Naringenin formation

Although naringenin has been established as the natural product of the synthase from parsley because 4-coumaroyl-CoA was the only substrate utilized efficiently (Hrazdina et al., 1976), production of eriodictyol (5,7,3, 4 -tetrahydroxyflavanone) (XIX) from caffeoyl-CoA and malonyl-CoA by a similar enzyme from H. gracilis was pronounced at a lower pH (6.5-7.0). Naringenin formation had a pH optimum of 8.0 (Saleh et al., 1978). Ligase enzymes responsible for the activation of appropriate acids to their CoA derivatives have been isolated from parsley (Knobloch and Hahlbrock, 1977) and a variety of plant tisues (Gross and Zenk, 1974 Knobloch and Hahlbrock, 1975) and require ATP, CoA, and Mg " " as cofactors. 

Chalcones with a C6-C3-C6 structure are flavonoids lacking a heterocyclic C-ring. Generally, plants do not accumulate chalcones. After its formation, naringenin... 

The stereospecific cyclization of chalcones to (2S)-flavanones is a prerequisite for the synthesis of the majority of fiavonoid subclasses derived from this branch point metabolite. This reaction is catalyzed by chalcone isomerase (CHI, CFI EC 5.5.1.6). CHI exists in two forms, one that accepts only 6 -hydroxychalcones and another that accepts both 6 -hydroxy-(naringenin chalcone) and 6 -deoxychalcones (isoliquirgentin), the latter generally found in legumes. Although 6 -hydroxychalcones will spontaneously convert to a racemic flavanone mixture, the CHI-catalyzed reaction proceeds at a rate 36 million-fold faster and is highly stereoselective for the formation of (25)-flavanones [60]. Spontaneous isomerization of 6 -deoxychalcones does not substantially occur without enzyme catalysis. 

Kreuzaler F, Hahlbrock K (1972) Enzymatic synthesis of aromatic compounds in higher plants formation of naringenin (5,7,4 -trihydroxyflavanone) from p-coumaroyl coenzyme A and malonyl coenzyme A. FEBS Lett 28(l) 69-72... 

Heller, W. and Hahlbrock, K. (1980) Highly purified flavanone synthase from parsley catalyzes the formation of naringenin chalcone. Archives of Biochemistry and Biophysics 200(2), 61 7-619. 

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... 

Figure 1. Proposed mechanism for the formation of (A) naringenin chalcone from 4-coumaroyl-CoA and three molecules of malonyUCoA by CHS, (B) triacetic lactone from acetyl-CoA and two molecules of malortyUCoA by 2PS, (C) aloesone from acetyl-CoA and six molecules of malonyUCoA by ALS, (D) 5,7-dihydroxy-2-methylchromone from five molecules of malonyl-CoA by PCS, and (E) SEK4 and SEK4b from eight molecules of malonyl-CoA by OKS. Bis-noryangonin (BNY) and 4-coumaroyltriacetic acid lactone (CTAL) are derailment by-products of the CHS reactions in vitro when the reaction mixtures are acidified before extraction. In A. arborescens PCS and OKS, acetyl-CoA, resulting from decarboxylation of malonyl-CoA, is also accepted as a starter but not so efficiently as in the case ofR. palmatum ALS.

Flavonoids also showed, to some extent, some antifungal and antiviral activity. In this case, there is an important structure-activity relationship. The flavonol quercetin and the flavanone hesperidin exhibit inhibition activity towards the infective capacity and/or replication of herpes simplex type viruses and polio viruses, while the flavanone naringenin totally lacks this ability [124]. For researchers the impossibility to dissociate, the viruses from the flavonol quercetin after 1 hour of interaction, either by dialysis or ultracentrifugation suggests the formation of quercetin-virus complexes, which may have lost the ability to induce infection. With respect to the antiviral activity of the methoxylated flavones, this is strongly related to a substitution pattern based on... 

Documented effects In modem medicine, water decoctions and infusions, liquid extracts, and dry concentrates of the inflorescences, as well as the preparation Flamin, are used as a choleretic for treating liver disease, cholecystitis and hepa-tocholecystitis (Khodzhimatov 1989). An ethanohc extract of the flowers and the compound naringenin chalcone (isolated from the extract) showed antiproliferative activity against mouse skin tumor cells in vitro. Application of isosalipurposide, isolated from the flowers, delayed formation of papillomas in an in vivo assay of carcinogenesis on mouse skin (Yagura et al. 2008). 

However, the flavanone naringenin (10) [but not dihydro-kaempferol (13)] is the substrate for flavone formation in snapdragons. Antirrhinum majus (Scrophulariaceae) (flavone synthase II) (Fig. 11.10). In this plant, flavones arise from dehydrogenation of flavanones and not from dehydration of dihydroflavonols (Britsch et al., 1981). A similar enzyme system converts dihydroflavonols to flavonols (Britsch et al., 1981). In other work, the enzyme responsible for oxidation of flavanones to flavones in snapdragon Antirrhinum majus) was isolated from a microsomal fraction and shown to require NADPH and molecular oxygen (Britsch et al., 1981 Dewick, 1989 Forkmann and Stotz, 1981). The system appears to be a cytochrome P-450-dependent monooxygenase. This system also is known from Glycine max... 

Scheme 5. Formation of bisnoryangonin (XVIII) and naringenin (XVI) by flavanone synthase (EI8). HS, Thiol binding sites (after Kreuzaler and Hahlbrock, 1975a).

The further biosynthetic pathway to anthocyanins involves the formation of L-phenylalanine from chorismic acid. L-phenylalanine is then converted to trans-cmrL mic acid through fra 5-elimination of ammonia. In a second step fra 5-cinnamic acid is hydroxylated and activated to yield 4-coumaroyl-CoA. In the next step, 4-coumaroyl-CoA is condensed with 3 molecules of malonyl-CoA to yield naringenin chalcone. naringenin chalcone is rapidly and stereospecifically isomerized to naringenin. 

Scheme 12.23. The formation of naringenin chalcone, the progenitor for flavonoids. The chalcone forms from 4-coumaroyl-CoA (produced from coumatic acid using the enzyme 4-coumarate-CoA ligase, EC 6.2.1.12, coenzyme A, and ATP) and 3 equivalents of malonyl-CoA (the enzyme is naringenin chalcone synthase, EC 2.3.1.74) followed by a cyclization.

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