Flavonoid precursor chalcone

Addition. Resveratrol. The biosynthetic pathway to resveratrol diverges from the flavonoid pathway after the third malonyl-CoA condensation. Cyclization of the common polyketide intermediate catalyzed by resveratrol synthase yields the stilbene derivative resveratrol, whereas the same intermediate catalyzed by chal-cone synthase yields the common flavonoid precursor chalcone (Fig. 6.8). Resveratrol, well known as a functional food ingredient (e.g., grape skin, red wine) with strong antioxidant properties (cardiovascular protection), and its 3-glucopyranoside piceid turned out to be also present in the skin of tomato fruits, S. lycopersicum (Ragab et al. 2006). 

Ring closure of the polyketide chain of (685) generates a chalcone (686), from which a flavanone is derived by a further cyclization (Scheme 276). The latter may be regarded as the precursor of all other flavonoids, although it should be noted that an enzyme-catalyzed equilibrium exists between chalcone and flavanone. Chalcone may therefore function as the flavonoid precursor rather than flavanone (68P1751). 

One mole 4-hydroxycinnamic acid (14) might react with 3 mol acetic acids to yield a precursor chalcone (57) and then flavonoids (58) (Fig. 11) [25,26]. The proposed biosynthesis of flavonoids was confirmed in a Antirrhinum majus... 

As described above, the first enzyme general to all flavonoid biosynthesis, chalcone synthase (naringenin-chalcone synthase), catalyzes the cyclization of a precursor formed from p-coumaryl-CoA and three units of malonyl-CoA (Fig. 11.6) (Dewick, 1989 Gerats and Martin, 1992 Heller and Forkmann, 1988). The enzyme, usually found in plant epidermal cells, has a molecular weight of about 42,000, requires no cofactors, and has been isolated from several plant cell cultures such as French bean Phaseolus vulgaris), parsley Petroselinum crispum), and the flowers of the carnation (Dianthus caryophyllus, Caryophyllaceae) (Hutchinson, 1986). p-Coumaiic acid and malonyl-CoA are the preferred precursors. Malonyl-ACP will not serve. 

Flavonoids are a diverse family of plant polyphenols and of special interest due to their potential in the treatment of various human diseases. The first attempts to produce flavonoid precursors were accomplished by cloning of the flavanone pathway consisting of cinnamate-4-hydroxylase (CYP73A5) from A. thalima together with 4-coumaroyl CoA ligase (4CL), chalcone synthase (CHS), and chalcone isomerase (CHI) in S. cerevisiae [410], The generated strain was able to convert cinnamic acid to 200 pg naringenin... 

Biogenetically, chalcones are the immediate precursors of flavanones, and some flavanones isomerize by ring opening into chalcones during isolation from plants or after chemical treatment with alkali. In turn, flavanones are intermediates in the biosynthesis of most other flavonoid groups, including flavones, flavonols, and isoflavonoids. For more information on the biosynthesis of flavonoids and flavanones in particular, the reader is referred to Chapter 3 and reviews by Heller and Forkmann. ... 

Their biosynthesis derives from the condensation of three acetyl units and of a derivative of hydroxycinnamic acid leading to the formation of a common intermediate, tetrahydroxychalcone. This chalcone is precursor of several compounds, the most important being the 4-oxo-flavonoids [19]. 

The parent nucleus of the flavonoids is flavone ((58), 2-phenylchromone or 2-phenylbenzopyran-4-one). Flavone and isoflavone ((59), 3-phenylchromone, the parent nucleus of the isoflavonoids) are the simplest oxygen-containing naturally occurring compounds that possess the 2-phenylnaphthalene -type structure. The chalcones, represented by the nucleus (60), may be regarded as open-chain flavonoids and are usually hydroxylated. The interconversion of chalcone and flavonone catalyzed by chalcone isomerase is well known [326, 327, 331], Chalcones can be precursors of both the flavonoids and the isoflavonoids [326-332]. 

The main flavonoid skeleton derives from the stepwise condensation of three molecules of malonyl CoA with one molecule of 4-coumaroyl CoA, a reaction catalyzed by chalcone synthase (CHS) to form naringenin (2, 4,4 ,6,-tetrahydroxy) chalcone, the common intermediate in the formation of all flavonoids with 5,7-dihydroxy (flavone numbering) A-ring substitution. In some plants, however, an NADP-dependent chalcone-ketide reductase coacts with CHS to form 6 -deoxychalcone, the precursor of 5-deoxyflavonoids. The resulting chalcones undergoe a stereospecific cyclization to the corresponding (2S) flavanones, the... 

Chalcone synthase (CHS), the first plant natural product polyketide synthase (PKS) to be characterized at the molecular level (39), catalyzes the condensation of 4-coumaroyl-CoA with three molecules of malonyl-CoA to afford naringenin chalcone, a precursor of the major classes of plant flavonoids. The cloning of a novel type III pentaketide chromone synthase (PCS) from aloe (Aloe arborescens, Liliaceae) rich in aromatic polyketides, especially quinones such as aloe-emodin and emodin, resulted in... 

BPS catalyzed the stepwise condensation of benzoyl-CoA with three molecules of malonyl-CoA to give a tetraketide intermediate that was cyclized by intramolecular Claisen condensation into 2,4,6-trihydroxybenzophenone (Figure 2). The enzyme was inactive with CoA-linked ciimamic acids such as 4-coumaroyl-CoA, the preferred starter substrate for chalcone synthase (CHS). BPS and CHS from H. androsaemum cell cultures shared 60.1% amino acid sequence identity. CHS is ubiquitous in higher plants and the prototype enzyme of the type III PKS superfamily (1,2). It uses the same reaction mechanism like BPS to form 2, 4,4, 6 -tetrahydroxychalcone, the precursor of flavonoids (Figure 2). 

Flavonoids are a large class of plant natural products of low molecular weight. Over 3,000 different flavonoids have been chemically characterised and novel ones are still being reported. Flavonoids are aromatic molecules synthesised from the amino acid phenylalanine and an acetate-derived precursor as malonyl-coenzyme A (Fig. 11.1) (Winkel-Shirley 2001). This reaction is carried out by the enzyme chalcone synthase (CHS) to produce chalcone. The chalcone can subsequently be isomerised by the enzyme chalcone flavone isomerase (CHI) to yield a flavanone. From these intermediates the pathway diverges into several side branches yielding different subclasses of flavonoids, as summarised in Fig. 

The basic structural model of flavanones is the 2-phenylbenzopiran-4-one skeleton [6], The flavanones are compounds of great interest due to the fact that they are a compulsory step in the metabolic pathway of the other flavonoids. Their metabolic precursors are the chalcones, and the flavones, the dihydroflavonols, and the isoflavones are biosynthesised from the flavanones. 

Alternatively, chalcone reductase (CHR also known as deoxychalcone synthase) together with chalcone synthase and NADPH as a cofactor act in the formation of isoliquiritigenin, which is then isomerized, again by the enzyme chalcone isomerase, to form liquiritigenin, the precursor to daidzein, and the pterocarpan phytoalexins. A type II chalcone isomerase that seems to be found exclusively in the legumes catalyzes this isomerization reaction. Glycitein synthesis is not yet clearly defined, but is likely derived from liquiritigenin via flavonoid 6-hydroxylase, and an unidentified methyltransferase. 

Chalcones (e.g., 9) are key intermediates in the formation of several major groups of flavonoids (see Fig. 11.2). In some plants, they are converted into aurones (such as 11). In other instances, chalcones undergo reduction of the exocy-clic double bond to produce dihydrochalcones (such as 12). Chalcones and flavanones (e.g., 10) exist in equilibrium in in vitro systems. However, as only flavanones with a (25)-configuration are known to occur naturally, this interconversion appears to be enzymatically controlled and does not involve racemization. Desaturation of flavanones can yield flavones (such as 4 and 5), whereas introduction of oxygen at the 3-position gives dihydroflavonols (flavanonols) (such as 13) which, in turn, are the precursors of flavonols (e.g., 6-8), anthocyanins (e.g., 1-3), and condensed tannin precursors (Ebel and H lbrock, 1982 Hahlbrock, 1981 Haslam 1974) (Figs. 11.7 and 11.8). 

The first product of the addition reaction between malonyl CoA and p-coumarate, a cinnamic acid derivative, is a chalcone derivative. Chalcones can be considered as the precursors of all other classes of flavonoids (Fig. 7). In general, all flavonoid compounds originate from a C5-C3-C6 chalcone unit, of which the central C3 moiety shows structural variations leading to the formation of various types of flavonoids. The number of hydroxyl groups introduced in ring A at the stage of cyclization depends upon the degree of reduction of the triacetate chain. The first... 

Chalcones are the major intermediates of flavonoid biosynthetic pathways they are produced by the condensation of three molecules of malonyl-CoA and a single molecule of 4-coumaryl-CoA. The major precursor malonyl-CoA is derived from citrate, an intermediate product of the TCA cycle. Acetyl-CoA is produced in mitochondria, plastids, peroxisomes, and cytosol via various routes. The cytosolic acetyl-CoA, produced by the multiple subunit enzyme ATP-citrate lyase, is used by acetyl-CoA carboxylase (ACC) to form malonyl-CoA for flavonoid biosynthesis. Another precursor, 4-coumaryl-CoA, is available via the polypropanoid pathway, in which phenylalanine generated via the shikimate and aerogenate pathway is... 

Havanols are a wide group of polyphenols that include flavan-3-ols (e.g., catechin and proanthocyanidins), flavan-4-ols, and flavan-3,4-diols. They arise from plant secondary metabolism through condensation of phenylalanine derived from the shikimate pathway with malonyl-CoA obtained from citrate that is produced by the tricarboxylic acid cycle, leading to the formation of the key precursor in the flavonoids biosynthesis the naringenin chalcone. The exact nature of the molecular species that undergo polymerization and the mechanism of assembly in proanthocyanidins are still unknown. From a structural point of view, flavanols... 

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