Polyketides flavonoids

The flavonoids, which comprise the largest group of these natural products, are derived from a mixed acetate-shikimate pathway. A shikimate-derived C6-C3 unit combines with a six-carbon polyketide chain to provide the open-chain precursor (685) of the group. The derivation of p-hydroxycinnamic add (p-coumaric acid), the C6-C3 component, from shikimic acid proceeds through chorismic acid, prephenic acid and phenylalanine. 

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). 

The polyketide synthases responsible for chain extension of cinnamoyl-CoA starter units leading to flavonoids and stilbenes, and of anthraniloyl-CoA leading to quinoline and acridine alkaloids (see page 377) do not fall into either of the above categories and have now been termed Type TTT PKSs. These enzymes differ from the other examples in that they are homodimeric proteins, they utilize coenzyme A esters rather than acyl carrier proteins, and they employ a single active site to perform a series of decarboxylation, condensation, cyclization, and aromatization reactions. 

The biogenesis of flavonoids in plants is well documented and known to take place by chain extension of 4-hydroxycinnamoyl-CoA (126) with malonyl CoA through the acetate pathway involving enzymes like chalcone S3mthase (86). Here, the initially formed polyketide 127 may undergo a Claisen-type condensation to form a chalcone and subsequently other flavonoids, as shown in Fig. 25. It is pertinent to... 

Stilbenoids are derived from cinnamic acid and three acetate units from mal-onyl coenzym A. The first part of the biosynthesis is in common to flavonoids. The two biosynthetic routes are diverging at the point of cyclization of a styryl-3,5,7-triketoheptanoic acid. A C-acylation produces a chalcone and subsequent modifications lead to the flavonoids. An aldol condensation of the same intermediate polyketide produces a stilbene-2-carboxylic acid that is unstable and constitutes a range of structures known as stilbenoids. Figure 9C.5 shows an overview of the biosynthetic pathway (Gorham 1995). 

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... 

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). 

Natural products represent a diversity of chemical compounds with varied biological activities. Natural products are an important source of novel pharmaceuticals as well as agricultural pesticides (1,2). Natural products are derived from a number of pathways that create basic scaffolds that are further modified by various tailoring enzymes to create the wide diversity of structures that exist in nature. Polyketide synthases are responsible for the synthesis of an array of natural products including antibiotics such as erythromycin in bacteria (3) and mycotoxins such as aflatoxin in fungi (4). Furthermore, in plants they are part of the biosynthetic machinery of flavonoids, phytoalexins, and phenolic lipi (5,6). 

The first PKS crystal structure, that of alfolfa chalcone synthase (CHS) in 1999 (6), had previously revealed foe type III PKS internal active site cavity and conserved Cys/His/Asn catalytic triad responsible for starter substrate loading and iterative polyketide extension (6). CHS provides the first committed chemical intermediate in flavonoid biosynthesis by catalyzing foe sequential decarboxylative addition of three acetate units from maionyl-CoA to a p-... 

G. Forkmann W. Fieller, Biosynthesis ot Flavonoids. In Comprehensive Natural Products Chemistry, Vol. 1 Polyketides and Other Secondary Metabolites Including Fatty Acids and Their Derivatives U. Sankawa, Ed., Sir D. H. R. Barton, K. Nakanishi, O. Meth-Cohn, Series Eds. Elsevier Oxford, 1999 pp 713-748. 

Biaryl structures are wide-spread in many of naturally occuring products including alkaloids, lignans, terpenes, flavonoids, tannins, as well as polyketides, coumarins, peptides, glycopeptides, etc. For example, vancomycin (1) is a basic structure of several related glycopeptide antibiotics [1] balhimycin, actinoidin A, ristocetin A, teicoplanin A2-2, complestatin, etc which are important in medicinal chemistry or as a HPLC chiral stationary phases (vancomycin) [2]. 

Aromatic biosynthesis, aromatizatioa biosynthesis of compounds containing the benzene ring system. The most important mechanisms are 1. the shi-kimate/chorismate pathway, in which the aromatic amino acids, L-phenylalanine, L-tyrosine and L-trypto-phan, 4-hydroxybenzoic acid (precursor of ubiquinone), 4-aminobenzoie acid (precursor of folic acid) and the phenylpropanes, including components of lignin, cinnamic acid derivatives and flavonoids are synthesized and 2. the polyketide pathway (see Polyke-tides) in which acetate molecules are condensed and aromatic compounds (e.g. 6-methylsalicylic acid) are synthesized via poly-fl-keto acids. Biosynthesis of flavonoids (e.g. anthocyanidins) can occur by either pathway. 

In Chapter 11, Abreu, Branco, and Matthew provide a rather comprehensive, highlighted overview of natural-product-like combinatorial libraries representing a range of secondary metabolites including carbohydrates, fatty acid derivatives, polyketides, peptides, terpenoids, steroids, alkaloids, and flavonoids. 

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