Stilbene biosynthetic pathway

In recent years, a growing number of transcription factors involved in the regulation of flavonol, lignin, and anthocyanin metabohsm have been characterized [1]. However, to date, no transcription factors responsible for regulating the stilbene biosynthetic pathway have been characterized. 

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 biosynthesis of flavonoids, stilbenes, hydroxycinnamates, and phenolic acids involves a complex network of routes based principally on the shikimate, phenyl-propanoid, and flavonoid pathways (Figs. 1.35 and 1.36). These biosynthetic pathways constitute a complex biological regulatory network that has evolved in vascular plants during their successful transition on land and that ultimately is essential for their growth, development, and survival [Costa et al., 2003]. 

Figure 1.36 Schematic diagram of the stilbene and flavonoid biosynthetic pathway. Enzyme abbreviations SS, stilbene synthase CHS, chalcone synthase CHR, chalcone reductase CHI, chalcone isomerase IFS, isoflavone synthase FNS, flavone synthase F3H, flavanone 3-hydroxylase FLS, flavonol synthase F3 H, flavonoid 3 -hydroxylase DFR, dihydroflavonol 4-reductase LAR, leucoanthocyanidin 4-reductase LDOX, leucocyanidin deoxygenase ANR, anthocyanidin reductase EU, extension units TU, terminal unit.

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). 

Scheme 1. Formation of viniferins and plausible biosynthetic pathways of some stilbene dimers...

Scheme 2. Plausible biosynthetic pathways of some stilbene tetramers...

It is also important to consider any possible deleterious effects that resveratrol and its metabolites may have on plants. Production of defensive stilbenes in plants results in resource competition between parallel biosynthetic pathways. For example, one group of metabolites that may be severely impacted by this competition is the chalcones and their metabolites that play a variety of important roles in plants. These compounds share a pool of basic precursors with the stilbenoids [134,135]. Alterations in stilbenoid production could have far reaching effects on the health of the plant. The severity of this problem has been highlighted by Fischer and colleagues [136] who reported that overexpression of a stilbene synthase gene in transgenic tobacco and petunia plants resulted male in sterility. 

Fig. 53.5 Biosynthetic pathways engineered in S. cerevisiae for the production of varieties of flavonoids, isoflavonoids, and stilbenes...

Katsuyama Y, Funa N, Miyahisa I, Horinouchi S (2007) Synthesis of unnatural flavonoids and stilbenes by exploiting the plant biosynthetic pathway in Escherichia coli. Chem Eiol 14 613-621. doi 10.1016/j.chembiol.2007.05.004... 

Fig. 51.1 Chemical structures of stilbenes (a) flavonoids biosynthetic pathway (b). The expression of a stilhene synthase gene in transgenic plants competes with substrates used in the first step of the complex route of flavonoids...

The biosynthesis of simple stilbenes has been found out, and it shared a similar biosynthetic pathway with the flavonoids. Taking resveratrol for example, it starts from a cinnamoyl-CoA unit and extended the chain with three malonyl-CoA molecules (Scheme 62.1) [105]. Then, the resveratrol structure is produced by aldol reaction with the presence of stilbene synthase. Nevertheless, the flavonoids are formed depending on chalcone synthase and Claisen reaction. 

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). 

Figure 10.10 Biosynthetic pathway of pro- 4CL, 4-coumarate coenzyme A iigase CCL, duction of resveratrol and its derivatives cinnamate/4-coumarate coenzyme A Iigase from phenylalanine or tyrosine. PAL, pheny- STS, stilbene synthase and ROMT, resveratrol lalanine ammonia-lyase C4H, clnnamate-4- 0-methyltransferase. (Adapted from Jeong hydroxylase TAL, tyrosine ammonla-lyase et al. [135].)...

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