Antioxidants by nature: an ancient feature at the heart of flavonoids' multifunctionality

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Abstract

Early land plants' ability to adapt to novel environmental pressures associated with an ever-changing terrestrial habitat was the result of a vast set of evolutionary innovations, including metabolic ones (Wagner, 2011; Bowman et al., 2017). Land plants, as sessile organisms, were driven to evolve integrated and modular metabolic pathways. Several of them were true metabolic network innovations, responsible for synthesizing several novel compounds (Cannell et al., 2020; Dadras et al., 2023b). The new specialized metabolites (SMs) contributed to thrive in these new and frequently hostile environments (Rensing, 2018; Cheng et al., 2019; Han et al., 2019; Buschmann, 2020; Fürst-Jansen et al., 2020). There is evidence that metabolic plasticity is a key component of a highly complex network in the plant–environment interaction, which also includes morphoanatomical traits. This network largely and ultimately determines the ability of terrestrial plants to escape from the most severe environmental threats, the so-called ‘flight strategy’ of sessile organisms (Potters et al., 2007; Lauder et al., 2019). While an elaborate metabolic system was already placed in the closest algal ancestors of land plants (Rieseberg et al., 2021; Dadras et al., 2023a), primary and particularly secondary metabolic networks have grown far more sophisticated throughout plant evolution (Keeling et al., 2010; Wang et al., 2015; Maeda, 2019; Bowles et al., 2020; Li et al., 2024). They contributed to land plant distribution toward more challenging habitats (Steemans et al., 2009). For instance, the R2R3MYB family of transcription factors (TFs), which regulates a wide array of biological processes, including the expression of genes involved in the biosynthesis of phenylpropanoids, has been extraordinarily expanded and diversified in the lineage of angiosperms (Feller et al., 2011; Bowman et al., 2017; Albert et al., 2018; Jiang & Rao, 2020; Davies et al., 2021). Enzymes involved in both the ‘decoration’ of basic phenylpropanoid skeletons (e.g. the C6-C3-C6 core skeleton of flavonoids) and their transport to different subcellular compartments have also expanded much throughout plant evolution (Kitamura, 2006; Tohge et al., 2018; Alseekh et al., 2020; Davies et al., 2020; Li et al., 2020; Wen et al., 2020). The extraordinary chemical diversity originated from the rise and evolution of multiple SM pathways, coupled with their location in different tissues and cellular compartments, well explains the outstanding plant adaptability to harsh stressful conditions (sensu stricto, that is, distance from pre-existing homeostasis) associated with the terrestrial habitat (Fürst-Jansen et al., 2020; Rensing, 2020). The pivotal role of SMs in the adaptability of land plants depends not only on their extraordinarily high number and diversified skeletons, synthesized by different taxa (Weng et al., 2021), but also on their inherent ability to play multiple functions (Milo & Last, 2012; Ehlers et al., 2020; Mutwil, 2020; Durán-Medina et al., 2021; Hu et al., 2021; de Vries et al., 2021; Weng et al., 2021). Although SM biosynthesis might have served as a sink for the excess of carbon available to plants during their initial exploration of a highly enriched CO2 atmosphere (Dadras et al., 2023a,b), SMs multifunctionality efficiently compensates for the energetic cost required for their biosynthesis (Kliebenstein, 2013; Erb & Kliebenstein, 2020). The multifunctional nature of SMs and their high responsiveness to abiotic and biotic stressors provide plants with an unlimited defense arsenal, in which each SM may play different roles depending on the severity of the stress events and the degree of plant body complexity. These factors determine the metabolite distribution at the organ, tissue, cellular, and subcellular levels (Schneider et al., 2019; Wang et al., 2019; Shitan & Yazaki, 2020; Weng et al., 2021). In simpler terms, the evolution of multifunctional SM biosynthesis follows the natural tendency to catch as many flies with one clamp as possible (Wink, 1999; Izhaki, 2002). Here, we focus on the ancient and ubiquitous class of flavonoids (Fig. 1), which are highly responsive to abiotic and biotic environmental stressors and are capable of regulating key steps in plant growth and development (Pollastri & Tattini, 2011; Schneider et al., 2019; Chapman & Muday, 2021; Garagounis et al., 2021; Venegas-Molina et al., 2021; Daryanavard et al., 2023). However, their multifunctionality makes it difficult to determine the foremost environmental drivers for the emergence and diversification of the flavonoid metabolic network, despite decades of extensive research (Rozema et al., 1997, 2002; Buer et al., 2010; Tripp et al., 2018; Yonekura-Sakakibara et al., 2019; Davies et al., 2020). We provide a detailed analysis of the complex relationship between the multifunctional nature of flavonoids and the environmental stimuli primarily responsible for the rise of the flavonoid metabolic network, offering conclusive evidence for the structural–functional relationship that is at the root of their functional versatility. The emergence of flavonoids represented an outstanding major metabolic innovation during the plants' water-to-land transition (de Vries et al., 2017; Davies et al., 2020; Dos Santos Nascimento & Tattini, 2022). This rise has been initially hypothesized to have occurred in response to herbivore pressure (Swain, 1977; Cooper Driver, 1980), the long-known ‘biochemical coevolutionary arms–race theory’ (Ehrlich & Raven, 1964). In brief, the rise and the diversification of flavonoids, in terms of number and structural complexity, paralleled with major changes in plant morphology, would have been a direct consequence of the selective pressure caused by predation and diseases (Levin, 1971; Swain, 1975, 1977). This coevolution hypothesis has been proven for several classes of SMs, but questioned in other instances, such as the case of flavonoids and other phenolics (Jones & Firn, 1991; Close & McArthur, 2002; Davies et al., 2020; Erb & Kliebenstein, 2020). For instance, Rausher (2001) argued that plant enemies are too rare to generate a frequent evolution of defensive features, such as the biosynthesis of many SMs, particularly flavonoids. Close & McArthur (2002) pointed out the relatively minor role of many phenolics, including flavonoids, as anti-herbivore agents, while providing evidence for their main functions as photo-protectants. Although tannins have historically been viewed as defense compounds against herbivore insects, relatively new evidence supports their antioxidant role (Salminen & Karonen, 2011; Constabel et al., 2014; Gourlay & Constabel, 2019). Finally, the vast literature concerning the phenylpropanoid biosynthesis in response to herbivores and their role in plant resistance has not provided proof of the predominant role of flavonoids as deterrents for herbivores (Serrano et al., 2012; Garcia-Molina & Pastor, 2024). For instance, UV-B radiation, which is known to trigger flavonoid biosynthesis, has been reported to either increase or decrease the resistance to herbivores in a range of species (Izaguiree et al., 2003; Rousseaux et al., 2004; Schneider et al., 2019). The biosynthesis of flavonoids is strongly suppressed by the bacterial flg22, which indeed stimulates other phenylpropanoid biosynthetic branch pathways (Serrano et al., 2012), in agreement with the observation that sinapic and caffeic acid derivatives offer higher herbivory resistance than flavonoids (for a review, see Ballaré, 2014). There is also convincing evidence that most angiosperms prioritize immune responses over stress-induced flavonoid accumulation under microbial attack, and this might represent an ancient evolutionary regulatory crosstalk mechanism (Lozoya et al., 1991; Lo & Nicholson, 1998; Logemann & Hahlbrock, 2002; Serrano et al., 2012). It is conceivable that, despite flavonoids' excellent resistance to natural enemies driven by of these compounds may a consequence of that to other Erb & Kliebenstein, 2020). This hypothesis is on both the multifunctional nature of SMs and the vast range of environmental other than that plants on land (Rensing, 2018; et al., 2021). It is that plants were with a novel set of abiotic environmental such as the of and high and of and in (Fürst-Jansen et al., 2020; & 2021; et al., 2021; et al., 2022). The evolution of a network stress resistance is indeed the of land plants (Rensing, 2020; et al., 2022). This supports the that the of abiotic but not a of and high was the for the rise of SM biosynthesis pathways, including for flavonoids (Rensing, 2018; et al., 2019; & 2024). biosynthesis is in response to stress and high et al., 2015; et al., 2015; et al., Wang et al., but it is also by and et al., et al., 2011; Albert et al., 2018; et al., 2019; et al., 2021). This to the hypothesis that changes in species as in plants to a wide range of environmental stressors et al., 2021; et al., & may have the flavonoid biosynthesis in land plants et al., & et al., This hypothesis well with the that the of most that the flavonoid biosynthetic including the are under et al., 2004; et al., 2018; et al., 2018; et al., & 2022). There is evidence that stress-induced increase in the pressure on and the in the of the transport as to flavonoid biosynthesis et al., et al., 2010; et al., 2023). While of flavonoid not to a primary of these as of stress-induced accumulation as flavonoids are of the integrated antioxidant network, at the a under the most severe stressful conditions for et al., 2020; et al., 2015; et al., 2015; et al., 2018; Chapman & Muday, 2021; et al., 2022). We that the of which is known to a more the biosynthesis of flavonoids and the of to which is the of is with UV-B et al., the several have a increase in to in several such as and with et al., et al., 2021; et al., 2023). increase in to or in to flavonoids, is in plant of different as and in response to a wide range of abiotic including to high and UV-B (for & Tattini, 2011; & 2018; et al., 2020; Davies et al., 2020; Dos Santos Nascimento & Tattini, et al., 2023). While and the to a have an ability to and this is not the case for in which the highly is et al., makes flavonoids in the cellular their their transport from the to different cellular compartments, but to their antioxidant (Fig. The of flavonoids depends on the of the in the by the of both and a in the in et al., et al., has a ability than but higher antioxidant than antioxidant (Fig. While we out the that flavonoids are the most (e.g. plants a of that may this & 2015; et al., et al., is body of evidence the of flavonoid in plant to such as in and tissues et al., 2011; et al., 2015; et al., 2017; et al., The functional of flavonoids as in an in has been (for see et al., et al., to of their location in the of et al., et al., et al., flavonoids in the the including the and the of (Fig. et al., 2006; et al., 2012; et al., in than in the tissues et al., 2021; This makes flavonoids for the in different subcellular compartments, as reported in several species et al., 2011; et al., 2018; Chapman et al., 2019; et al., 2020; et al., 2021; et al., 2023). et provided conclusive evidence that flavonoids (Fig. efficiently by a excess of in the and the of et al., see the for ability to may in plants with multiple environmental such as severe stress et al., 2011; et al., It is known that plants severe on a and that for as during the of the excess is by high and pressure The of which in is to excess and in the of et al., 2015; et al., 2021). There is evidence that the of antioxidant may during the of the to the of high & et al., et al., 2015; et al., The in flavonoid reported in a range of with higher in the et al., et al., 2021), plants with not only an against the of higher levels of UV-B but also with a more We have provided evidence that the increase in flavonoid at the tissues and flavonoids et al., 2021). This is with the observation that flavonoids with to stress and to a of other abiotic stimuli et al., 2012; While flavonoids have been reported to stress of different in a wide range of angiosperms et al., is conclusive evidence for this role in the that a flavonoid was to provide flavonoid for However, it is that flavonoid in the range are to the and the lineage of flavonoids to Albert et al., 2018; et al., 2022). has that the the biosynthesis of in and to stress by and et al., 2021). The increase in to in also an antioxidant role of flavonoids in et al., see the This supports the hypothesis of the antioxidant role of flavonoids during the evolution of land plant by a wide range of environmental There is relatively literature the that an increase in particularly UV-B was the primary for the rise of flavonoid plants from to which is with the that UV-B flavonoid biosynthesis & It has been that the accumulation of flavonoids in land plants is to primarily these plants with an against the of the of a that a secondary role with during plant (for a review, see & 2022). In other while the biosynthesis of is an of land plants (Rensing, this not a primary UV-B of flavonoids in the of different land plant including the & Tattini, of land plants an increase in UV-B from it is that flavonoids have a at the UV-B while at the of the in the range et al., This to the hypothesis that flavonoids are to a primary UV-B in land plants of & It is a for a metabolite to a primary in the between and the responsible for The biosynthesis of flavonoids, which over the range of et al., is a of land plants, and it is to a species et al., Alseekh et al., 2020; Wen et al., 2020). For instance, we have reported and derivatives of with outstanding to over the in the of in of most of et al., et al., we that acid derivatives are to of flavonoids under UV-B radiation, are to UV-B et al., et al., 2004; This which to the observation of increase in flavonoids to & Tattini, 2010; conclusive to the of a relatively minor role of flavonoids as UV-B in UV-B the over the UV-B of the the phenylpropanoid synthesized by most taxa et al., 2013; et al., 2014; We that on the in both the and the of may the of UV-B in the in in to of UV-B high et al., & et al., 2022). The of may represent an mechanism for et al., on the observation that the of and of most largely that of the of angiosperms et al., 2022). The functional of associated with the and the in UV-B has been et al., et al., et al., 2010; et al., However, the is of the of land plants at a degree of body et al., 2017). evidence of highly for and UV-B in the the and the plant is of and to the that the has already originated during the of plants from the to et al., 2019). the species the and the a of and to to changes in UV-B et al., 2018; et al., 2018; et al., 2021). UV-B changes the flavonoid in both and only the biosynthesis of and is by UV-B et al., 1998; & Tattini, 2010; et al., 2010; et al., 2012; It has been that flavonoids are more involved in the stress by UV-B radiation, their than in stress by as et al., et al., 2012; et al., 2013; Dadras et al., 2023b). a this to that high UV-B is as an stress et al., as plants a wide array of abiotic and biotic the antioxidant flavonoids to a in response to high or UV-B in a range of species et al., 2011; et al., Albert et al., 2018; et al., 2018; et al., 2018; et al., 2021). The antioxidant role of flavonoids to high may well such as which are in phenylpropanoid biosynthesis, flavonoids at the of in et al., et al., 2002; It is with the primary functions to in of et al., 2022). We that the diversification and of flavonoid which to the of and et al., coupled with a transport plants a vast of metabolites capable of the and the of are This plants to efficiently stress of their in more challenging habitats (Pollastri & Tattini, 2011; Dos Santos Nascimento & Tattini, 2022). The that flavonoids as metabolites has been reported in and this ability is primarily responsible for the to flavonoids et al., The of flavonoids to the of a range of that may as in pathways of has been to a in plants, in & & 2006; et al., 2019; Daryanavard et al., 2023). decades that flavonoids key functions as and chemical than as during the of land by plants indeed a flavonoid with an transport system is to the with flavonoid to UV-B in land and a primary role not with the extraordinary degree of of the flavonoid in most plant the of flavonoids, which hypothesized as been synthesized by the land plants, have been to by on both transport and been as of their ability to the of in at at and by at in et al., & et al., both and biosynthesis, while strongly derivatives biosynthesis in et al., In the derivatives were to as of while derivatives the et al., the of was evidence of antioxidant flavonoids also most in on their ability to the of the transport acid to a & flavonoids and at to this was the role of flavonoids during plant argued that flavonoids might these functions in the the of their biosynthesis, that is, the of the This such as the and were to at the et al., et al., 2014; et al., 2022). is also the of biosynthesis et al., 2017; et al., There is evidence of and in and et al., 2019; et al., and has been reported to growth and in both et al., 2024). These of an role of flavonoids as of and We have also hypothesized that flavonoids served a major as chemical during plant et al., but this is far from as we The role of flavonoids as chemical has been reported for the growth of in angiosperms & 2012; et al., 2020; et al., such as in the The of flavonoids on result from their ability to both and the of of the as during et al., et al., The that flavonoid which are by are more in with et al., et al., 2021; et al., to the that the multifunctionality of flavonoids with their antioxidant was an of for the adaptability of in and terrestrial habitats (for see Dos Santos Nascimento & Tattini, et al., & 2024). Although the role of flavonoids in in is an the relationship between flavonoids and in angiosperms conclusive in flavonoids have been reported to transport and to transition in et al., 2021). There is also evidence that a of the direct regulates development in by the distribution on flavonoid biosynthesis et al., 2024). These are and the of a role of flavonoids as of response and in The features, the of the in the flavonoids other the to and with a range of as well (Pollastri & Tattini, For instance, flavonoids may the of a wide array of including by strongly with their as well as at the the of both and et al., 2002; & There is evidence that the as in and is pivotal for with (for a review, see & This to the observation that and are more than and in the of a range of et al., 2013; & 2022). There is that these are more than the role to the of flavonoids in the of growth and & 2010; et al., 2019). and the of a wide range of in plant including but not to For instance, flavonoids the of which are that the et al., 2012; & their distribution at the and the the transport However, flavonoids may also the of several resistance et al., at both the and the the et al., 1998; et al., In flavonoids both and major et al., direct with et al., 2020; et al., 2023). the of transport was to to in and to in et al., 2021). It is not that the antioxidant flavonoids, particularly the the on the of and et al., and in in different tissues and & 2007; et al., 2007; et al., & This may well the for by & a of these in both plants and We that flavonoids may in and not only by transport at the organ, tissue, cellular, and subcellular but also by Early research that flavonoids et al., et al., a for which flavonoids as is also the case for that flavonoids as to et al., This has with the which flavonoids that is, by as to for and by during steps of et al., It is not that and derivatives are much more of than the these indeed as of at et al., et al., The largely different of and derivatives on may in by the of but not of to a of et al., The ability of flavonoids to transition & has also been to their ability to in plant flavonoids may efficiently involved in the the of et al., 2012). that the major which is in and land plants is by the of for et al., a of the and an the antioxidant the of et al., to the of and of & 2017). The of antioxidant flavonoids on the of regulating is as of than their of and in at cellular and subcellular levels in regulating plant growth & 2017). this evidence that flavonoids play a role in the network the distribution of at both and relatively the that flavonoids as of a regulatory of the et have that the of by on the in may in a The relationship is et al., et al., and provide conclusive evidence that the a of response with the biosynthesis and decrease accumulation in of et al., 2024). There is also evidence of a relationship between and the acid et al., 2021; et al., which may have contributed to the of plants to the harsh terrestrial habitat et al., 2019). The high of and which at the of primary such as the and et al., may well the of biosynthesis, of in a vast range of species et al., 2010; et al., et al., et al., 2023). It is that the crosstalk between and is an ancient and of terrestrial plants as the and of and are and land plants et al., 2013; & in the at the of network such as and et al., 2019). at have that in the and of the of by the levels of a of the network et al., 2017). However, it that the of that of to et al., et al., et al., 2019). The functional of the diversity and of specialized has been on and the most SMs synthesized pathways have biological and the of a of SMs functional and evolutionary & & et al., & 2024). the extraordinary chemical diversity the flavonoid caused by the vast range of and of the C6-C3-C6 a of their flavonoids in antioxidant the in plant flavonoid for of and are (Fig. 1), and their in an in have been from in or flavonoid in too many 2002). While flavonoid may the functions of flavonoid classes in (e.g. root et al., Chapman & Muday, 2021), this is not the case for which flavonoid in their we that has a antioxidant than but has a higher ability than The antioxidant of is indeed in a range with in the cellular (Fig. and have multifunctional than their It may not a that in plants to a of environmental including the increase in UV-B or the biosynthesis of antioxidant flavonoids is while the flavonoid (for extensive see & Tattini, 2010; et al., 2020; reported flavonoids' key in both stress-induced and different stress-induced pathways. both levels and the of of pathways, such as a wide range of in plants and The antioxidant of flavonoids is, and strongly to the ability to evolve in an ever-changing terrestrial In antioxidant flavonoids play a role in stress-induced responses a of plants to a wide range of 2002; et al., which strongly on & Muday, 2020; et al., 2022). the by the of that while by on that at and flavonoids have been as plant development in Daryanavard et al., particularly root growth and 2018; & Muday, 2020). the of flavonoids in the development of such as have et al., 2007; Buer & Buer et al., 2013; et al., 2017). This is most research has been under growth conditions different from by plants multiple stressors in their natural makes et al., For high levels of and UV-B or biosynthesis and et al., 2012; et al., 2014; both the biosynthesis of antioxidant flavonoids et al., 2020). In a high increase in biosynthesis also the biosynthesis of particularly of et al., 2011; et al., 2012). In may as in plants under natural conditions et al., 2014; et al., The of and flavonoids in angiosperms is to in but new on this et al., 2021; et al., 2024). The functional of the regulatory roles of on the network has not despite the have the to the of plants multiple environmental pressures associated with such as a of and in high However, the is of primary for the of plants with highly complexity. we have that while flavonoids with have to and in their ability to and to both and pathways. We have provided conclusive evidence that these coupled with the distribution in different tissues and cellular compartments, only to antioxidant flavonoids the ability to efficiently several functions in plants changes in cellular of a of The observation that the biosynthesis of antioxidant flavonoids is a response of different land plants with a range of environmental pressures is that this might represent an ancient of land We are to and of for on the by as of the and the and the and analysis of and the ability of flavonoids for and and the of and the and the

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