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Adaptive mechanisms of plant specialized metabolism connecting chemistry to function - Nature Chemical Biology

Abstract . As sessile organisms, plants evolved elaborate metabolic systems that produce a plethora of specialized metabolites as a means to survive challenging terrestrial environments. Decades of research have revealed the genetic and biochemical basis for a multitude of plant specialized metabolic pathways. Nevertheless, knowledge is still limited concerning the selective advantages provided by individual and collective specialized metabolites to the reproductive success of diverse host plants. Here we review the biological functions conferred by various classes of plant specialized metabolites in the context of the interaction of plants with their surrounding environment. To achieve optimal multifunctionality of diverse specialized metabolic processes, plants use various adaptive mechanisms at subcellular, cellular, tissue, organ and interspecies levels. Understanding these mechanisms and the evolutionary trajectories underlying their occurrence in nature will ultimately enable efficient bioengineering of desirable metabolic traits in chassis organisms. You have full access to this article via your institution. Download PDF Download PDF Main . Approximately 470 million years ago, pioneering plants migrated from water to land and have since flourished, establishing the foundation of terrestrial ecosystems as we know them now 1 . Unlike animals that leverage highly complex motor and nervous systems to actively hunt for food, evade danger and find mates, plants are sessile organisms that have to cope with all challenges arising from a fixed location throughout their entire life cycle. As a result, plants evolved a plethora of functionally diverse metabolites as a main evolutionary strategy to enhance their reproductive success. The great expansion of specialized metabolic networks thus enabled plants to diversify, occupy a multitude of terrestrial environmental niches and establish intricate biotic interactions with other co-evolving organisms. Humans have consumed plants for their nutritional and medicinal properties for millennia 2 . Modern scientific inquiry into the chemical makeup of plants began in the early nineteenth century, which gave birth to the field of phytochemistry (Fig. 1 ). Since the first isolation of the antimalarial drug quinine from the bark of the cinchona tree in the 1820s, hundreds of thousands of natural products have been discovered from a wide selection of plants, and, in fact, most early modern pharmaceuticals are plant natural products or their derived analogs 3 . The advancement of phytochemistry as a field also promoted the development of analytical chemistry and later organic chemistry, laying the foundation for the modern chemical and pharmaceutical industries. Studies of plant natural product biochemistry began in the early twentieth century. Using radiotracing and basic enzymology, knowledge regarding how diverse classes of plant specialized compounds are derived from various primary metabolite precursors was uncovered for the first time. The rise of model organisms (for example, Arabidopsis thaliana and Oryza sativa ) in the 1990s, together with the wide adoption of molecular genetics and recombinant DNA technologies, greatly facilitated plant biochemistry research and contributed to elucidation of the molecular basis for numerous important plant specialized metabolic pathways, ranging from relatively conserved networks such as phenylpropanoid metabolism and phytohormone biosynthesis to more taxonomically restricted pathways such as glucosinolate biosynthesis. Entering the twenty-first century, the advent of next-generation sequencing technologies and burgeoning synthetic biology tools further ignited a renaissance of phytochemistry research, which allows researchers to return to diverse nonmodel plants for exploration of their vast natural product biosynthetic pathways 4 , 5 . Fig. 1: A brief history of phytochemistry research. Select milestones in humans’ exploration of plant chemistry and biochemistry using modern scientific methods since the seventeenth century are denoted on a spiral timeline. Before modern science, humans harnessed the medicinal properties of plants for millennia. The field of phytochemistry started as a subdiscipline of chemistry and progressed into biochemistry, molecular genetics and bioengineering in the following decades, often propelled by technological advances in these fields. The selected advances are representative of a greater number of achievements that were made during each era. Full size image While the lion’s share of plant specialized metabolism research has been devoted to elucidating unknown natural product biosynthetic pathways, resulting in considerable advances in this area, much less is known about the biological functions of these specialized metabolites in their native plant hosts under varying environmental conditions. Moreover, it is well recognized that, beyond the emergence of new catalysts during plant metabolic evolution, subcellular-, cellular-, tissue-, organ- or interspecies-level adaptations have also occurred in diverse plants, tailoring structures to the functions of various specialized metabolic traits. In this Review, we focus on recent literature that addresses the ‘form and function’ question of plant specialized metabolism. These underexplored aspects of plant specialized metabolism are essential for an integral understanding of the role of metabolism in plant organismal evolution and for devising efficient metabolic engineering strategies for producing high-value plant natural products. Metabolites enable dynamic below-ground interactions . The world of plant specialized metabolites is enormous, with more than 200,000 different compounds known to date and more to be discovered 6 . An increasing body of evidence indicates that plants utilize these diverse compounds to manipulate their surroundings via plant–plant, plant–insect and plant–microorganism interactions. Metabolites may be produced individually or in mixtures in response to certain environmental or developmental cues and serve as signaling molecules, attractants, repellents or inhibitors of other organisms 7 . Certain metabolites carry information about the physiological and metabolic status of the host plant that is readily interpreted by other plants, insects and microorganisms, which respond accordingly 8 . However, our ability to decrypt the chemical languages of plants is still in its infancy. The roles of plant specialized metabolites in above-ground communications have been extensively studied and reviewed 9 . The recent advent of metagenomics and untargeted metabolomics techniques, however, has greatly facilitated research into the below-ground interspecies and interkingdom interactions of plants 10 . Plant metabolites released into the rhizosphere via root exudation can (1) serve as allelochemicals inhibiting the growth of neighboring plants 11 , (2) drive plant–microbiome interactions, (3) function as defense compounds against soilborne microbial pathogens and (4) shape the composition of the root microbiota (Fig. 2a ). Flavonoids, for example, contribute to all the above functions, as they are involved in allelopathic interference, repel parasitic nematodes, inhibit pathogenic fungi and attract mycorrhizal fungi that form a beneficial symbiosis with plants 12 . In addition, the makeup of the Arabidopsis root bacterial community can be modulated by iron-mobilizing coumarins that inhibit the proliferation of Pseudomonas species via a redox-mediated mechanism, as was discovered using a combination of a synthetic community of Arabidopsis root-isolated bacteria and mutants deficient in various specialized metabolic pathways 13 . At the same time, plant roots are constantly exposed to thousands of different microorganisms, and the rhizosphere microbiota promote systemic changes in the metabolite profile of root exudates 14 . Thus, not only do plant root exudates shape the root-associated microbiota, but the rhizosphere microbiome also modulates the chemical composition of root exudation. For example, in tomato, glycosylated azelaic acid was recently identified as a potential microbiome-induced signaling molecule, which is transported via shoots to uncolonized roots and is exuded in the free acid form to promote rhizosphere chemical diversification and interactions within the microbial community 14 . Plants can also further metabolize signal molecules released from soil organisms, converting these metabolites for their own benefit; for example, ascaroside pheromones secreted by parasitic nematodes were chain-shortened via peroxisomal β-oxidation to nematode deterrents as a means to reduce infection 15 (Fig. 2b ). Fig. 2: Modes of below-ground biotic interaction mediated by plant specialized metabolism. a , Influence of root-secreted metabolites (for example, flavonoids) on promoting colonization of beneficial microorganisms while inhibiting colonization of detrimental microorganisms. b , Plant metabolic enzymes use nonplant substrates in the synthesis of repellants for attacking species 15 . ascr, ascarosides. c , d , Secreted metabolites act as signals to neighboring plants, either directly ( c ) or after modification by rhizosphere microorganisms 16 ( d ). DIMBOA, 2,4-dihydroxy-7-methoxy-1,4-benzoxazin-3-one. Full size image Beyond below-ground effects, root exudates can carry information to receiver plants that affects their above-ground performance. The fitness of the next generation of plants, for example, can be influenced by altered soil microbiota as a result of exudation of bioactive secondary metabolites from the parents’ roots. Indeed, maize roots secrete to the rhizosphere substantial amounts of tryptophan-derived benzoxazinoids. In addition to their allelopathic functions 11 , benzoxazinoids trigger changes in microbiome composition, which in turn increases jasmonic acid signaling in leaves of the next generation of plants, leading to enhancement of jasmonic acid-dependent defense and herbivore resistance while decreasing plant growth 16 . These observed phenotypic changes were attributed to 6-methoxy-benzoxazolin-2-one (MBOA), a compound produced by degradation of the maize-secreted benzoxazinoids 16 (Fig. 2c ). Communication via root exudates extends beyond defense and can carry information about other environmental conditions as well. For instance, application of root exudates from Brassica rapa grown in long-day conditions can promote accelerated flowering of plants grown under short-day conditions 17 . Similarly, an informational cascade about water deficiency can be passed from drought-stressed plants to their neighbors, which in turn propagate this information further to plants that were never in contact with the original stressed individuals. Thus far, the nature of the below-ground signaling compounds in these plant–plant interactions is still unknown and awaits further investigation. Volatiles released from roots to the soil not only act in below-ground plant defense but also influence ecological interactions between herbivores and neighboring plants 18 . It is well known that the ( E )-β-caryophyllene released by insect-damaged maize roots recruits entomopathogenic nematodes, thus protecting plants via below-ground tritrophic interaction 19 . However, more recently, it was shown that a mixture of sesquiterpenes with a high abundance of ( E )-β-caryophyllene constitutively released from the roots of spotted knapweed ( Centaurea stoebe ) can modify the plant–herbivore interactions of different sympatric plant species by increasing their susceptibility to herbivores 20 (Fig. 2d ). In addition to influencing herbivory, the same mixture of volatiles can increase the germination and growth of neighboring plant species, thus contributing to below-ground plant–plant interactions and impacting the structure of natural plant communities 21 . However, what benefit the emitters attain from promoting the growth and/or herbivory of competitors remains unknown. Several recent studies have also demonstrated that insects and other phytoparasites can exploit plants’ metabolic status for their own benefit. By manipulating the enzymatic machinery of the turpentine tree ( Pistacia palaestina ), gall-inhabiting aphids enhance monoterpene accumulation, thus intensifying their own defenses against natural enemies 22 . Host plant manipulation by insects can also be extended to neighboring plants via airborne signals. Indeed, attacking whiteflies on tomato plants induce the release of volatiles that reduce the levels of jasmonic acid-mediated defense compounds in neighboring plants, making these plants more susceptible to infestation 23 . During plant colonization, some nematodes and biotrophic fungi secrete chorismate mutase, thereby suppressing plant immunity via perturbing salicylic acid biosynthesis 24 , 25 . Integrated plant body plan and metabolic adaptation . Metabolic evolution has profoundly impacted body plan adaptation in many plants, contributing to the development of highly specialized cell and tissue types that enable specialized metabolite production and/or storage. Prominent examples include glandular trichomes 26 , latex-producing laticifers 27 , pigment-accumulating petal epidermal cells 28 and root tubers 29 , some of which are discussed below. Moreover, numerous specialized metabolic pathways are interconnected with phytohormone biosynthetic pathways or produce specific downstream metabolites that have gained new signaling properties, in turn regulating plant growth and development in coordination with overall metabolic function. Trichomes are hair-like epidermal protuberances found in almost all plants and serve as the first line of physical defense for the host plant against herbivory 30 . In about 30% of all vascular plants, simple ancestral trichomes have evolved into structurally more elaborate glandular trichomes that produce and store a wide array of specialized metabolites to instigate an additional layer of chemical defense 26 . In-depth microscopic examination of cannabis ( Cannabis sativa L.) unveiled three morphologically distinct types of glandular trichomes on female flowers, classified as stalked, sessile and bulbous trichomes 31 . Among these, stalked glandular trichomes contain the highest cannabinoid levels 31 (Fig. 3a ). The stem portion of the stalked glandular trichome is photosynthetic and supplies nutrients to the nonphotosynthetic head. Secretory disc cells situated at the base of the head manufacture cannabinoids as well as other terpenes and transport them into the balloon-like secretory cavities at the top 31 . Analysis of the glandular trichome-specific transcriptome uncovered a rich set of candidate genes likely involved in cannabinoid metabolism and trafficking 31 . However, the exact molecular machineries underlying these highly specialized and coordinated cellular processes are yet to be fully characterized. Like cannabis, nightshade plants also harbor several morphological types of glandular trichomes within individual species 32 . Instead of cannabinoids, the secretory glandular trichomes of nightshade plants produce structurally diverse acylsugars as lineage-specific defense compounds against herbivores and pathogens 32 . Cell-type-specific metabolomic analysis revealed distinct specialized metabolite profiles among different glandular trichome types in tomato, suggesting divergent biological functions associated with various glandular trichome types 32 . Furthermore, genetic variations of several acylsugar biosynthetic genes found in cultivated and wild tomato species, including in genes encoding acylsugar acyltransferases and acylsucrose fructofuranosidases, contribute to the rapid expansion of acylsugar diversity within the Solanum genus 33 . In addition to the direct antiherbivory properties of acylsugars, research of coyote tobacco ( Nicotiana attenuata ) in its native ecological environment uncovered an intricate indirect protective mechanism: ingestion of acylsugars by the larvae of lepidopteran herbivores imparts a distinct volatile profile to their body, tagging them for predation by rough harvester ants ( Pogonomyrmex rugosus ) 34 . Fig. 3: Integration of plant specialized metabolism with body plan adaptation and growth regulation. a , The stalked glandular trichome is a highly adaptive tissue in C. sativa L. that biosynthesizes cannabinoids and other terpenes and stores them in the secretory cavities in the head region. THC, tetrahydrocannabinol. b , Laticifers, specialized secretory cells in the vascular tissues of many plants, including Ficus amplissima , accumulate latex and ooze it upon injury. Latex contains polyisoprene units and other lineage-specific defense compounds. c , An example of interconnection of metabolic and signaling networks, where the indole glucosinolate and phenylpropanoid pathways are linked to production of auxin, regulating plant growth according to the metabolic status of these pathways. Trp-AT, tryptophan aminotransferase. d , Certain glucosinolates produced in response to insect herbivory in Brassicales can regulate plant growth through the TOR signaling pathway. 3OHP GSL, 3-hydroxyl-propyl glucosinolate; TORC, target of rapamycin complex. Full size image An estimated 20,000 plants, across 40 families, have evolved laticifers, which are specialized elongated secretory cells found in leaves and stems that contain a white viscous material known as latex 27 (Fig. 3b ). Laticifers can either be individual long coenocytic cells (nonarticulated), which are among the longest cells known in plants, or be composed of multiple cells separated by their respective cell walls (articulated) 27 . The main components in latex by dry weight are long-chain polyisoprene units (for example, natural rubber) 27 , while a broad range of specialized metabolites are also present, such as terpenoids, alkaloids, dihydroxybenzoic acids, furanocoumarins and flavonoids, among others 35 . Following physical damage, latex rapidly oozes from broken laticifers at the wound site and has dual roles in chemical defense against insects and other herbivores and wound healing through coagulation 36 . A well-studied example is the latex of opium poppy ( Papaver somniferum ), which contains morphine, a benzylisoquinoline alkaloid well known for its potent agonist activity against mammalian opioid receptors 37 . Triterpenoid cardenolides and sesquiterpene lactones found in the latex of milkweed ( Asclepias spp.) and common dandelion ( Taraxacum officinale ), respectively, have been shown to act as effective defense molecules against various herbivores 38 , 39 . In addition to specialized metabolites, latex also contains an array of defense proteins, such as serine and cysteine peptidases, chitinases, thaumatin-like protein and others, with comprehensive roles in defense against herbivory 40 . Although latex-producing laticifers provide a strong line of defense against most herbivores, some insects, especially those that specialize in feeding on specific host plants, have developed strategies to circumvent ingesting latex, illustrating the evolutionary arms race between plant-eating insects and host plants. Two such specialists, the caterpillars of the monarch butterfly ( Danaus plexippus ) and arctiids ( Pygarctia roseicapitis ), cut veins on their host plant’s petiole in a behavior called trenching 41 , 42 , to allow the latex to leak from the wound, and then feed on the distal, latex-deficient portion of the leaf. The burgeoning specialized metabolic pathways sometimes stem from branches of primary metabolism that also support phytohormone biosynthesis. Such metabolic links thus impose control over plant growth in response to certain specialized metabolic states 43 (Fig. 3c ). For example, cytosolic phenylalanine biosynthesis, which is necessary for optimal production of many phenylpropanoid natural products, influences tryptophan-dependent auxin production via a shared phenylpyruvate intermediate 44 . Similarly, auxin biosynthesis and signaling are also tied to indole glucosinolates, a class of defense compounds found in Brassicaceae plants. Not only do the major plant auxin indole-3-acetic acid (IAA) and indole glucosinolates share the common precursor tryptophan, but indole glucosinolate biosynthetic intermediates also suppress metabolic flux toward phenylpropanoids through Mediator- and proteome-dependent degradation of phenylalanine ammonia-lyase (PAL), the first committed enzyme of phenylpropanoid metabolism 45 . This complex regulatory network therefore enables the coordination of auxin-mediated growth control with multiple defense compound biosynthetic pathways. An increasing number of specialized metabolites have been recognized to contain recently evolved signaling properties. For example, the indole glucosinolate breakdown product indole-3-carbinol acts as an auxin antagonist and induces indole-3-carbinol-dependent autophagy in Arabidopsis root upon wounding 46 , 47 . Another aliphatic glucosinolate, namely, 3-hydroxypropylglucosinolate (3OHP), inhibits root growth and development in Arabidopsis through the target of rapamycin (TOR) signaling pathway 48 (Fig. 3d ). Terpene metabolism has also yielded numerous niche signaling molecules. For instance, phaseic acid, an ancestral catabolite of the plant stress hormone abscisic acid (ABA), was recruited by seed plants to function as a biased ligand that only activates a subset of the ABA receptor family proteins to provide nuanced regulation of seed germination and long-term drought response 49 . Additionally, other carotenoid-derived terpenoids, including anchorene, zaxinone and retinal, were recently reported to impact various aspects of root development, either through modulating classical phytohormone signaling pathways 50 , 51 or by engaging novel ligand-activated signaling pathways 52 . In petunia flowers, sesquiterpenes released by the tubes within the enclosed floral buds accumulate in the pistils and are required for optimal pistil growth, as this interorgan aerial transport likely coordinates the timing of pistil maturation with petal development to ensure successful reproduction 53 . Similarly, in N. attenuata flowers, malonylated 17-hydroxygeranylinalool diterpene glucosides regulate floral style length by influencing stylar cell size 54 . These observations suggest that the rise of new signaling properties among specialized metabolites might be a common phenomenon during plant evolution and further implicate the presence of respective specialized signaling pathways waiting to be uncovered. Higher-level organization of specialized metabolism . To achieve optimal multifunctionality of a given specialized metabolic pathway, such as high metabolic output, alleviation of enzyme inhibition by structurally similar metabolites 55 or avoidance of autotoxicity 56 , many plant specialized metabolic processes partition into different subcellular compartments or sometimes across different cell types and rely on transport of intermediates to bring spatially separated enzymatic steps into a complete biosynthetic pathway. The infamous pungent-tasting glucosinolates of the cabbage family, their metabolism, their transport and release of the ‘mustard bomb’ are an exemplary case illustrating many aspects of these subcellular and intercellular mechanisms, which have been extensively reviewed by others 57 . Here we focus on recent literature that provides new insights on higher-order organization of numerous plant metabolic systems. Various classical eukaryotic organelles are common sites of compartmentalized plant specialized metabolic processes. For instance, phenylpropanoid biosynthesis occurs mainly in the cytosol but relies predominantly on plastidial production of the phenylalanine precursor (Fig. 4a ) 58 . As an integral part of this metabolic network, the recently discovered plastidial cationic aromatic amino acid transporter (CAT) was shown to control flux through the network, influence organellar metabolite concentrations and relax naturally occurring feedback regulation of phenylalanine biosynthesis in plastids 58 . On the other hand, a drastic increase in phenylalanine levels in the cytosol is tempered by sequestering phenylalanine in the vacuole away from the metabolically active pool, via the action of a vacuolar CAT-family transporter, thereby sustaining cytosolic homeostasis and preventing toxicity 59 . Fig. 4: Contribution of subcellular and intercellular mechanisms to the optimal multifunctionality of plant specialized metabolic processes. a , Phenylalanine, the precursor of plant phenylpropanoid metabolism, is biosynthesized in plastids and transported through PhpCAT to the cytosol 58 . Excess phenylalanine can be sequestered in the vacuole by PhCAT2 (ref. 59 ). b , Formation of tannosomes from redifferentiated chloroplasts. Tannosomes containing condensed tannins and other polyphenols are trafficked to and stored in vacuoles. c , Cross-section of the vascular tissue of opium poppy illustrating the partitioning of morphine biosynthetic pathway enzymes into laticifers (LA) and neighboring sieve elements (SE). Companion cells (CC) also contribute to production of morphine biosynthetic enzymes, which are transported into laticifers and sieve elements 68 . PP, parenchyma; VC, vascular cambium; XP, xylem parenchyma; XY, xylem vessels. d , Assembly of the dhurrin metabolon at the cytosolic face of the ER membrane in sorghum 77 . Full size image Sequestration of specialized metabolites in the vacuole is a common strategy used by plants to accumulate high quantities of specialized metabolites 60 . Nevertheless, vacuoles can also host certain enzymatic steps of natural product biosynthesis. In Catharanthus roseus , the vacuolar strictosidine synthase conjugates tryptamine and secologanin imported from the cytosol to form strictosidine, which is subsequently exported by tonoplast-localized nitrate/peptide-family transporters en route to formation of monoterpene indole glucoside final products 61 . Moreover, vacuole-localized papain-like cysteine proteases and asparaginyl endopeptidases are responsible for several proteolytic cleavage steps in the biosynthesis of various classes of plant ribosomally synthesized and post-translationally modified peptide (RiPP) natural products 62 , 63 . In addition to compartmentalization by conventional organelles, various plant-specific organelles have also been implicated in specialized metabolite synthesis and storage. For example, microscopic examination of tannin-rich tissues from a number of vascular plants identified the tannosome as a new organelle involved in tannin polymerization and trafficking 64 . In these tissues, proanthocyanidin monomers enter chloroplasts and polymerize inside of thylakoids. Tannosomes form by pearling of the thylakoids, bud from chloroplasts and traffic through the cytoplasm to the vacuole, where the enclosed condensed tannin is terminally deposited (Fig. 4b ). Likely through a similar mechanism, dedifferentiated chloroplasts in cells of vanilla fruit give rise to another specialized organelle, the phenyloplast, which accumulates a high concentration of 4- O -(3-methoxybenzaldehyde) β- d -glucoside, a major phenol glucoside produced by vanilla fruit 65 . Interestingly, vanilla β- d -glucosidase, the enzyme responsible for hydrolyzing 4- O -(3-methoxybenzaldehyde) β- d -glucoside to release the sweet-scented aglycone vanillin, was found to localize around phenyloplasts, suggesting a role for phenyloplasts in volatile emission in vanilla fruit 65 . In tapetum cells, which are specialized nutritive cells within floral anthers, two types of morphologically distinct organelles—elaioplasts and tapetosomes—have been visualized through classic microscopy studies 66 . Although the particular molecular compositions and biochemical functions of these organelles remain unknown, it is hypothesized that they evolved to support the biosynthesis of sporopollenin, the hydrophobic inert plant polymer that coats the outer wall of plant pollen grains 67 . Some plant specialized metabolic pathways divide the labor between different cell types. For example, enzymic steps involved in morphine biosynthesis were shown to be distributed among phloem sieve elements, companion cells and laticifers 68 (Fig. 4c ). Pyrethrins, natural insecticidal compounds produced in Pyrethrum plants and related Tanacetum species, present another example where biosynthesis involves a multiorganellar and multicellular process. Plastids, the endoplasmic reticulum (ER), the cytosol and peroxisomes in ovary trichomes are all involved in the biosynthesis of terpene-derived chrysanthemic acid, which is then transported to the pericarp for methylation and final esterification with a jasmonic acid-derived alcohol 69 . To achieve their biological functions, many specialized metabolites have to be secreted from the producing cells either to the environment or into specialized storage structures such as trichomes, laticifers and resin ducts. Active transport of metabolites often relies on members of the ATP-binding cassette (ABC) transporter family. This includes plasma membrane-localized pleiotropic drug resistance transporters (PDRs), which have been implicated in transport of terpenoids to trichomes in Artemisia annua 70 , as well as to the site of pathogen invasion in Nicotiana benthamiana 71 . PDR-type transporters can export not only terpenoids but also other classes of specialized metabolites, such as phenylpropanoid-derived O-methylated coumarins that are secreted from Nicotiana tabacum roots to the rhizosphere in response to iron deficiency 72 . Additionally, efficient transport of phenylpropanoid/benzenoid volatiles across the plasma membrane in petunia flowers was shown to require an ABCG transporter, the action of which was essential to prevent internal accumulation and cellular self-intoxication 73 . Excretion of specialized metabolites often involves crossing the cuticle, which itself passively sustains the export process by serving as a sink for hydrophobic metabolites 74 . A deeper understanding of the molecular mechanisms and structure–function relationships of metabolite transport and retention, especially in nonmodel plants, will greatly improve our abilities to engineer biosynthesis of metabolites in heterologous hosts. The elaborate series of enzymatic reactions involved in many plant specialized metabolic pathways requires higher-order organization of the participating enzymes. Instead of relying on diffusion to find their substrates, enzymes in some metabolic pathways have been implicated to form physical assemblies in vivo, also known as metabolons, that channel reactive or hydrophobic intermediates to prevent them from being consumed by competing reactions or sequestered by lipid membranes 75 . Early isotope dilution assays conducted on N. tabacum cells, together with microsomal assays and colocalization experiments, suggest that PAL and cinnamate 4-hydroxylase (C4H), the first two committed enzymes in general phenylpropanoid metabolism, form a metabolon 76 . By using styrene maleic acid copolymers, the ER-tethered metabolon responsible for the biosynthesis of dhurrin, a cyanogenic glucoside present in Sorghum bicolor , was recently isolated and found to contains at least four enzymes involved in dhurrin biosynthesis: P450 oxidoreductase (POR), two cytochromes P450 proteins (CYP79A1 and CYP71E1) and a glucosyltransferase (UGT85B1) 77 (Fig. 4d ). In Arabidopsis , the tryptophan-derived defense compound camalexin is also thought to be produced by an ER-anchored metabolon 78 . As a result of this architecture, intermediates along the pathway, such as indole-3-acetaldoxime, do not accumulate during camalexin production 78 . The fact that many plant specialized metabolic metabolons are membrane associated raises the possibility that the membrane itself may also have a role in channeling hydrophobic intermediates 76 , although dissecting this possibility from channeling by adjacent enzyme active sites is technically difficult. Recent studies have suggested that some metabolons require nonenzyme scaffolding proteins to assemble and function properly. For example, a pair of membrane steroid-binding proteins (MSBPs) were found to serve as a scaffold to physically organize three monolignol biosynthetic CYP proteins on the ER membrane in Arabidopsis , likely mediating the formation of a lignin biosynthetic metabolon 79 . Characterization of plant metabolons remains challenging, where it is critical to establish (1) transient physical interaction between enzymes in a pathway and (2) substrate channeling in vivo to identify a metabolon, distinguishing these from other enzyme–enzyme assemblies 80 . Recent advancement in super-resolution imaging 81 and proximity labeling techniques, such as development of the biotin ligase TurboID 82 , may help in future research of metabolons involved in plant specialized metabolism. Evolutionary mechanisms contributing to chemodiversity . The remarkable per-species and collective chemodiversity observed in the plant kingdom suggests that plants must be permissive to evolving new metabolic enzymes. In comparison to conserved primary metabolic pathways (for example, glycolysis and the TCA cycle), which have been under stringent selection for billions of years in all life forms, disparate specialized metabolic traits have arisen in response to varying selection pressures at different times during the past 470 million years of land plant evolution, resulting in a great number of less perfected extant enzymes. Indeed, large-scale analyses of available kinetic parameters for known enzymes revealed that enzymes of specialized metabolism are on average 30-fold slower than those involved in central metabolism 83 . Perhaps this general dichotomy between primary and specialized metabolic enzymes is a result of organism-level selection, which ensures that less critical specialized metabolic processes do not siphon significant amounts of flux away from more important primary and other secondary biosynthetic pathways. Early iterations of novel specialized metabolic pathways can arise from enzyme promiscuity intrinsic to the ancestral metabolic system 84 . Promiscuous activities of enzymes may occur at the level of (1) substrates, when an enzyme can perform the same type of reaction on multiple substrates, as is well documented for CYP proteins, acyltransferases, methyltransferases, glycosyltransferases and more; (2) products, when an enzyme can produce different products from the same set of substrates, as commonly observed for terpene synthases, type III polyketide synthases and other regio- or catalytic cycle-permissive enzymes; or (3) catalysis, when one enzyme can catalyze different reaction types, usually in a substrate-dependent manner, as exemplified by soybean 2-hydroxyisoflavanone dehydratase, which has both dehydratase activity for 2-hydroxyisoflavanone and esterase activity against ester substrates 85 . Niche-specific evolutionary pressures select for certain promiscuous activities of ancestral enzymes to produce divergent beneficial compounds, charting unique trajectories toward taxonomically restricted specialized metabolism. Motif enrichment analysis and molecular dynamics simulations of BAHD acyltransferase family members, for example, revealed that such specialization may result in sequence variations concentrated in specific motifs, rather than globally distributed variations throughout the enzyme structure 86 . Nevertheless, the pressure to evolve new functions often conflicts with the need to preserve the original function of the progenitor enzyme, and this conflict is ultimately resolved through gene duplication followed by subfunctionalization or neofunctionalization 87 . Gene duplication events are caused by genetic aberrations such as replication slippage, retrotransposition, ectopic recombination, aneuploidy or polyploidy 88 , which seem to be better tolerated by plants than other eukaryotic organisms 89 . These serendipitous events sow seeds for metabolic evolution 87 . In recent years, the rapidly growing number of sequenced plant genomes has helped to unveil detailed processes of metabolic innovation following gene duplication events. For instance, copy number variations of metabolic genes were found to be a major contributor to divergence of specialized metabolic traits between the closely related species A. thaliana and Arabidopsis lyrata 90 . Such an increase in copy number of enzyme-encoding genes enables broadened catalytic specificity, thereby potentiating subsequent subfunctionalization or neofunctionalization 91 . In the medicinal plant Chinese skullcap ( Scutellaria baicalensis ), neofunctionalized gene duplicates from the ancestral scutellarein pathway and at least one subfunctionalized gene were found to contribute to the novel flavone pathway leading to synthesis of baicalein and wogonin 92 . Likewise, nepetalactone, an insect-repelling volatile iridoid uniquely found in catnip ( Nepeta spp.), evolved from a gene duplication event involving a progenitor enzyme with moonlighting iridoid synthase (ISY) activity, which later gave rise to a dedicated iridoid biosynthetic enzyme 5 (Fig. 5a ). Further formation of the nepetalactone isomers requires the activities of nepetalactol-related short-chain reductase/dehydrogenase enzymes. Again, these new enzymes arose via a series of gene duplication events from a single common ancestor followed by subsequent functional diversification and have co-evolved with the iridoid synthase gene 5 . Recently, the conserved chalcone isomerase in flavonoid biosynthesis was found to have been neofunctionalized from a more ancient fatty acid-binding protein 93 , thereby providing a unique example of an enantioselective cyclase that emerged de novo from a noncatalytic progenitor. Fig. 5: Evolutionary mechanisms contributing to novel plant specialized metabolic traits. a , The evolutionary trajectory underlying the occurrence of nepetalactone biosynthesis in catnip involves multiple gene duplication events followed by neofunctionalization or subfunction of a promiscuous P5βR ancestral gene and a NEPS-like gene 5 . The promiscuous ISY activity of P5βR is depicted as purple stripes. Several NEPS enzymes contribute to the production of various stereoisomers of nepetalactones. NEPS, nepetalactol-related short-chain reductase/dehydrogenases; P5βR, progesterone 5β-reductase; 8OG, 8-oxogeranial. b , Co-regulation of the biosynthetic genes of the thalianol gene cluster in Arabidopsis is facilitated by specific three-dimensional topologies of the encompassing chromosome 98 , 100 . These genes are likely connected via topologically associating domain (TAD) compartments of chromosome 5 to coordinate their expression in root cells. In contrast, association of the thalianol gene cluster with repressed TAD compartments is correlated with suppressed expression, for example, in leaves. THAA, thalianol acyltransferase; THAO, thalianol oxidase; THAH, thalianol hydroxylase; THAS, thalianol synthase. Full size image En route to assembling a new and efficient specialized metabolic pathway, participating enzymes need not only to have the appropriate catalytic functions, but also to acquire proper expression patterns that fit the functional needs of the newly evolved pathway. Altering gene expression profiles often involves genetic changes to promoters and other DNA regulatory elements that activate and ultimately control transcription of the newly evolved genes in a temporal, spatial and/or stimulus-dependent manner. New transcriptional regulatory elements may arise by repurposing ancestral elements through single-nucleotide mutation, deletion, insertion or rearrangement or by de novo evolution. Although these mechanisms have yet to be studied in depth in the context of plant metabolic evolution, the former was recently highlighted in Drosophila melanogaster 94 . It appears that mutations in both cis and trans elements could occur over relatively short evolutionary timescales and contribute to differential expression profiles of orthologous genes in different genotypes 94 . To explore the potential of de novo evolution, the lac operon promoter in Escherichia coli was replaced by random 103-bp-long sequences; of these sequences, approximately 10% are capable of eliciting transcription and an additional 60% are only one mutation away from being active promoters 95 . It is not known yet whether such a level of permissiveness to alteration of existing promoters or generation of novel ones prevails in plants, but this would provide the necessary evolutionary flexibility for diverse plant specialized metabolic pathways to gain optimal expression patterns specifically suited to their functions. It is well established that prokaryotes and fungi contain operons or gene clusters in their genomes to facilitate co-regulation of genes participating in the same biological process. In plants, as in other eukaryotes, the absence of functional operons and the prevalence of mechanisms that act to disperse genes (translocation, inversion and unequal crossing over) gave little reason to expect clustering of co-functioning genes. While this expectation still holds true in general, the rapidly expanding plant genomic resources have revealed that co-functioning specialized metabolic genes can form gene clusters in plant genomes 96 . These observations have also led to the development of bioinformatic tools that predict unknown metabolic pathways in a sequenced genome on the basis of gene clustering patterns 97 . One explanation for the existence of plant specialized metabolic gene clusters is the necessity of co-segregation of these genes in a population to maintain the overall integrity of the pathway. However, recent studies have also uncovered the role of gene clustering in coordinated transcriptional regulation. Known gene clusters across multiple plant species exhibit distinct chromatin signatures, which implies that genes on the same gene cluster—sometimes over long chromosomal distances—could be brought together through specific three-dimensional chromosomal topologies to facilitate co-regulation ? 98 (Fig. 5b ). Through this mechanism, the host plant could more effectively suppress multiple genes of a specialized metabolic pathway in a resting state or an inappropriate tissue and co-activate their expression when conditions warrant 99 . Future perspectives . The rapidly expanding tool sets in chemistry, genomics, and molecular and synthetic biology now have facilitated exploration of new territories in plant specialized metabolism at an unprecedented pace. These efforts have already started to expand into the rich biodiversity of nonmodel plants, including those harboring interesting chemistry and bioactivities and crop plants cultivated and used by populations around the world. 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This work was supported by grants from the Keck Foundation (J.-K.W.), the Mathers Foundation (J.-K.W.), the Family Larsson-Rosenquist Foundation (J.-K.W.), the National Science Foundation (CHE-1709616 (J.-K.W.) and IOS-1655438 (N.D.)) and Agriculture Hatch (177845 (N.D.)). We thank V.W. Weng for assistance in scientific illustration. Author information . Author notes Joseph H. Lynch Present address: Division of Plant and Soil Sciences, West Virginia University, Morgantown, WV, USA Affiliations . Whitehead Institute for Biomedical Research, Cambridge, MA, USA Jing-Ke Weng?&?Jason O. Matos Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA Jing-Ke Weng Department of Biochemistry, Purdue University, West Lafayette, IN, USA Joseph H. Lynch?&?Natalia Dudareva Purdue Center for Plant Biology, Purdue University, West Lafayette, IN, USA Joseph H. Lynch?&?Natalia Dudareva Authors Jing-Ke Weng View author publications You can also search for this author in PubMed ? Google Scholar Joseph H. Lynch View author publications You can also search for this author in PubMed ? Google Scholar Jason O. Matos View author publications You can also search for this author in PubMed ? Google Scholar Natalia Dudareva View author publications You can also search for this author in PubMed ? Google Scholar Corresponding authors . Correspondence to Jing-Ke Weng or Natalia Dudareva. Ethics declarations . Competing interests . J.-K.W. is a member of the scientific advisory board and a shareholder of DoubleRainbow Biosciences, Galixir and Inari Agriculture, which develop biotechnologies related to natural products, drug discovery and agriculture. All other authors have declared no competing interests. Additional information . Peer review information Nature Chemical Biology thanks Matthias Erb and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Rights and permissions . Reprints and Permissions About this article . Cite this article . Weng, JK., Lynch, J.H., Matos, J.O. et al. Adaptive mechanisms of plant specialized metabolism connecting chemistry to function. Nat Chem Biol (2021). https://doi.org/10.1038/s41589-021-00822-6 Download citation Received : 09 December 2020 Accepted : 21 May 2021 Published : 22 September 2021 DOI : https://doi.org/10.1038/s41589-021-00822-6 Share this article . Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative .

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