8. Shikimates and Phenylpropanoids

8. Shikimates and Phenylpropanoids
RA Macahig FM Dayrit

8.0 Shikimates & phenylpropanoids (Dayrit)
Introduction Shikimic acid is the key intermediate of a large group aromatic natural products. The isolation of shikimic acid was first reported from aniseed (Illicium anisatum) and the fruit of I. religiosum, whose Japanese name was “shikimi-no-ki” (shi  four; kimi  seasons; no  of; ki  tree, literally “tree of four seasons”). Shikimic acid has since been found in many plants, bacteria, yeasts and moulds. It is estimated that this group accounts for 35% of plant dry mass, and that one-fifth of the carbon fixed by plants is channeled to shikimic acid metabolites, such as the lignins. Shikimic acid is the precursor of three important aromatic amino acids: phenylalanine, tyrosine, and tryptophan. 8.0 Shikimates & phenylpropanoids (Dayrit)

Overview Shikimic acid is produced directly from two D-glucose metabolites: phosphoenol pyruvate (C3) and D- erythrose-4-phosphate (C4) condense to form the seven carbon heptulose. Heptulose cyclizes to form 5- dehydroquinate which loses water to form shikimic acid. 8.0 Shikimates & phenylpropanoids (Dayrit)

Shikimic acid is converted to 5-enolpyruvylshikimate-3-phosphate, which loses phosphate to yield chorismic acid and prephenic acid. Chorismic acid is the branch point to a group of benzoic acid metabolites and tryptophan. Prephenic acid leads to the phenyl propanoids (C6-C3) and the flavonoids (C6-C3-C6), and the amino acids phenylalanine and tyrosine. 8.0 Shikimates & phenylpropanoids (Dayrit)

Overview of biosynthesis of quinones
Overview of biosynthesis of quinones. Depending on the organism, quinones can arise via the polyketide or shikimate pathways. 5. Polyketides (Dayrit)

Shikimates comprise a large group of aromatic natural products. 8.0 Shikimates & phenylpropanoids (Dayrit)

Shikimic acid picks up three carbons from of phosphoenol pyruvate to form chorismic acid and prephenic acid. Chorismic acid is converted to prephenic acid via a concerted [3,3]-sigmatropic shift. 5-EPSP 8.0 Shikimates & phenylpropanoids (Dayrit)

Prephenate is the precursor of phenylalanine and tyrosine. 8.0 Shikimates & phenylpropanoids (Dayrit)

C6, C6-C1 and C6-C2 The shikimate metabolites can be grouped according to the number of carbons atoms in the side chain. C6: phenols and quinones C6-C1: benzoic acid derivatives, including tannins C6-C2: phenyl ethyl compounds 8.0 Shikimates & phenylpropanoids (Dayrit)

C6 Metabolites Quinones are formed mainly from the polyketide and shikimate pathways, although other groups may produce quinones from extensive modification. The biosynthesis of ubiquinone, the compound which assists in biological electron transfer, is shown.

C6-C1. Tannins are a group of benzoic acid plant metabolites which precipitate proteins. The gallotanins, which are hydrolyzable tannins, contain glucose and gallic acid joined by ester linkages. 8.0 Shikimates & phenylpropanoids (Dayrit)

Two benzoic acid derivatives of some interest are gallic acid and ellagic acid. Gallic acid and ellagic acid are constituents of hydrolyzable tannins but these are found in many other natural products. These compounds are natural antioxidant in aqueous and micellar environments. Ellagic acid is also a naturally-occuring phytochemical pesticide and antimicrobial. 8.0 Shikimates & phenylpropanoids (Dayrit)

Ellagitannins are hydrolyzable tannins which are formed from the condensation of a sugar core and ellagic acid units. Ellagitannis from banaba, Lagerstroemia speciosa, were shown to increase uptake of adipocytes in rats, and could be responsible for lowering the blood glucose level. (Hayashi, et al., “Ellagitannins from Lagerstroemia speciosa as Activators of Glucose Transport in Fat Cells,” Planta Med., 2002, 68, ) 8.0 Shikimates & phenylpropanoids (Dayrit)

The benzoic and cinnamic acids are biosynthesized in a metabolic grid
The benzoic and cinnamic acids are biosynthesized in a metabolic grid. These compounds occur widely in plants.

Cyanogenic glycosides: C6-C2 A cyanogenic glycoside has an aglycone with a cyanide group and an attached sugar. Cyanogenic glycosides release the poisonous hydrogen cyanide enzymatically. Cyanogenic glycosides are found in cassava, and the fruits and wilting leaves of the rose family (including cherries, apples, plums, almonds, peaches, apricots, and raspberries). Sorghum (Sorghum bicolor) expresses cyanogenic glycosides in its roots and thus is resistant to pests such as rootworms. The dotted arrow is a metabolic link to aromatic glucosinolates. (Jorgensen et al., Curr Opinion in Plant Biol 2005, 8:280–291) 8.0 Shikimates & phenylpropanoids (Dayrit)

Glucosinolates The glucosinolates are found in Brassicales and contain sulfur, nitrogen and a group derived from glucose. About 120 glucosinolates are known in plants, where the R group is alkyl, derived from methionine, alanine, leucine, or valin; aromatic, derived from phenylalanine and tyrosine; or indolic derived from tryptophan. (R group variable)‏ Glucosinolates act as natural pesticides and defense against herbivores. These substances are also responsible for the bitter or sharp taste of many common foods such as mustard, radish, horseradish, cress, cabbage, Brussels sprouts, cauliflower, broccoli, and turnip. 8.0 Shikimates & phenylpropanoids (Dayrit)

Phenyl propanoids: C6-C3 The phenylpropanoid metabolism is unique to plants. Many intermediates and end products of the phenylpropanoid pathway play important roles in plants as phytoalexins, antioxidants, antiherbivory compounds, UV protectants, pigments, and aroma compounds. Phenylpropanoids polymerize to form lignins, which are essential components of the cell wall stability. Phenylpropanoid biosynthesis is one of the best-studied pathways in plants. The enzymes of the phenylpropanoid pathway are organized in multi-enzyme complexes and there is evidence for the coordinated expression of genes and enzymes. Genes encoding enzymes of this pathway are developmentally and tissue-specifically regulated and may be induced by environmental stresses such as nutrient deficiency, exposure to cold, UV light, and pathogen attack. 8.0 Shikimates & phenylpropanoids (Dayrit)

Phenylalanine and tyrosine are deaminated by phenylalanine ammonia lyase (PAL) or tyrosine ammonia lyase (TAL) to cinnamic acids. The cinnamic acids (C6-C3) are the precursors to the phenyl propanoids, coumarins, styrenes, benzoic acids, phenols, and flavonoids. A multi-enzyme complex enables coordinated action of PAL and cinnamate-4-hydroxylase (C4H) which control the flux of intermediates in phenylpropanoid biosynthesis. C4H 8.0 Shikimates & phenylpropanoids (Dayrit)

Examples of cinnamic acids and the C6-C3 derivatives. Cinnamic acids themselves do not usually occur in the free form but are isolated as glycosides. Cinnamic acids are precursors of lignans and lignins. 8.0 Shikimates & phenylpropanoids (Dayrit)

Examples of cinnamic acids and the C6-C3 derivatives. Rosmarinic acid is a dimer of two different C6-C3 units. Coumarins are aromatic lactone C6-C3 derivatives. They are widely distributed in plants, particularly the Umbelliferae and Rutacea families. 8.0 Shikimates & phenylpropanoids (Dayrit)

Examples of coumarin compounds. 8.0 Shikimates & phenylpropanoids (Dayrit)

Lignans are phenylpropanoid dimers. They can be rationalized by formation by coupling of resonance-stabilized by radicals with the assistance of “dirigent” proteins. 8.0 Shikimates & phenylpropanoids (Dayrit)

The diversity of lignan structures can be rationalized by bond formation via different radical sites. 8.0 Shikimates & phenylpropanoids (Dayrit)

(/ Lignins The majority of carbon in the phenylpropanoid group is channeled toward the synthesis of lignin, a complex three-dimensional polymer that is a principal structural component of plant cell walls. Lignin has far-reaching impacts on agriculture, industry and the environment, making phenylpropanoid metabolism a globally important part of plant biochemistry. Lignin is the second most abundant polymer on earth, next to cellulose. Lignin is a major carbon sink in the biosphere, accounting for about 30% of the more than 1.4 × 1012 kg of carbon sequestered into terrestrial plant material each year. 8.0 Shikimates & phenylpropanoids (Dayrit)

Lignins are extensively crosslinked phenylpropanoid polymers. Similar to the lignans, they are formed by coupling between different radicals arising from phenylpropanoids. Lignins contribute to the strength and robustness of plants and as a protective barrier against biochemical degradation by microorganisms. 8.0 Shikimates & phenylpropanoids (Dayrit)

Intermediates and enzymes of the lignin pathway.
Humphreys and Chapelle, Current Opinion in Plant Biology 2002, 5:224–229. Intermediates and enzymes of the lignin pathway. 4CL, 4-(hydroxy)cinnamoyl CoA ligase C3H, p-coumarate 3-hydroxylase C4H, cinnamate 4-hydroxylase CAD, cinnamyl alcohol dehydrogenase CCoAOMT, caffeoyl CoA O-methyltransferase CCR, cinnamoyl CoA reductase COMT, caffeic acid/5-hydroxyferulic acid O-methyltransferase CQT, hydroxycinnamoyl CoA:quinate hydroxycinnamoyltransferase CST, hydroxycinnamoyl CoA:shikimate hydroxycinnamoyltransferase F5H, ferulate 5-hydroxylase PAL, phenylalanine ammonia-lyase pCCoA3H, p-coumaryl CoA 3-hydroxylase SAD, sinapyl alcohol dehydrogenase. 8.0 Shikimates & phenylpropanoids (Dayrit)

Flavonoids The flavonoids are a very widely occurring group of natural products. There are over 5,000 flavonoids identified in plants. Most flavonoids, except for the catechins, are naturally found in their glycosylated form. Flavonoids are universally distributed among vascular plants and are found throughout the plant- roots, bark, fruit, seeds, leaves and flowers—where they play important functions. Flavonoids are physiologically important because of their many antioxidant properties. A B C 1 4 5 7 1’ 3’ 4’ Flavonoids have a characteristic “C6-C3-C6” structure, with three rings: an aromatic A and B ring, and a -pyrone C ring. 8.0 Shikimates & phenylpropanoids (Dayrit)

Flavonoids Flavonoids have attracted wide interest due to the following: a. Distribution of flavonoids. The flavonoids are one of the most numerous and widespread groups of secondary metabolites. They are present in most parts of the plant, often in various methylated and glycosylated forms. b. Functions of flavonoids in plants. The colored pigments in flowers of angiosperms (blues, purples, reds, and yellows) are produced by the flavonoid group known as the anthocyanidins. In leaves, the chlorophylls mask these colors. The highly oxygenated flavonoids are UV-active and are thought to protect the plant against UV radiation. Various flavonoids are believed to play specific roles in the physiology of plants. A number of flavonoids, for example, are known to be antifungal, antibacterial, and allelopathic. 8.0 Shikimates & phenylpropanoids (Dayrit)

Flavonoids c. Biological activity of flavonoids. A number of flavonoids have been shown to protect cells against oxidative attack. This is thought to explain its anti-inflammatory and cancer-protective properties. In addition, flavonoids have been shown to strengthen blood capillaries, and have found use in protection against weak arteries, strokes and hemorrhoids. Flavonoids are formed from the condensation of a phenylpropanoid + triketide. The flavonoids can be subdivided according into oxidation level and position at the three rings. Extensive biosynthetic studies have been carried out using tissue culture of parsley. Chalcone is the entry point to the flavonoids. Further oxidation and methylation occur after flavonoid ring formation. 8.0 Shikimates & phenylpropanoids (Dayrit)

Overview of the condensation of phenylpropanoid + (3 x acetyl CoA).

Flavonoids arise from condensation of a phenylpropanoid, (C6- C3), with three acetyl CoA units (3 x C2). The addition of acetyl CoA probably occurs stepwise yielding intermediates with the following structures: (C6-C3) + C2; (C6-C3) + C4; (C6-C3) + C6. The first member of the flavonoid group is chalcone.

Flavonoids arise from condensation of phenylpropanoid + triketide
Flavonoids arise from condensation of phenylpropanoid + triketide. The first member formed is chalcone. (polyketide cyclization)‏

The principal structural feature of the flavonoids is C6-C3-C6. The flavonoids can be subdivided by oxidation level and oxidation position. 8.0 Shikimates & phenylpropanoids (Dayrit)

The principal structural feature of the flavonoids is C6-C3-C6. Flavonoids can be subdivided by oxidation level at the C ring. 8.0 Shikimates & phenylpropanoids (Dayrit)

Six flavonoid subgroups Apigenin Luteolin 1. Flavones: Quercetin Kaempferol 2. Flavonols: Naringenin 3. Flavanones: 8.0 Shikimates & phenylpropanoids (Dayrit)

Six flavonoid subgroups 4. Isoflavones: Epigallocatechin Epicatechin 5. Flavan-3-ols: Cyanidin 6. Anthocyanidins: 8.0 Shikimates & phenylpropanoids (Dayrit)

Biosynthetic studies in tissue culture of parsley: Chalcone is the entry to the flavonoids. Flavonoids can be further grouped according to the specific position of oxidation at the three rings. Note that further oxidation and methylation occur after flavonoid ring formation. 8.0 Shikimates & phenylpropanoids (Dayrit)

Occurrence of flavonoids in various plants (Wink, Biochemistry of Secondary Metabolites 2010). There are some taxonomic patterns but many questions remain.

Numerous flavonoids are formed by further modifications of the basic flavonoid rings. For example, glycosylation and acetylation are commonly observed modifications. 8.0 Shikimates & phenylpropanoids (Dayrit)

Isoflavonoids Isoflavonoids are formed from flavonoids by 1,2-migration of the B-ring from the 2- to the 3-position. Studies using labeled phenylalanine are consistent with the proposed origin of the isoflavonoids. 8.0 Shikimates & phenylpropanoids (Dayrit)

Isoflavonoids The isoflavonoids, which are produced in legumes, are essential for plant-microbe interactions, such as chemo- attractants and signal molecules for symbiotic Rhizobium bacteria. The nodD gene-encoded proteins of Rhizobia have been shown to physically bind to flavonoids and isoflavonoids, and this ligand association initiates transcription of the nod operon leading to root nodule formation. Different isoflavonoids are also either precursors to, or are themselves the major phytoalexins in legumes, which play key roles in non-specific plant defense against bacterial and fungal pathogens. The activation of isoflavonoid synthesis during the disease resistance response is important for providing these many defense compounds. 8.0 Shikimates & phenylpropanoids (Dayrit)

Isoflavonoids Isoflavonoid synthesis is a branch of the general phenylpropanoid pathway that exists in all higher plants. An enzyme found almost exclusively in the legumes, isoflavone synthase (IFS), converts the phenylpropanoid pathway intermediates tetrahydroxy-chalcone (naringenin) and trihydroxy-chalcone (isoliquiritigenin) into the isoflavones genistein and daidzein, respectively. Isoflavones are produced at significant levels only in tissues where the phenylpropanoid pathway activity is elevated, such as in floral tissues, in UV-treated tissues, and in tissues where expression of a heterologous transcription factor was used to activate genes of the phenylpropanoid pathway. 8.0 Shikimates & phenylpropanoids (Dayrit)

Flavonoids are converted enzymatically to the isomeric isoflavonoids. The isoflavonoids are found mostly in the Leguminosae family. 8.0 Shikimates & phenylpropanoids (Dayrit)

Rotenone is one of the best known of the isoflavonoids. Rotenone is found in mangrove plants and is a fish poison, but is considered safe for mammals. 8.0 Shikimates & phenylpropanoids (Dayrit)

Anthocyanins are the sugar- derivatives of the anthocyanidins (the aglycone). Anthocyanins are water-soluble pigments in flowers, leaves and fruits. They also impart many of the colors of fruit juices and wines. A. List of the best-known anthocyanins and anthocyanidins; 8.0 Shikimates & phenylpropanoids (Dayrit)

B. Anthocyanin color is produced in compounds which can achieve a planar conformation which gives maximum delocalization. 8.0 Shikimates & phenylpropanoids (Dayrit)

Anthocyanins and flower color (“The Big Bloom: Birth of Flowering Plants, National Geographic, July 2002)‏ The yellow day lily has a near uniform hue in the visible spectral range. However, in the UV range which is invisible to most animals but visible to bees, the lily has a two-toned pattern. The UV pattern of many flowers is due to anthocyanins. 8.0 Shikimates & phenylpropanoids (Dayrit)

Leaf color is due to several compounds: Chlorophyll, which is green, gives leaves its predominant color. It is responsible for photosynthesis. As the temperature drops and the days shorten, it is destroyed enzymatically, revealing the presence of the other leaf pigments. Carotenoids are responsible for the yellow, orange and gold hues. Different species of trees contain various types of carotenoids. Anthocyanins give rise to the reds, purple and magenta hues. In contrast to the carotenoids, which are always present, anthocyanins are actively formed in the leaves during autumn. Anthocyanins and autumn leaves Why do leaves turn yellow, orange, red, purple and magenta during autumn? 8.0 Shikimates & phenylpropanoids (Dayrit)

Anthocyanins and autumn leaves Why do leaves turn yellow, orange, red, purple and magenta during autumn? What is the special role of anthocyanins? It is hypothesized that anthocyanins protect the leaf from free radicals which are produced by the destruction of the photosynthetic system. They provide some environmental protection from UV radiation and nutrient deficiency. The net effect is that anthocyanins slow down leaf death and abscission. 8.0 Shikimates & phenylpropanoids (Dayrit)

Catechins are flavan-3-ols which are believed to be biosynthetically related to the anthocyanidins and may be produced during the extraction of anthocyanidins. The best known catechins are ()- catechin and ()- epicatechin which are major constituents of tea. 8.0 Shikimates & phenylpropanoids (Dayrit)

Condensed tannins are polymeric compounds made up of catechin monomers. 8.0 Shikimates & phenylpropanoids (Dayrit)

MK biosynthetic pathways. (A) Classical pathway
MK biosynthetic pathways. (A) Classical pathway. Chorismate is converted into isochorismate by MenF (isochorismate synthase) and then into 2-succinyl-6-hydroxy-2,4-cyclohexadiene-1-carboxylate by MenD. This compound is dehydrated by MenC to o-succinylbenzoate, followed by the attachment of coenzyme A to yield o-succinylbenzoyl-CoA by MenE. o-Succinylbenzoyl-CoA is then converted into 1,4-dihydroxy-2-naphthoate by MenB. In the last two steps of the pathway, MK is converted by MenA and MenG, which catalyze prenylation and methylation, respectively. Red and black bold lines show carbons originated from erythrose-4-phosphate and phosphoenolpyruvate, respectively.

MK biosynthetic pathways. (B) Alternative pathway
MK biosynthetic pathways. (B) Alternative pathway. Green and blue bold lines indicate two carbon units derived from C-5 and C-6 of glucose via different metabolic pathways. Based on the annotation of the open reading frames of S. coelicolor A3(2), we presumed that SCO4491 (prenylation), SCO4556 (methylation), SCO4490 (decarboxylation), and SCO4492 (decarboxylation) would be involved in the late step of the MK biosynthetic pathway.

Metabolons of Phenylpropanoid Genes Jorgensen et al., Curr Opinion in Plant Biol 2005, 8:280–291 A metabolon is a temporary functional complex of several sequential enzymes held together by noncovalent interactions in a given metabolic pathway. Organization of the branched pathways of phenylpropanoid metabolism within separate individual metabolons. Enzymes that participate in multiple branches are shown in red and blue, whereas enzymes that are thought to be unique to specific pathways are shown in other colors. Enzymes that are known to be present as multiple isoforms are marked with an asterix. 4CL, 4-(hydroxy)cinnamoyl CoA ligase C3H, p-coumarate 3-hydroxylase C4H, cinnamate 4-hydroxylase CAD, cinnamyl alcohol dehydrogenase CCoAOMT, caffeoyl CoA O-methyltransferase CCR, cinnamoyl CoA reductase COMT, caffeic acid/5-hydroxyferulic acid O-methyltransferase CQT, hydroxycinnamoyl CoA:quinate hydroxycinnamoyltransferase CST, hydroxycinnamoyl CoA:shikimate hydroxycinnamoyltransferase F5H, ferulate 5-hydroxylase PAL, phenylalanine ammonia-lyase pCCoA3H, p-coumaryl CoA 3-hydroxylase SAD, sinapyl alcohol dehydrogenase. 8.0 Shikimates & phenylpropanoids (Dayrit)

Metabolons and the Biosynthesis of Natural Products Metabolon formation and metabolic channeling in plant secondary metabolism enable plants to effectively synthesize specific natural products and to avoid metabolic interference. Channeling can involve different cell types, take advantage of compartmentalization within the same cell or proceed directly within a metabolon. New experimental approaches document the importance of channeling in the synthesis of isoprenoids, alkaloids, phenylpropanoids, flavonoids and cyanogenic glucosides. Metabolon formation and metabolic channeling in natural-product synthesis facilitate attempts to genetically engineer new pathways into plants to improve their content of valuable natural products. They also offer the opportunity to introduce new traits by genetic engineering to produce plant cultivars that adhere to the principle of substantial equivalence. (Jorgensen et al., Curr Opinion in Plant Biol 2005, 8:280–291)‏ 8.0 Shikimates & phenylpropanoids (Dayrit)

Metabolic channeling of biosynthesis: flavonoids  isoflavonoids  phytoalexins Biosynthesis of O-methylated isoflavonoids in licorice, and conversion to phytoalexins. (Jorgensen et al., Curr Opinion in Plant Biol 2005, 8:280–291) IFS: 2-hydroxyisoflavanone synthase HI4’OMT: 2,7,4’-trihydroxyisoflavone 4’-O- methyltransferase D7OMT: daidzein 7-O-methyltransferase HID: 2-hydroxyisoflavanone dehydratase 8.0 Shikimates & phenylpropanoids (Dayrit)

Summary Many of the aromatic compounds found in higher plants belong to the shikimates. The shikimates have for a diverse range of properties and functions in plants, ranging from structural (lignins), flower and leaf coloration (anthocyanins and flavonoids), scent (some aryl propanes), and plant defense (flavonoids and isoflavonoids). The shikimates can be grouped by C6-Cn classification: C6: phenols and quinones C6-C1: benzoic acids; benzaldehydes; benzyl alcohols C6-C2: phenylethyl amines; styrenes; acetophenones C6-C3: phenyl propanoids: cinnamaldehydes; aryl propanes; lignins; lignans C6-C3-C6: flavonoids; isoflavonoids; catechins 8.0 Shikimates & phenylpropanoids (Dayrit)

Summary of the shikimates

8. Shikimates and Phenylpropanoids

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