Elsevier

Phytochemistry

Volume 66, Issue 20, October 2005, Pages 2399-2407
Phytochemistry

Molecules of Interest
Flavones and flavone synthases

https://doi.org/10.1016/j.phytochem.2005.07.013Get rights and content

Abstract

Within the secondary metabolite class of flavonoids which consist of more than 9000 known structures, flavones define one of the largest subgroups. Their natural distribution is demonstrated for almost all plant tissues. Various flavone aglyca and their O- or C-glycosides have been described in the literature. The diverse functions of flavones in plants as well as their various roles in the interaction with other organisms offer many potential applications, not only in plant breeding but also in ecology, agriculture and human nutrition and pharmacology. In this context, the antioxidative activity of flavones, their use in cancer prevention and treatment as well as the prevention of coronary heart disease should be emphasized. The therapeutic potential of flavones makes these compounds valuable targets for drug design, including recombinant DNA approaches. The biosynthesis of flavones in plants was found to be catalyzed by two completely different flavone synthase proteins (FNS), a unique feature within the flavonoids. The first, FNS I, a soluble dioxygenase, was only described for members of the Apiaceae family so far. The second, FNS II, a membrane bound cytochrome P450 enzyme, has been found in all other flavone accumulating tissues. This phenomenon is particularly of interest from the evolutionary point of view concerning the flavone biosynthesis and functions in plants. Recently, FNS I and FNS II genes have been cloned from a number of plant species. This now enables detailed biochemical and molecular characterizations and also the development of direct metabolic engineering strategies for modifications of flavone synthesis in plants to improve their nutritional and/or biopharmaceutical value.

Graphical abstract

Flavones represent one of the largest subgroups within the flavonoids. Two independently evolved and mechanistically different enzymes can convert the precursors, flavanones, into flavones. Various biological activities of flavones in plants and in human nutrition and health make them valuable targets for metabolic engineering.

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Introduction

Flavonoids represent a highly diverse class of secondary plant metabolites with about 9000 structures which have been identified up to now. These compounds are found in all vascular plants as well as in some mosses (Harborne and Baxter, 1999, Williams and Grayer, 2004). Even in the same species a number of different flavonoids may occur. It is already well established that flavonoids have a significant impact on various aspects of plant biology. They exhibit a wide range of functions in physiology, biochemistry, and ecology, for example in UV-protection, flower coloration, interspecies interaction, and plant defence. Moreover, for a long time flavonoid pattern are useful tools in phylogenetic studies. Other highly remarkably properties of certain flavonoids are their nutritional values and medicinal benefits to humans, represented among others by antioxidant or putative anticancer activities.

All flavonoids derive their 15-carbon skeletons from two basic metabolites, malonyl-CoA and p-coumaroyl-CoA. Basically, flavonoids are derivatives of 1,3-diphenylpropan-1-one (C6–C3–C6). The crucial biosynthetic reaction is the condensation of three molecules malonyl-CoA with one molecule p-coumaroyl-CoA to a chalcone intermediate. Chalcones and dihydrochalcones are classes of flavonoids that consist of two phenolic groups which are connected by an open three carbon bridge. Derived from the chalcone structure, a flavonoid-class containing three rings, the flavanones, can be formed. Here, the three-carbon bridge is part of an additional heterocyclic six-membered ring that involves one of the phenolic groups on the adjacent ring (for numbering convention to identify positions see Fig. 1). Based on these flavanones all other flavonoid-classes are generated, including isoflavones, flavanols, anthocyanidines, flavonols, and flavones (Fig. 2) (for review see Harborne and Baxter, 1999). This latter flavonoid-class is characterized by the presence of a double bond between C2 and C3 in the heterocycle of the flavan skeleton. The B-ring is attached to C2 and usually no substituent is present at C3. This exactly represents the difference to the flavonols where a hydroxyl group can be found at that C3 position. The term ‘flavone’ was used for the first time in 1895 by von Kostanecki and Tambor who were pioneers in the structural work of this particular class of flavonoids. Interestingly, higher plants evolved two completely independent enzyme systems to catalyze flavone synthesis using the same substrates. Both enzymes never occur side by side in the same organism: only in Apiaceae a soluble 2-oxoglutarate- and Fe2+-dependent dioxygenase, flavone synthase I (FNS I), is present; on the other hand a NADPH- and molecular oxygen-dependent membrane bound cytochrome P-450 monooxygenase, flavone synthase II (FNS II), being more widespread among the plants, has been described (Heller and Forkmann, 1993).

Here, we first review the enzymatic mechanisms of both biosynthetic reactions catalyzed by the two flavone synthases, as well as the genetic and molecular aspects regarding their evolution. Moreover, the distribution, structural diversity and the various roles of flavones in the plants’ physiology and ecology – with a focus on chemical communication with other organisms – and also their meaning for human health will be presented. At last, metabolic engineering strategies of flavone pathways will be discussed.

Section snippets

Biosynthesis of flavones in plants

Flavones are synthesized at a branch point of the anthocyanidin/proanthocyanidin pathway from flavanones as the direct biosynthetical precursor (Fig. 2). At least two completely different proteins were found to be responsible for the particular enzymatic oxidative conversion, namely the introduction of a double bound between C2 and C3 by the abstraction of two hydrogen atoms (Fig. 3). Mainly, flavone formation in various tissues of a wide range of higher and lower plant species is catalyzed by

Diversity and distribution of flavones

The flavones can be classified into several subgroups which are mainly indicated either by (i) hydroxylation, (ii) O-methylation, (iii) C-methylation, (iv) isoprenylation, or (v) methylenedioxy substitution. Besides the aglycon structures, O- and C-glycosides are well known. Flavones mostly occur as 7-O-glycosides, but substitution can be found at any other hydroxylated position. Chemically, flavonols are simply 3-hydroxyflavones. However, as flavones and flavonols are biosynthetically distinct

Role of flavones in plants

It is well accepted that the flavonoids appeared when plants moved onto land. The high diversity of flavonoids that is established nowadays raises the question of the driving force behind this evolution. One criterion for selection might have been the ability of flavonoids, including flavones, to absorb UV radiation in the same range that is detrimental to nucleic acids; thus they can act as UV protection shield (Lowry et al., 1980). However, this view of a primary driving force has been

Flavones in nutrition and health

Besides their important functions in the biochemistry, physiology and ecology of plants, flavones are important compounds for human nutrition and health. There is an increasing body of evidence for health-protecting functions of flavonoid compounds, such as antioxidative and antitumor effects in various cell lines, as well as antiinflammatory, antibacterial, antiviral, and antiatherosclerotic activities. Here, we will mainly focus on selected flavones regarding their anticancercogenic potential.

Metabolic engineering strategies of flavone pathway in plants

Flavones become more and more commercially important for the floricultural, agricultural, food and pharmaceutical industry, respectively. In the latter case due to the dietary uptake of efficient antioxidants as described above. Consequently, genetic engineering can provide a valuable tool to expand the plant gene pool and thus promoting the generation of new commercial plant varieties or plant-derived products (e.g., food supplements, functional foods, herbal drugs). The biosynthesis of floral

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