression of a tomato flavanone 3-hydroxylase-like protein gene improves chilling tolerance in tobacco. Plant Physiol. Biochem. 2015;96:388-400. doi:
  47. 47. Han Y, Huang K, Liu Y, Jiao T, Ma G, Qian Y, et al. Functional analysis of two flavanone-3-hydroxylase genes from Camellia sinensis: a critical role in flavonoid accumulation. Genes. 2017;8:E300. doi: 10.3390%2Fgenes8110300
  48. 48. Holton TA, Brugliera F, Tanaka Y. Cloning and expression of flavonol synthase from Petunia hybrida. Plant J. 1993;4:1003-1010. doi:
  49. 49. Owens DK, Alerding AB, Crosby KC, Bandara AB, Westwood JH, Winkel BS. Functional analysis of a predicted flavonol synthase gene family in Arabidopsis. Plant Physiol. 2008;147:1046-1061. doi:
  50. 50. Nielsen K, Deroles SC, Markham KR, Bradley MJ, Podivinsky E, Manson D. Antisense flavonol synthase alters copigmentation and flower color in lisianthus. Mol Breeding. 2002; 9:217-229. doi:
  51. 51. Shi M-Z, Xie D-Y. Biosynthesis and metabolic engineering of anthocyanins in Arabidopsis thaliana. Recent patents on biotechnology. 2014;8(1):47-60. doi:
  52. 52. Shimada N, Sasaki R, Sato S, Kaneko T, Tabata S, Aoki T, et al. A comprehensive analysis of six dihydroflavonol 4-reductases encoded by a gene cluster of the Lotus japonicus genome. Journal of Experimental Botany. 2005;56(419):2573-2585. doi:
  53. 53. Hua C, Linling L, Shuiyuan C, Fuliang C, Feng X, Honghui Y, et al. Molecular cloning and characterization of three genes encoding dihydroflavonol-4-reductase from Ginkgo biloba in anthocyanin biosynthetic pathway. PloS one. 2013;8(8):e72017–e. doi:
  54. 54. Ahmed NU, Park J-I, Jung H-J, Yang T-J, Hur Y, Nou I-S. Characterization of dihydroflavonol 4-reductase (DFR) genes and their association with cold and freezing stress in Brassica rapa. Gene. 2014;550(1):46-55. doi:
  55. 55. Tian J, Han Z-Y, Zhang J, Hu Y, Song T, Yao Y. The Balance of Expression of Dihydroflavonol 4-reductase and Flavonol Synthase Regulates Flavonoid Biosynthesis and Red Foliage Coloration in Crabapples. Scientific Reports. 2015;5. doi:
  56. 56. Luo P, Ning G, Wang Z, Shen Y, Jin H, Li P, et al. Disequilibrium of Flavonol Synthase and Dihydroflavonol-4-Reductase Expression Associated Tightly to White vs. Red Color Flower Formation in Plants. Frontiers in Plant Science. 2016;6. doi:
  57. 57. Tanner GJ, Francki KT, Abrahams S, Watson JM, Larkin PJ, Ashton AR. Proanthocyanidin biosynthesis in plants. Purification of legume leucoanthocyanidin reductase and molecular cloning of its cDNA. J Biol Chem. 2003;278:31647-33156. doi:
  58. 58. Xie DY, Sharma SB, Dixon RA. Anthocyanidin reductases from Medicago truncatula and Arabidopsis thaliana. Arch. Biochem Biophys. 2004;422:91-102. doi:
  59. 59. Xie DY, Sharma SB, Paiva NL, Ferreira D, Dixon RA. Role of anthocyanidin reductase, encoded by BANYULS in plant flavonoid biosynthesis. Science. 2003;299:396-399. doi:
  60. 60. Pang Y, Abeysinghe IS, He J, He X, Huhman D, Mewan KM, et al. Functional characterization of proanthocyanidin pathway enzymes from tea and their application in metabolic engineering. Plant Physiol. 2013;161:1103-1116. doi:
  61. 61. Gargouri M, Chaudière J, Manigand C, Maugé C, Bathany K, Schmitter JM, et al. The epimerase activity of anthocyanidin reductase from Vitis vinifera and its regiospecific hydride transfers. Biol Chem. 2010;391:219-227. doi:
  62. 62. Zhao J, Dixon RA. MATE transporters facilitate vacuolar uptake of epicatechin 3′-O-glucoside for proanthocyanidin biosynthesis in Medicago truncatula and Arabidopsis. Plant Cell. 2009;21:2323-2340. doi:
  63. 63. Liu C, Jun JH, Dixon RA. MYB5 and MYB14 play pivotal roles in seed coat polymer biosynthesis in Medicago truncatula. Plant Physiol. 2014;165:1424-1439. doi:
  64. 64. Sanchez IJF. Polyketide synthase in Cannabis sativa L. PhD thesis. Leiden University, Leiden, The Netherlands; 2008
  65. 65. Iwashina T. The structure and distribution of the flavonoids in plants. J Plant Res. 2000;113:287-99. doi:
  66. 66. Zhu F, Jiang D, Zhang M, Zhao B. 2,4-Dihydroxy-3′-methoxy-4′-ethoxychalcone suppresses cell proliferation and induces apoptosis of multiple myeloma via the PI3K/akt/mTOR signaling pathway. Pharm Biol. 2019;57(1):641-648. doi:
  67. 67. Escobar-Ramos A, Lobato-García CE, Zamilpa A, Gómez-Rivera A, Tortoriello J, González-Cortazar M. Homoisoflavonoids and Chalcones Isolated from Haematoxylum campechianum L., with Spasmolytic Activity. Molecules. 2017;22(9):1405. doi:
  68. 68. Meng C-Y, Han Y, Duan Y-X, Chen J-X, Hu Q-F, Gao X-M. Isolation of Chalcones from the Root of Codonopsis cordifolioidea and Their Antitobacco Mosaic Virus Activities. Asian Journal of Chemistry. 2013;25(17):9517-9519. doi:
  69. 69. Namratha V, Rao GV. Isolation and structure determination of a new 2, 2-dimethyl chromeno dihydro chalcone from Crotalaria ramosissima. Int J Chem Sci. 2009;7(2):981-985
  70. 70. Alawaf H. Phytochemical analysis, isolation and identification of flavan-3ol from Syrian Pinus halepensis. Chemistry and Materials Research. 2017;9(4)
  71. 71. Parvez MK, Al-Dosari MS, Ahmed S, Rehman MT, Al-Rehaily AJ, Alajmi MF. Oncoglabrinol C, a new flavan from Oncocalyx glabratus protects endothelial cells against oxidative stress and apoptosis, and modulates hepatic CYP3A4 activity. Saudi Pharmaceutical Journal. 2020;28:648-656. doi:
  72. 72. Guyasa B, Melaku Y, Endale M. Antibacterial activity of two flavans from the stem bark of Embelia schimperi. Adv Pharmacol Sci. 2018;2018:5870161. doi:
  73. 73. Gleńsk M, Dudek MK, Ciach M, Włodarczyk M. Isolation and structural determination of flavan-3-ol derivatives from the Polypodium vulgare L. rhizomes water extract. Natural Product Research. 2019;1-10. doi:
  74. 74. DuyCuong DT, Dat HT, Duan NT, Thuong PD, Phat NT, Tri MD, Son DV, Hoa NT, KimTuyen PN, PhiPhung NK. Isolation and characterization of six flavonoids from the leaves of Sterculia foetida Linn. Vietnam J Chem. 2019;57(4):438-442. doi:
  75. 75. Meesakul P, Pudhom K, Pyne SG, Laphookhieo S. Hybrid flavan–flavanones from Friesodielsia desmoides and their inhibitory activities against nitric oxide production. RSC Adv. 2017;7:17545. doi:
  76. 76. Yang M-X, Liang Y-G, Chen H-R, Huang Y-F, Gong H-G, Zhang T-Y, Ito Y. Isolation of Flavonoids From Wild Aquilaria sinensis Leaves by an Improved Preparative High-Speed Counter-Current Chromatography Apparatus. Journal of Chromatographic Science. 2018;56(1):18-24. doi:
  77. 77. Abreu AC, Coqueiro A, Sultan AR, Lemmens N, Kim HK, Verpoorte R, van Wamel WJB, Simões M, Choi YH. Looking to nature for a new concept in antimicrobial treatments: isoflavonoids from Cytisus striatus as antibiotic adjuvants against MRSA. Sci Rep. 2017;7(1):3777. doi:
  78. 78. QuirozA,MendezL,MutisA,HormazabalE,OrtegaF,BirkettMA,ParraL.Antifeedant activity of red clover root isoflavonoids on Hylastinus obscurus.Journal of Soil Science and Plant Nutrition.2017;17(1):231-239. doi:
  79. 79. Dizamatova A, Zhumanova K, Zhusupova GE, Zhussupova AI, Srivedavyasasri R, Ibrahim MA, Ross SA. A new prenylated isoflavonoid from Limonium leptophyllum. Natural Product Communications. 2019;1-5. doi:
  80. 80. Kothari M, Jain DK. Quantification of phytoconstituents and isolation of Flavonoids from procedure to extract isoflavones from soybean seeds. Journal of Cleaner Production. 2018;170:1102e1110
  81. 81. He J, Fan P, Feng S, Shao P, Sun P. Isolation and purification of two isoflavones from Hericium erinaceum mycelium by High-Speed Counter-Current Chromatography. Molecules. 2018;23(3):560. doi:
  82. 82. Kishore N, Twilley D, vanStaden AB, Verma P, Singh B, Cardinali G, Kovacs D, Picardo M, Kumar V, Lall N. Isolation of Flavonoids and Flavonoid Glycosides from Myrsine africana and Their Inhibitory Activities against Mushroom Tyrosinase. J Nat Prod. 2018;81:49−56. doi:
  83. 83. Gupta R, Gupta GD. Isolation and characterization of flavonoid glycoside from Cordia obliqua Willd. Leaf. International Journal of Green Pharmacy. 2018;12(2). doi:
  84. 84. Arora S, Itankar P. Extraction, isolation and identification of flavonoid from Chenopodium album aerial parts. Journal of Traditional and Complementary Medicine. 2018;8(4):476-482. doi:
  85. 85. Ahmed SI, Hayat MQ, Zahid S, Tahir M, Mansoor Q, Ismail M, Keck K, Bates R. Isolation and identification of flavonoids from anticancer and neuroprotective extracts of Trigonella foenum graecum. Trop J Pharm Res. 2017;16(6):1391. doi:
  86. 86. Utari F, Itam A, Syafrizayanti S, Putri WH, Ninomiya M, Koketsu M, Tanaka K, Efdi M. Isolation of flavonol rhamnosides from Pometia pinnata leaves and investigation of α-glucosidase inhibitory activity of flavonol derivatives. Journal of Applied Pharmaceutical Science. 2019;9(08):053-065. doi:
  87. 87. Sun Q, Pan G, Xu W, Lu X, Bai C, Liu M, Chen Y. Isolation and structure elucidation of a new flavonol glycoside from Sabia Parviflora. Natural Product Research. 2019;1-6. doi:

Written By

Mohd Rehan

Submitted: 12 November 2020 Reviewed: 08 February 2021 Published: 18 May 2021