Chalcones tetrahydroxychalcone

In addition to the bitter acids and essential oils, the flowers of hops offer a rich array of polyphenolic compounds, primarily chalcones and their accompanying flavanones, many of which are prenylated derivatives (Stevens et al., 1997,1999a, b). The most prominent flavonoid in all plants studied was xanthohumol [342] (3 -prenyl-6 -0-methylchalconaringenin chalconaringenin is 2, 4, 6, 4-tetrahydroxychalcone) (see Fig. 4.11 for structures 342-346). Several additional chalcones—variously adorned with 0-methyl and/or C-prenyl functions—were also encountered, along with their respective flavanones. Three new compounds were described in the Stevens et al. 

Recently, a new polyketide biosynthetic pathway in bacteria that parallels the well studied plant PKSs has been discovered that can assemble small aromatic metabolites.8,9 These type III PKSs10 are members of the chalcone synthase (CHS) and stilbene synthase (STS) family of PKSs previously thought to be restricted to plants.11 The best studied type III PKS is CHS. Physiologically, CHS catalyzes the biosynthesis of 4,2, 4, 6 -tetrahydroxychalcone (chalcone). Moreover, in some organisms CHS works in concert with chalcone reductase (CHR) to produce 4,2 ,4 -trihydroxychalcone (deoxychalcone) (Fig. 12.1). Both natural products constitute plant secondary metabolites that are used as precursors for the biosynthesis of anthocyanin pigments, anti-microbial phytoalexins, and chemical inducers of Rhizobium nodulation genes.12... 

The biological activity of isoprenylated chalcones from the Moraceae has been described both in original papers and reviews. Of particular interest is the potent 5-a-reductase inhibition shown by a geranylated chalcone (84) isolated from leaves of Artocarpus incisus The inhibitory effect is decreased by a factor of 2 when the geranyl substituent is lacking, as in butein (2, 4, 3,4-tetrahydroxychalcone). Compound 41, which was obtained from the leaves of Madura tinctoria together with four known isoprenylated flavonoids, showed inhibitory... 

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]. 

Flavonoid biosynthesis (Figure 3-7) is initiated from the condensation of / -coumaroyl-CoA (3.31) with three molecules malonyl-CoA (3.48), which is catalyzed by the enzyme chalcone synthase (CHS), and gives rise to 4,2, 4, 6 tetrahydroxychalcone (3.49). This compound can undergo a number of reactions that give rise to the different classes of compounds described in Section 3.6 of Chapter 1. 

Biochanin A (= 5,7-Dihydroxy-4 -methoxyisoflavone Pratensol) (isoflavone) Butein ( = 2, 4, 3,4-Tetrahydroxychalcone) (chalcone)... 

Chalcone synthase (CHS) and chalcone reductase (CHR) convert 4-coumaro-yl-CoA (15) and 3 mol malonyl-CoA (16) to trihydroxychalcone (a chalcone) (17) via tetrahydroxychalcone (a chalcone) (18). Chalcone isomerase (CHI) converts trihydroxychalcone (a chalcone) (17) into liquiritigenin (7,4/-dihydroxyllavanone, a flavanone) (19). Isoflavone synthase (IFS) converted flavanone (19) to isoflavones (20) such as daidzein (21) and genis-tein (22). Isoflavone 2/-hydroxylase (I2 H) hydroxylated isoflavones (20) to 4/-methoxyisoflavones (23). Isoflavone 2 -hydroxylase (I2 H) hydroxylated 4/-methoxyisoflavones (23) into 2/-hydroxy-4/-methoxyisoflavones (24). Isoflavone reductase (IFR) reduced 2/-hydroxy-4/-methoxyisoflavones (24) to 2/-hydroxy-4/-methoxyisoflavonones (25). Finally, vestitone reductase (VR) and 4/-methoxyisoflavanol dehydrogenase (DMID) cyclized 2/-hydroxy-4/-methoxyisoflavonones (25) to form isoflavonoids (26) such as medicarpin (27) (Fig. 4) [23,24]. 

Aurones (28) were synthesized from 4-coumaroyl-CoA (15) and malonyl-CoA (16) via tetrahydroxychalcone (chalcone, 18) and trihydroxychalcone (17)), using chalcone synthase (CHS) and chalcone reductase (CHR). Au-reusidin synthase (AS) converted trihydroxychalcone (17) to aurones (28) (Fig. 5) [23,24],... 

Tetrahydroxychalcone (18) was converted to naringenin (1) by chalcone iso-merase (CHI), and then to flavones (29) by flavone synthase I (FSI) and flavone synthase II (FSII), respectively (Fig. 6). 

Fig. 7 Biosynthesis of flavonols (35) via naringenin (1) from tetrahydroxychalcone (chalcone, 18)...

Type III polyketide synthases are responsible for the biosynthesis of a vast number of plant-derived natural products, including flavonoids derived from the important branch metabolite 4 ,2 ,4 ,6 -tetrahydroxychalcone, the product of the enzyme chalcone synthase (39). Because chalcone synthase was the first type III enzyme discovered, and a second flavonoid pathway type III enzyme, stilbene synthase, was discovered shortly thereafter, type III PKSs are also collectively referred to as the chalcone synthase/stilbene synthase superfamily of enzymes (24,25). 

Type III synthases, as a whole, employ a wider spectrum of physiological starter molecules than their type I and II counterparts, including a variety of aromatic and aliphatic CoA esters such as coumaiyl-CoA, methyl-anthraniloyl-CoA, as well as the recently identified medium- and long-chain fiitty acyl-CoA ester starters used by certain bacterial and plant type III enzymes involved in the biosyndiesis of phenolic lipids (22, 24, Cook et al., unpublished results). The most extensively studied type III en mie, chalcone synthase (Fig. 4), uses 4-coumaryl-CoA as the starter unit and catalyzes three successive condensation reactions with malonyi-CoA as the extender. Cyclization and aromatization of the linear tetraketide intermediate is performed within the same active site, yielding the final product 4 ,2 ,4 ,6 -tetrahydroxychalcone. 

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). 

Type I and Type II PKSs catalyze multiple rounds of reactions by catalytic modules encoded either by a single polypeptide (PKS I) or on separate polypeptides (PKS II) by analogy to FAS-I and FAS-II. In contrast, PKS Ills are dimers of KASs that catalyze multiple condensation reactions in one active site and include chalcone synthase, stilbene synthase, and 2-pyrone synthase (see Chapters 1.05, 1.07, and 1.04). In the case of chalcone synthase, three consecutive condensation reactions each utilizing malonyl-CoA, followed by a cyclization reaction, lead to the formation of 4, 2, 4, 6 -tetrahydroxychalcone from 4-hydroxycinnamoyl-CoA (Figure 3). Recruitment of a reductase leads to the formation of a product lacking the 6 -hydroxy group, a reaction that requires an intermediate in the synthesis of chalcone to dissociate from the synthase active site. 

A large number of phenolics are derived from the C15 flavonoid skeleton, which is synthesised via the chalcone synthase (CHS) catalysed condensation of p-coumaroyl-coenzyme A and three molecules of malonyl-CoA. In most plant families, the initial CHS product is a tetrahydroxychalcone, which is further converted to other flavonoid classes, such as flavones, flavonols, flavanones, flavan-3-ols, isoflavones and anthocyanins (Fig. 2). Structural diversity among the phenylpropanoids arises from a variety of modifications, including... 

The biosynthetic pathway for isoflavonoids in soybean and the relationship of the isoflavonoids to several other classes of phenylpropanoids is presented in Fig. 8.2. Production of /i-coumaryl-CoA from phenylalanine requires phenylalanine ammonia lyase to convert phenylalanine to cinnamate, cinnamic acid hydroxylase to convert cinnamate to /7-coumarate, and coumaraterCoA ligase to convert jt -coumarate to -coumaroyl-CoA. Lignins may be produced from j3-coumaroyl-CoA or from />-coumarate. Chalcone synthase catalyzes the condensation of three molecules of malonyl CoA with p-coumaroyl-CoA to form 4, 2 , 4 , 6 -tetrahydroxychalcone, which is subsequently isomerized in a reaction catalyzed by chalcone isomerase to naringenin, the precursor to genistein, flavones, flavonols, condensed tannins, anthocyanins, and others. 

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