Bergapten

Figure 7.14 Transformation of the coumarin umbelliferone gives rise to marmesin, which is transformed to psoralen by the action of psoralen synthase. Hydroxylation of psoralen and the following esterification give rise to the furanocoumarins bergaptol and bergapten, respectively.

in humans remain unclear. Several beneficial health effects in adults have been associated with phyto-oestrogens, such as a protective role against the development of breast and prostate cancers (Haddad and Fuqua, 2001).

The biosynthesis of the major classes of flavonoid derivatives is depicted in Figure 7.16. The enzymes involved in the main flavonoid transformations are: CHS, chalcone synthase; CHR, chalcone reductase; CHI, chalcone isomerase; FSI, flavone synthase I; FSII, flavone synthase II; FLS, flavonol synthase; IFS, isoflavone synthase, consisting of

Figure 7.15 Early steps in the biosynthesis of flavonoids by the action of the two key enzymes chal-cone synthase (CHS) and chalcone isomerase (CHI).
Biosynthesis Anthocyanins
Figure 7.16 Biosynthesis of the major flavonoids: flavonols, isoflavones and anthocyanins. See text for details. (Reprinted from Trends in Plant Science, Dixon and Steele, 1999, with permission from Elsevier Science.)

2-hydroxy-isoflavanone synthase (2-HIS) and 2-hydroxyisoflavanone dehydratase (2-HID); F3^H, flavanone hydroxylase; F3'H, flavonoid 3'-hydroxylase; F3'5'H, flavonoid 3',5'-hydroxylase; DFR, dihydroflavonol reductase; ANS, anthocyanidin synthase; 3GT, anthocyanidin 3-glucosyltransferase; IOMT, isoflavone O-methyltrans-ferase; IFR, isoflavone reductase; VR, vestitone reductase; DMID, 7,2'-dihydroxy, 4'-methoxyisoflavanol dehydratase. Three types of enzymes are involved: 2-oxoglutarate-dependent dioxygenases (in white), cytochrome P450s (in black bold), and NADPH-dependent reductases (highlighted in grey). Parallel pathways function in the formation of anthocyanins with mono- and tri substituted B-rings. In the latter, F3'5'H can act at the level of the dihydroflavonol with a mono- or disubstituted Bring. The pathway to epicatechin from a dihydroflavonol has been shown to follow two routes, both via leucocyanidin. The 4'-O-methylation of the B-ring of isoflavones occurs in alfalfa, pea and other legumes, but not in soy or other beans (Dixon and

Steele, 1999).

Soybeans are a unique dietary source of the isoflavone genistein, which possesses weak oestrogenic activity and has been shown to act in animal models as an anti-oestrogen. Genistein is also a specific inhibitor of protein tyrosine kinases; it also inhibits DNA topoisomerases and other critical enzymes involved in signal transduc-tion (Messina et al, 1994). Genistein is highly bioavailable in rats because its enterohepatic circulation may accumulate within the gastrointestinal tract (Sfakianos et al, 1997). The branch pathway for the formation of isoflavonoids shares several mechanistic features with the anthocyanin pathway. However, the first reaction specific for isoflavonoid biosynthesis is unique. It comprises 2-hydroxylation coupled to aryl migration of the B-ring of a flavanone (naringenin or daidzein) to yield, after a dehydration reaction that might be spontaneous or enzyme-catalysed (Hakamatsuka et al, 1998), the corresponding isoflavone (genistein or daidzein, respectively). The aryl migration enzyme (2-hydroxyisoflavanone synthase, 2-HIS) has been cloned recently from soybean, which accumulates isoflavone phyto-oestrogens in the seed and more complex isoflavonoid-derived phytoalexins, such as glyceollin, in pathogen-infected tissues (Figure 7.17). The cloning of 2-HIS opens up the possibility of introducing isoflavone nutraceuticals into a range of food crops (Dixon and Steele, 1999).

Recently, a renewed interest in flavonoids has been fuelled by the antioxidant and oestrogenic effects ascribed to them. This has led to their proposed use as anticarcino-gens and cardioprotective agents, prompting a dramatic increase in their consumption as dietary supplements. Unfortunately, the potentially toxic effects of excessive flavonoid intake are largely ignored. At higher doses, flavonoids may act as mutagens, pro-oxidants that generate free radicals, and as inhibitors of key enzymes involved in hormone metabolism. Thus, in high doses, the adverse effects of flavonoids may outweigh their beneficial ones, and caution should be exercised in ingesting them at levels above that which would be obtained from a typical vegetarian diet. The unborn fetus may be especially at risk, since flavonoids readily cross the placenta. More research on the toxicological properties of flavonoids is warranted, given their increasing levels of consumption (Skibola and Smith, 2000).

Phenylalanine —— trans-Cinnamic acid -»--»- 4-Coumaroyl-CoA 3 x Malonyl-CoA

Phenylalanine —— trans-Cinnamic acid -»--»- 4-Coumaroyl-CoA 3 x Malonyl-CoA

Glyceollin

Glyceollin I v OH

Figure 7.17 Metabolism of isoflavonoids. Biosynthesis of the bioactive isoflavonoid daidzein and of the natural phytoalexin glyceollin I. (Reprinted from Trends in Plant Science, Dixon and Steele, 1999, with permission from Elsevier Science.)

Glyceollin I v OH

Figure 7.17 Metabolism of isoflavonoids. Biosynthesis of the bioactive isoflavonoid daidzein and of the natural phytoalexin glyceollin I. (Reprinted from Trends in Plant Science, Dixon and Steele, 1999, with permission from Elsevier Science.)

Polymeric phenolic compounds

Plants consumed by humans also contain thousands of phenolic compounds which are present as polymeric molecules, the polyphenols. Interest has been rekindled with the recognition that many polyphenols, although non-nutrients, show antioxidant, antiinflammatory, anti-oestrogenic, anti-mutagenic and/or anti-carcinogenic effects, at least in in vitro or in animal systems (Bravo, 1998). A popular belief is that dietary polyphenols are anticarcinogens because they are antioxidants, but direct evidence for this supposition is lacking. Polyphenols may inhibit carcinogenesis by affecting the molecular events in the initiation, promotion and progression stages. Isoflavones and some other polyphenols have weak affinity for the oestrogen receptor and may be referred to as phyto-oestrogens. Understanding the bioavailability and blood and tissue levels of polyphenols is important in extrapolating results from studies in cell lines to animal models and humans. Epidemiological studies concerning polyphenol consumption and human cancer risk suggest the protective effects of certain food items and polyphenols, but more studies are needed for clear-cut conclusions (Yang et al, 2001).

Compounds of interest as dietary supplements include: (a) ellagic acid, a dicoumarin derivative found commonly in various fruits, nuts and vegetables; (b) cur-cumin, a diarylheptane that forms the yellow pigment in turmeric (Curcuma longa); (c) resveratrol, a stilbene (3,5,4-O-trihydroxystilbene), the parent compound of a family of molecules found in a narrow range of plants including grapes (Vitis vitifera) (see below); (d) silybin, also known as silymarin, a flavonoid derived from milk thistle (Silybum marianum); (e) epigallocatechin gallate (EGCG), a flavonoid considered to be the major antioxidative green tea flavonoid. The likely biological consequences of polyphenols taken either as dietary supplements or in food are also determined by various factors governing uptake and retention in the body tissue. These include their basic structure, the degree of acylation and/or glycosylation, conjugation with other phenolics and degree of polymerization. This information is often not available for compounds or mixtures sold as dietary supplements (Ferguson, 2001). Figure 7.18 depicts the structure of some phenolic compounds commonly sold or being developed as dietary supplements.

Although most of our information on polyphenols comes from analyses of live tissues, the relative composition and activity of polyphenols can change considerably during plant tissue senescence. Substantial decreases in the number and concentration of LMWP (low-molecular-weight protein), and large increases in the protein-binding capacity of polyphenols, have been observed in leaf litter compared with green leaves (Gallet and Lebreton, 1995). According to Ferguson (2001), given the possibility that some polyphenol supplements and sources could be detrimental, there is an urgent need to perform controlled trials that incorporate estimates not only of antioxidant effects, but also of chromosomal damage in a relevant human tissue. Despite literally thousands of studies on plant polyphenols, it is still an open question as to whether or not they may provide a genuine beneficial effect in human populations, and if so, which should be consumed and at what level.

Terpenoids

Plants produce a wide array of lipidic compounds that are used for a series of metabolic and functional roles. We must remember that lipids are the main constituents of biological membranes, which are made by fatty acids. There are many other categories of lipids that do not contain fatty acids and the most important among them is the category of isoprenoids or terpenoids. More than 25,000 representatives with a variety of biological functions have been reported in the plant kingdom (Sacchettini and Poulter, 1997). To give just a few examples, volatile mono- and sesquiterpenes are highly involved in chemical defence and signalling, carotenoids serve as light-harvesting and light-protecting pigments, sterols play important roles as modulators of membrane properties, the phytol side-chain of chlorophyll (the most abundant organic pigment) is of terpenoid origin, and a wide variety of other plant terpenoids function as insect attractants or repellents. Various terpenoids have attracted commercial interest as pharmaceuticals and/or nutraceuticals. Thus, paclitaxel (Taxol), a diterpene from yew, has been established as a major cytostatic agent. Lycopene and lutein were recently registered as oncopreventive agents (Eisenreich et al., 2001).

All terpenoids are derived by repetitive fusion of branched five-carbon units based on an isopentane skeleton. These monomers are generally referred to as isoprene units because thermal decomposition of many terpenoid substances yields the alkene gas iso-prene as a product and because suitable chemical conditions can induce isoprene to polymerize in multiples of five carbons, generating numerous terpenoid skeletons. For these reasons, the terpenoids are often called isoprenoids, although researchers have known for well over 100 years that isoprene itself is not the biological precursor of this

Figure 7.18 Representative phenolic compounds sold or used as dietary supplements. (See text for details.)

family of metabolites. The major subclasses of terpenoids are biosynthesized from the basic five-carbon unit, isopenthenyl pyrophosphate (IPP), and from the initial prenyl (allylic) diphosphate, dimethylallyl diphosphate (DMAPP), which is formed by iso-merization of IPP. In reactions catalysed by a class of enzymes known as the prenyl-transferases, monoterpenes (C10), sesquiterpenes (C15) and diterpenes (C20) are derived from the corresponding intermediates by sequential head-to-tail addition of C5 units. Triterpenes (C30) are formed from two C15 (farnesyl) units joined head-to-head, and tetraterpenes (C40) are formed from two C20 (geranylgeranyl) units joined head-to-head (Figure 7.19) (Croteau et al., 2000). During a period of several decades, the mevalonate pathway was considered as the universal source of the biosynthetic precursors DMAPP and IPP. The existence of a second isoprenoid pathway was discovered relatively recently by the research groups of Rohmer and Arigoni in the course of stable isotope incorporation studies using various eubacteria and plants (Rohmer et al, 1993). These

Ipp And Dmapp

Figure 7.19 The biosynthesis of terpenoids starts from the building block molecules isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP). Monoterpenes, sesquiterpenes and diterpenes are synthesized by addition of IPP units, whereas triterpenes and tetraterpenes result from the condensation of two units of farnesyl pyrophosphate and geranylgeranyl pyrophosphate, respectively. (From Croteau et al., 2000, copyright of the American Society of Plant Biologists, reproduced with permission.)

Figure 7.19 The biosynthesis of terpenoids starts from the building block molecules isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP). Monoterpenes, sesquiterpenes and diterpenes are synthesized by addition of IPP units, whereas triterpenes and tetraterpenes result from the condensation of two units of farnesyl pyrophosphate and geranylgeranyl pyrophosphate, respectively. (From Croteau et al., 2000, copyright of the American Society of Plant Biologists, reproduced with permission.)

data suggested that pyruvate and a triose phosphate can serve as precursors for the formation of IPP and DMAPP by an alternative pathway (Arigoni and Schwarz, 1999; Rohmer, 1999).

An important feature of the organization of terpenoid metabolism exists at the subcellular level. The sesquiterpenes (C15), triterpenes (C30) and polyterpenes appear to be produced in the cytosolic and endoplasmic reticulum (ER) compartments, whereas iso-prene, the monoterpenes (C10), diterpenes (C20), tetraterpenes (C40) and certain preny-lated quinones originate largely, if not exclusively, in the plastids. The biosynthetic pathways for the formation of the fundamental precursor IPP differ markedly in these compartments, with the classical acetate/mevalonate pathway being active in the cytosol and ER and the glyceraldehyde phosphate/pyruvate pathway operating in the plastids (Figure 7.20) (Croteau et al, 2000).

The cytosolic pathway that leads to IPP formation involves the condensation of three molecules of acetyl-CoA. The resulting product, 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA), is subsequently reduced to form mevalonic acid, the six-carbon compound that gives its name to the pathway. Two sequential ATP-dependent phos-phorylations of mevalonic acid and a subsequent phosphorylation/elimination-assisted decarboxylation yield IPP (Figure 7.21).

In the deoxyxylulose phosphate pathway, D-glyceraldehyde 3-phosphate and pyruvate are converted into 1-deoxy-D-xylulose 5-phosphate in a decarboxylative reaction. Subsequent rearrangement and reduction leads to 2C-methyl-D-erythritol

Figure 7.20 Compartmentalization of terpenoid biosynthesis. Sesquiterpenes and triterpenes are synthesized in the cytoplasm, whereas monoterpenes, diterpenes and tetraterpenes are made inside the plastids. (Croteau et al., 2000, copyright 1998 National Academy of Sciences, USA.)
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