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Shikimic acid
Shikimic acid
Shikimic acid
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Shikimic acid
Chemical structure of shikimic acid
Chemical structure of shikimic acid
3D model of shikimic acid
3D model of shikimic acid
Names
Preferred IUPAC name
(3R,4S,5R)-3,4,5-Trihydroxycyclohex-1-ene-1-carboxylic acid
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.004.850 Edit this at Wikidata
EC Number
  • 205-334-2
KEGG
UNII
  • InChI=1S/C7H10O5/c8-4-1-3(7(11)12)2-5(9)6(4)10/h1,4-6,8-10H,2H2,(H,11,12)/t4-,5-,6-/m1/s1 checkY
    Key: JXOHGGNKMLTUBP-HSUXUTPPSA-N checkY
  • InChI=1/C7H10O5/c8-4-1-3(7(11)12)2-5(9)6(4)10/h1,4-6,8-10H,2H2,(H,11,12)/t4-,5-,6-/m1/s1/f/h11H
  • InChI=1/C7H10O5/c8-4-1-3(7(11)12)2-5(9)6(4)10/h1,4-6,8-10H,2H2,(H,11,12)/t4-,5-,6-/m1/s1
    Key: JXOHGGNKMLTUBP-HSUXUTPPBZ
  • C1[C@H]([C@@H]([C@@H](C=C1C(=O)O)O)O)O
Properties
C7H10O5
Molar mass 174.15 g/mol
Melting point 185 to 187 °C (365 to 369 °F; 458 to 460 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

Shikimic acid, more commonly known as its anionic form shikimate, is a cyclohexene, a cyclitol and a cyclohexanecarboxylic acid. It is an important biochemical metabolite in plants and microorganisms. Its name comes from the Japanese flower shikimi (シキミ, the Japanese star anise, Illicium anisatum), from which it was first isolated in 1885 by Johan Fredrik Eykman.[1] The elucidation of its structure was made nearly 50 years later.[2]

Biosynthesis

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Phosphoenolpyruvate and erythrose-4-phosphate condense to form 3-deoxy-D-arabinoheptulosonate-7-phosphate (DAHP), in a reaction catalyzed by the enzyme DAHP synthase. DAHP is then transformed to 3-dehydroquinate (DHQ), in a reaction catalyzed by DHQ synthase. Although this reaction requires nicotinamide adenine dinucleotide (NAD) as a cofactor, the enzymic mechanism regenerates it, resulting in the net use of no NAD.

Biosynthesis of 3-dehydroquinate from phosphoenolpyruvate and erythrose-4-phosphate

DHQ is dehydrated to 3-dehydroshikimic acid by the enzyme 3-dehydroquinate dehydratase, which is reduced to shikimic acid by the enzyme shikimate dehydrogenase, which uses nicotinamide adenine dinucleotide phosphate (NADPH) as a cofactor.

Biosynthesis of shikimic acid from 3-dehydroquinate

Shikimate pathway

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Main article: Shikimate pathway

Biosynthesis of the aromatic amino acids

[edit]

The shikimate pathway, named after shikimic acid as important intermediate, is a seven-step metabolic route used by bacteria, fungi, algae, parasites, and plants for the biosynthesis of aromatic amino acids (phenylalanine, tyrosine, and tryptophan). This pathway is not found in animals; therefore, phenylalanine and tryptophan are essential nutrients and must be obtained from the animal's diet. Tyrosine is not essential, as it can be synthesized from phenylalanine, except for individuals unable to hydroxylate phenylalanine to tyrosine.

Starting point in the biosynthesis of some phenolics

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Phenylalanine and tyrosine are the precursors used in the phenylpropanoids biosynthesis. The phenylpropanoids are then used to produce the flavonoids, coumarins, tannins and lignin. The first enzyme involved is phenylalanine ammonia-lyase (PAL) that converts L-phenylalanine to trans-cinnamic acid and ammonia.

Gallic acid biosynthesis

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Gallic acid is formed from 3-dehydroshikimate by the action of the enzyme shikimate dehydrogenase to produce 3,5-didehydroshikimate. This latter compound spontaneously rearranges to gallic acid.[3]

Other compounds

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Shikimic acid is a precursor for:

Mycosporine-like amino acids

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Mycosporine-like amino acids are small secondary metabolites produced by organisms that live in environments with high volumes of sunlight, usually marine environments.

Uses

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In the pharmaceutical industry, shikimic acid from the Chinese star anise (Illicium verum) is used as a base material for production of oseltamivir (Tamiflu). Although shikimic acid is present in most autotrophic organisms, it is a biosynthetic intermediate and in general found in very low concentrations. The low isolation yield of shikimic acid from the Chinese star anise is blamed for the 2005 shortage of oseltamivir. Shikimic acid can also be extracted from the seeds of the sweetgum (Liquidambar styraciflua) fruit,[2] which is abundant in North America, in yields of around 1.5%. For example, 4 kg (8.8 lb) of sweetgum seeds is needed for fourteen packages of Tamiflu. By comparison, star anise has been reported to yield 3% to 7% shikimic acid. Biosynthetic pathways in E. coli have recently been enhanced to allow the organism to accumulate enough material to be used commercially.[4][5][6] A 2010 study released by the University of Maine showed that shikimic acid can also be readily harvested from the needles of several species of pine tree.[7]

Protecting groups are more commonly used in small-scale laboratory work and initial development than in industrial production processes because their use adds additional steps and material costs to the process. However, the availability of a cheap chiral building block can overcome these additional costs, for example, shikimic acid for oseltamivir.

Aminoshikimic acid is also an alternative to shikimic acid as a starting material for the synthesis of oseltamivir.

Target for drugs

[edit]

Shikimate can be used to synthesise (6S)-6-fluoroshikimic acid,[8] an antibiotic which inhibits the aromatic biosynthetic pathway.[9] More specifically, glyphosate inhibits the enzyme 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS). "Roundup Ready" genetically modified crops overcome that inhibition.[10]

Occurrence

[edit]

It occurs in tree fern fronds, a specialty called fiddlehead (furled fronds of a young tree fern in the order Cyatheales, harvested for use as a vegetable). These fronds are edible, but can be roasted to remove shikimic acid.[11]

Shikimic acid is also the glycoside part of some hydrolysable tannins. The acid is highly soluble in water and insoluble in nonpolar solvents, and this is why shikimic acid is active only against Gram-positive bacteria, due to outer cell membrane impermeability of Gram-negatives.[12]

See also

[edit]

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Shikimic acid

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Shikimic acid is a naturally occurring with the molecular formula C₇H₁₀O₅ and the systematic name (3R,4S,5R)-3,4,5-trihydroxycyclohex-1-ene-1-carboxylic acid, serving as a crucial intermediate in the for the biosynthesis of aromatic amino acids such as , , and in microorganisms, , fungi, and . This pathway, absent in animals, consists of seven enzymatic steps starting from phosphoenolpyruvate and erythrose-4-phosphate, with shikimic acid formed in the fourth step via the reduction of 3-dehydroshikimate by shikimate dehydrogenase, leading to chorismate. The compound appears as a white crystalline solid with a melting point of 183–186 °C and is highly soluble in (18 g/100 mL at 23 °C), contributing to its role in metabolic processes. Shikimic acid occurs widely in nature, particularly in plants like the fruits of Illicium religiosum (Japanese star anise), leaves of Ginkgo biloba, and seeds of sweetgum trees (Liquidambar styraciflua), as well as in bacteria such as Escherichia coli and fungi like Streptomyces nigra. Beyond its biological function in synthesizing essential aromatic compounds—including precursors for proteins, vitamins (such as E and K), and secondary metabolites like lignins and alkaloids—it holds significant industrial value as the primary starting material for producing oseltamivir (Tamiflu), an antiviral drug used to treat influenza by inhibiting neuraminidase. Due to limited natural supplies, especially during influenza outbreaks, microbial fermentation using engineered E. coli or yeast strains has become a key method for large-scale production, yielding up to 50–60 g/L of shikimic acid from glucose. The shikimate pathway's uniqueness makes it a target for herbicides like , which inhibits its 5-enolpyruvylshikimate-3-phosphate synthase, disrupting production in and microbes without affecting animals. Shikimic acid also exhibits mild biological activities, including potential and effects, though its primary applications remain in pharmaceutical synthesis and research. Safety profiles indicate low , with an intraperitoneal LD50 of 1,000 mg/kg in mice, but it can cause eye irritation upon direct contact.

Chemical Properties

Structure and Nomenclature

Shikimic acid has the molecular formula C₇H₁₀O₅ and the IUPAC name (3R,4S,5R)-3,4,5-trihydroxycyclohex-1-ene-1-carboxylic acid. The molecule features a six-membered ring with a between carbons 1 and 2, a group attached to carbon 1, and hydroxyl groups at positions 3, 4, and 5. This arrangement positions the functional groups in a way that supports its role as a biochemical intermediate, with the unsaturated ring providing rigidity and the polar substituents enabling hydrogen bonding. The natural form of shikimic acid exhibits the specific stereochemistry (3R,4S,5R), which defines its absolute configuration and distinguishes it from synthetic enantiomers or diastereomers such as epi-shikimic acid. This chiral arrangement is crucial for its biological activity and interactions in metabolic pathways. Shikimic acid was first isolated in 1885 by Dutch chemist Johan Fredrik Eykman from the fruits of Illicium religiosum, a plant known as Japanese star anise. Its full structure and stereochemistry were elucidated in the 1930s through the work of Hermann O.L. Fischer and Gerhard Dangschat, who used chemical degradation and synthesis to confirm the cyclohexene framework. The name "shikimic acid" derives from "shikimi," the Japanese term for the plant from which it was extracted.

Physical Properties

Shikimic acid is a white crystalline solid with a of 174.15 g/mol. It has a of 185–187 °C and decomposes upon heating before reaching its , emitting acrid smoke and irritating fumes. The compound exhibits high in (>100 g/L at 20 °C), as well as in and (approximately 2.25 g/100 mL in absolute alcohol at 23 °C), but it is insoluble in non-polar solvents such as , , , and . As an optically active molecule, shikimic acid displays a of [α]_D -180.0 ± 5.0° (c = 4 in H₂O). It remains stable under neutral conditions, such as in at 7.2, where solutions up to 10 mg/mL can be prepared without immediate degradation. However, it is sensitive to strong acids and bases; the group has a pK_a of approximately 4.0, leading to in basic environments, while extreme conditions may promote or other degradative reactions. Spectroscopic analysis provides characteristic signatures for identification. In infrared (IR) spectroscopy, prominent absorption bands appear around 3400 cm⁻¹ for O-H stretching of the hydroxyl groups and approximately 1710 cm⁻¹ for the C=O stretch of the . (¹H NMR) in D₂O at 7.4 shows key shifts, such as 6.62 ppm for the vinylic proton and 4.43 ppm for the methine proton adjacent to the , with hydroxy protons appearing broadly around 3–4 ppm. (UV) absorption occurs at 212–213 nm (ε ≈ 8200–8900 M⁻¹ cm⁻¹ in ), attributable to the conjugated enoate system involving the and moiety.

Chemical Reactivity

Shikimic acid possesses a group at C1, which readily undergoes esterification with alcohols under acidic conditions to form shikimate esters such as methyl shikimate, and amidation with amines to yield amides. The three hydroxyl groups—at C3, C4, and C5—exhibit reactivity typical of polyols, enabling with to protect the oxygens and for the synthesis of carbohydrate conjugates. The C3 hydroxyl, being allylic to the C1=C2 , is particularly susceptible to oxidation, as demonstrated by selective transformations to carbonyl derivatives using reagents like . The endocyclic double bond between C1 and C2 confers additional reactivity, allowing reduction via catalytic with to produce dihydroshikimic acid, a saturated analog with preserved at the chiral centers. This is also sensitive to epoxidation, proceeding with high regio- and using m-chloroperoxybenzoic acid to afford the cis-epoxide as a single . Although the enol-like arrangement involving the C5 hydroxyl and adjacent suggests potential for Michael-type additions, such reactions are less commonly exploited due to competing hydroxyl reactivities. As a chiral building block, shikimic acid's three stereocenters (at C3, C4, and C5) enable its use in asymmetric synthesis, where the scaffold undergoes stereocontrolled modifications while maintaining optical purity. A notable is fluoroshikimic acid, such as 6α-fluoroshikimate, synthesized via fluorodeoxygenation and serving as a reactive analog for probing enzymatic mechanisms in the .

Natural Occurrence

Sources in Organisms

Shikimic acid is primarily sourced from , where it accumulates as an intermediate in the , with the highest concentrations reported in species of the genus. The fruits of Chinese star anise () contain 3–7% shikimic acid by dry weight, making it the most abundant natural plant source commercially exploited. Other species, such as Illicium religiosum, also harbor significant levels in their fruits, up to ~25% dry weight—higher than in I. verum—though not commercially used due to associated with the species (synonymous with I. anisatum). Additional plant sources include the leaves of , which have been identified as a viable reservoir due to their relatively high content of shikimic acid, particularly in waste streams from processing. Pine needles from Pinus species yield 0.07–5% shikimic acid depending on species, age, and conditions, e.g., up to 1.6% in and 5.71% in Pinus massoniana. The seeds of sweetgum () provide around 1.5% shikimic acid, offering an abundant North American alternative. Shikimic acid is also present in lower amounts in fruits like apples and in certain ferns, contributing to its widespread distribution in plant tissues. In microbial organisms, shikimic acid is produced via the shikimate pathway in bacteria, fungi, and algae, though typically at low intracellular levels as a metabolic intermediate. Bacteria such as Escherichia coli and Bacillus subtilis synthesize it during aromatic compound biosynthesis. Fungi like Aspergillus species and various algae also generate shikimic acid as a metabolic intermediate, but yields are generally modest and vary with growth conditions. Animals do not synthesize shikimic acid, lacking the entirely, and instead obtain it indirectly through dietary intake as a precursor to essential aromatic amino acids like and . Quantification of shikimic acid in organismal tissues commonly employs (HPLC) with UV detection or (ESI-MS), offering high sensitivity and specificity for complex matrices. Gas chromatography-mass spectrometry (GC-MS) serves as an alternative for derivatized samples, particularly in microbial and extracts.

Ecological and Biological Roles

In plants, shikimic acid functions as a key precursor in the for synthesizing defensive phenolic compounds, including and , which deter herbivores and inhibit invasion by acting as phytoalexins or preformed barriers. These metabolites accumulate in response to biotic stresses, enhancing plant resistance through direct toxicity and activation of signaling pathways like salicylic acid-mediated defenses. Furthermore, the pathway contributes to tolerance, such as under or UV radiation, by producing antioxidants like that scavenge and reinforce structural barriers via deposition. Exogenous application of shikimic acid has been shown to mitigate stress in tea by boosting phenolic production and improving physiological resilience. In microorganisms, particularly soil bacteria, shikimic acid is vital for aromatic compound synthesis, supporting essential metabolic processes and enabling adaptation to environmental niches. In species like Streptomyces hygroscopicus, resistance to shikimic acid or its exogenous addition enhances flux through the pathway, increasing production of antibiotics such as ascomycin by up to 36% via elevated activity of enzymes like 3-deoxy-D-arabino-heptulosonate-7-phosphate synthase. Similarly, shikimic acid supplementation doubles rapamycin yields in Streptomyces rapamycinicus by providing precursors for polyketide biosynthesis. This role extends to soil ecology, where the shikimate pathway in microbes facilitates nutrient cycling through the breakdown of aromatic components in organic matter, though disruptions like glyphosate exposure lead to shikimic acid accumulation and altered microbial community function. Ecologically, shikimic acid is present in ferns like (bracken fern). In plant communities, it exhibits allelopathic potential, as demonstrated by extracts from (star anise) where shikimic acid (comprising ~7% dry weight) inhibits radicle growth in lettuce and other species with EC₅₀ values as low as 60–100 ppm, suggesting a role in suppressing competitor establishment. Regarding health implications, shikimic acid displays antibacterial activity against , notably , with a of 2.5 mg/mL achieved by disrupting integrity, increasing permeability, and causing leakage. It exhibits low , with an oral LD₅₀ of 2800 mg/kg in rats and no observed mortality at doses up to 10,000 mg/kg in mice, indicating safety for incidental human exposure.

Biosynthesis

Pathway Initiation

The biosynthesis of shikimic acid initiates within the , a metabolic route conserved across , fungi, , and other microorganisms, but absent in animals. The pathway begins with the convergence of two central metabolic intermediates: phosphoenolpyruvate (PEP), derived from , and erythrose-4-phosphate (E4P), produced via the . These precursors provide the carbon skeleton necessary for aromatic compound synthesis, with PEP contributing three carbons and E4P four, linking to the formation of shikimic acid. The first committed step is the condensation of PEP and E4P to form 3-deoxy-D-arabino-heptulosonate 7-phosphate (), catalyzed by (EC 2.5.1.54). This irreversible reaction is rate-limiting and highly regulated, with multiple isozymes in bacteria such as , including AroF (inhibited by ), AroG (inhibited by ), and AroH (inhibited by ), ensuring balanced flux based on end-product needs. In and other organisms, analogous isoforms exist, often localized to plastids. The enzyme's activity establishes the entry point for carbon flow into the pathway. The second step involves the conversion of to 3-dehydroquinate, mediated by 3-dehydroquinate synthase (DHQS, EC 4.6.1.3). This complex, multi-step transformation includes phosphate elimination, intramolecular , and , resulting in the first cyclic intermediate of the pathway without net change. DHQS is essential for pathway progression and is targeted in development due to its conservation in pathogens. Following this, 3-dehydroquinate undergoes by 3-dehydroquinate dehydratase (DHQD, EC 4.2.1.10) to yield 3-dehydroshikimate, setting the stage for the final initiation step. The initiation culminates in the reduction of 3-dehydroshikimate to shikimic acid, catalyzed by shikimate dehydrogenase (SDH, EC 1.1.1.25), which utilizes NADPH as a cofactor. This proceeds as follows: 3-dehydroshikimate+NADPH+H+→shikimic acid+NADP+\text{3-dehydroshikimate} + \text{NADPH} + \text{H}^+ \rightarrow \text{shikimic acid} + \text{NADP}^+ SDH introduces stereospecificity to the ring, completing the formation of shikimic acid, the pathway's namesake intermediate. In , this occurs in the , while in , the entire initiation sequence is compartmentalized within plastids, such as chloroplasts, to optimize precursor availability and isolate the pathway from cytosolic processes.

Key Enzymatic Steps

The key enzymatic steps following the formation of shikimate in the involve the sequential modification of shikimate to chorismate, a central intermediate for . These transformations occur primarily in the plastids of and the of , with shared enzymatic mechanisms but organism-specific isoforms and localizations. In the fifth step, shikimate kinase catalyzes the ATP-dependent of shikimate at the 3-position to yield shikimate-3-phosphate, requiring a divalent cation such as Mg²⁺ or Mn²⁺ as a cofactor. This exists as multiple isoforms in , such as two in Arabidopsis thaliana (AtSK1 and AtSK2), facilitating fine-tuned activity in plastidial compartments. The sixth step is mediated by 5-enolpyruvylshikimate-3- (EPSP) , which transfers the enolpyruvyl moiety from phosphoenolpyruvate (PEP) to shikimate-3-, forming EPSP and releasing inorganic . This reaction incorporates PEP as a key cofactor and is a primary target for the , which inhibits the in both and , though plant versions are typically class I and plastid-localized. Chorismate synthase then performs the seventh step, catalyzing the 1,4-elimination of the phosphate group from EPSP to produce chorismate through a cyclization reaction, dependent on reduced flavin mononucleotide (FMNH₂) as a cofactor. In bacteria like Escherichia coli, the enzyme is monofunctional, while in plants it is similarly plastid-resident, with single or dual genes reported (e.g., two in tomato). Chorismate serves as a critical , diverging to pathways for aromatic and secondary metabolites; for instance, anthranilate synthase initiates by converting chorismate to anthranilate using as an donor. This versatility underscores chorismate's role as a precursor for , , and diverse compounds like phenazines in .

Shikimate Pathway Details

Aromatic Amino Acid Production

The shikimate pathway culminates in chorismate, a central branch-point intermediate that diverges to produce the three aromatic amino acids: phenylalanine, tyrosine, and tryptophan. In this downstream phase, chorismate serves as the precursor for these essential metabolites, with the pathways branching immediately after its formation. The synthesis of phenylalanine and tyrosine typically proceeds via the prephenate intermediate, often through the arogenate route in plants and many microorganisms, while tryptophan biosynthesis follows a distinct anthranilate-mediated path. This divergence highlights the pathway's role in channeling carbon flux toward proteinogenic amino acids critical for cellular function. For and , chorismate is first converted to prephenate by chorismate mutase, a pivotal that catalyzes the essential for ring aromatization. Prephenate then undergoes to form pretyrosine (for ) or prephenyllactate (less common), but in predominant cases—especially in and select —the arogenate pathway prevails, where prephenate is directly transaminated to L-arogenate by prephenate aminotransferase. L-Arogenate is subsequently dehydrated by arogenate dehydratase to yield or dehydrogenated by arogenate to produce , with the latter often requiring NAD+ as a cofactor. In contrast, tryptophan synthesis begins with anthranilate synthase, a multi-subunit complex that converts chorismate to anthranilate through an amide transfer from , followed by further steps including phosphoribosylanthranilate formation and ring closure. These enzymatic steps ensure efficient partitioning of chorismate, with prephenate and prephenate dehydratase playing key roles in the and branches, respectively, in organisms utilizing the classical or hybrid routes. The overall of the leading to production is notably resource-intensive, requiring three molecules of phosphoenolpyruvate (PEP) and one molecule of erythrose-4-phosphate (E4P) to generate one molecule of chorismate, which then yields one upon branching—a simplified representation that underscores the pathway's demand on central carbon metabolism. This biosynthetic route is indispensable in , fungi, and most microorganisms, where it provides the sole endogenous source of these for protein synthesis and other metabolic needs. , however, lack the entirely, rendering , , and essential dietary nutrients obtained from external sources. Evolutionarily, the pathway is conserved across (present in approximately 75% of analyzed genomes, predominantly free-living species), , , and fungi, reflecting its ancient prokaryotic origins and horizontal transfer events that facilitated its spread. 3 PEP+E4P→1 aromatic amino acid3 \ \mathrm{PEP} + \mathrm{E4P} \rightarrow 1 \ \mathrm{aromatic \ amino \ acid}

Phenolic and Other Metabolites

The shikimate pathway serves as a critical branch point for the biosynthesis of phenolic compounds, extending beyond the primary aromatic amino acids to produce a diverse array of secondary metabolites essential for plant defense, structural integrity, and stress responses. Chorismate, a key intermediate, is converted to isochorismate by isochorismate synthase (ICS), which then leads to salicylic acid, a phytohormone involved in pathogen defense and systemic acquired resistance. In parallel, prephenate is transaminated to arogenate and subsequently decarboxylated to phenylalanine, which acts as the precursor for the phenylpropanoid pathway yielding flavonoids, lignins, and tannins—compounds that contribute to pigmentation, antimicrobial activity, and mechanical support in plants. Specific phenolic metabolites highlight the pathway's versatility. For instance, , a building block for hydrolyzable , is synthesized in from 3-dehydroshikimate via dehydroshikimate dehydrogenase (also known as gallic acid decarboxylase), branching directly from the . Lignins, complex polymers formed via the phenylpropanoid route from , constitute up to 30% of the dry weight in wood, providing rigidity and water impermeability to vascular tissues. In many , a substantial carbon flux—estimated at 30-40% of photosynthetically fixed carbon—is directed through phenylalanine toward these phenolic products, underscoring their metabolic prominence. Mycosporine-like amino acids (MAAs), another class of shikimate-derived phenolics, function as UV-absorbing sunscreens in , , and microbes. These compounds arise from the pathway's early intermediates, such as 3-dehydroquinic acid, and are upregulated under to dissipate harmful UV-B as , protecting cellular components from photodamage. Beyond phenolics, the contributes to other essential metabolites, including ubiquinone (coenzyme Q), a redox carrier in the synthesized from chorismate via 4-hydroxybenzoate; , a cofactor derived from 6-hydroxymethyl-7,8-dihydropteroate; and naphthoquinones, such as phylloquinone ( K1), which support and processes. Additionally, from the pathway serves as a precursor for indole alkaloids, a diverse group including auxins like and pharmaceutically relevant compounds such as , formed through and steps.

Pathway Regulation

The shikimate pathway is primarily regulated through feedback inhibition mechanisms that prevent overaccumulation of aromatic amino acids and maintain metabolic balance. In bacteria such as Escherichia coli, the first committed enzyme, 3-deoxy-D-arabino-heptulosonate 7-phosphate (DAHP) synthase, is allosterically inhibited by the end products phenylalanine, tyrosine, and tryptophan, with each amino acid binding to distinct isozymes to fine-tune flux entry based on cellular needs. Chorismate mutase, a branch-point enzyme directing flux toward phenylalanine and tyrosine, is similarly subject to feedback inhibition by these aromatic amino acids, ensuring coordinated production across pathway branches. In contrast, regulation of plant DAHP synthases is complex; while some isoforms exhibit hysteretic activation by tryptophan, recent studies show that others, such as AthDHS2 in Arabidopsis, are inhibited by tyrosine and tryptophan, enabling fine-tuned responses to developmental and environmental demands. Transcriptional regulation further controls pathway expression, varying between organisms. In bacteria, the aro genes encoding shikimate pathway enzymes are repressed by the TyrR and TrpR transcription factors; TyrR responds to phenylalanine and tyrosine levels to downregulate the common pathway and phenylalanine/tyrosine branches, while TrpR specifically represses the tryptophan branch under high tryptophan conditions. In plants, MYB transcription factors play a prominent role, with factors like PgMyb308-like activating expression of shikimate pathway genes to enhance production of aromatic amino acids and downstream lignins, while repressing flavonoid synthesis for metabolic prioritization. Allosteric regulation extends beyond feedback inhibition, influencing overall flux. While 5-enolpyruvylshikimate-3-phosphate (EPSP) synthase shows limited direct allosteric control, pathway flux is modulated by substrate availability from central metabolism, with increased carbon allocation under high phosphoenolpyruvate levels and adjustments to nitrogen limitation that redirect resources toward aromatic compounds. In plants, the pathway can account for 20–30% of photosynthetically fixed carbon flux, rising under abiotic stress to support secondary metabolite production for defense. Regulatory variations highlight evolutionary adaptations and engineering potential. In microbial pathogens, stringent feedback and transcriptional controls minimize intermediate accumulation to evade host defenses, differing from plant hosts where looser regulation supports high-flux production of phenolics for stress responses. Engineered microbes, such as feedback-resistant E. coli strains with deregulated DAHP synthase and inactivated repressors like TrpR, enable overproduction of shikimic acid and aromatics, achieving titers up to 101 g/L through optimized flux.

Production Methods

Extraction from Natural Sources

Shikimic acid is primarily extracted from the dried fruits of star anise (), which serve as the most abundant natural source, containing 3–7% of the compound by weight. The traditional extraction process begins with grinding the fruits and performing solvent extraction using hot water or ethanol (often a 30:70 ethanol-water mixture) to dissolve the shikimic acid. The resulting extract is filtered, acidified with to precipitate impurities, and then concentrated; shikimic acid is isolated through recrystallization, achieving purity levels exceeding 98%. Modern variants, such as pressurized , enhance efficiency and yields up to 4–5.5%, enabling multigram-scale isolation in a single operation. Alternative natural sources include pine needles (Pinus sylvestris) and sweetgum seeds (Liquidambar styraciflua), though they offer lower yields. From pine needles, shikimic acid is obtained via hot water extraction at 45–75°C or polar solvent methods, followed by chromatographic purification, with reported yields around 1.6% by weight. For sweetgum seeds, maceration in water or solvents precedes high-performance liquid chromatography (HPLC) purification, yielding 2.4–3.7% pure shikimic acid. These methods address supply diversification but face challenges like lower efficiency compared to star anise. Extraction from natural sources encounters limitations, including the seasonal availability of star anise harvests and generally low yields from alternative plants, such as approximately 2% in Ginkgo biloba leaves. During the 2005 avian influenza outbreak concerns, reliance on star anise extraction for oseltamivir (Tamiflu) production highlighted supply vulnerabilities, with global demand reaching about 10 tons annually. Sustainable practices emphasize harvesting from non-endangered species like star anise, which supports ongoing commercial viability without ecological strain.

Microbial Fermentation

Microbial fermentation represents a key biotechnological approach for producing shikimic acid, leveraging genetically engineered microorganisms to enhance yields beyond natural levels. Commonly used host organisms include and Corynebacterium glutamicum, which are modified through strategies such as overexpression of genes (Aro genes, including aroG, aroB, and aroE) and deletion of feedback inhibitors like aroK () and regulatory genes such as tyrR or pheA to redirect carbon flux toward shikimic acid accumulation. These modifications prevent downstream conversion of shikimic acid into aromatic and other metabolites, allowing titers that are economically viable for industrial applications. The production process typically employs fed-batch fermentation using glucose as the primary carbon source, with initial concentrations of 50–100 g/L supplemented as needed to maintain growth. Optimal conditions include a pH range of 6.5–7.0, maintained via base addition, and temperatures of 30–37°C, tailored to the host (E. coli at 37°C and C. glutamicum at 30°C). Early engineered strains from the achieved yields of 50–70 g/L, but advancements have pushed titers to 100–140 g/L in optimized systems. Byproducts are minimal due to targeted pathway blocks, facilitating downstream purification primarily via ion-exchange chromatography, where shikimic acid is adsorbed as its anionic form and eluted with or similar agents. Further optimization involves pathway engineering, such as modification of the phosphotransferase system (PTS) in E. coli to improve phosphoenolpyruvate availability by replacing it with alternative glucose transporters like galP and glk. Post-2010 advances, including CRISPR-based editing for precise gene knockouts and promoter tuning in both E. coli and C. glutamicum, have enabled yields exceeding 100 g/L, with productivities up to 2.6 g/L/h. This method offers advantages in scalability and independence from seasonal plant harvests, contributing to a growing share of commercial shikimic acid supply in the through renewable feedstocks and processes.

Synthetic Routes

Shikimic acid has been the target of numerous total syntheses since the , aimed at establishing efficient routes independent of natural extraction to enable analog preparation and . Early efforts focused on achieving the correct (3R,4S,5R) at the three chiral centers through multi-step sequences from structurally similar precursors. A prominent route involves transformation from , which shares the core but differs in saturation and substitution. This typically entails selective protection of hydroxyl groups, followed by oxidation to introduce the and to eliminate the C-6 hydroxyl. For instance, Snyder and Rapoport described a 1984 method using Hunsdiecker degradation to access shikimic acid derivatives from , though it produced a 1:1 mixture of regioisomers requiring separation. More recently, Whitehead et al. optimized the step with Martin's sulfurane , achieving an 83% yield for the conversion to methyl shikimate while maintaining enantiopurity from (-)-. Shi et al. further refined this approach in a 10-step sequence involving dibromination and , yielding enantiopure shikimic acid in 38% overall from (-)-. Alternative total syntheses utilize precursors to build the carbocyclic framework via cyclization. D-Ribose serves as a versatile starting material due to its and availability; Mirza and Vasella reported a multi-step route in 1984 employing aldol condensations and reductions to form the shikimate skeleton, providing access to labeled variants for biosynthetic studies. Similarly, Mirza and Harvey in 1991 used on D-ribose derivatives, followed by stereoselective reductions, to obtain shikimic acid in moderate yields suitable for analog elaboration. From D-mannose, Fleet et al. applied Wadsworth-Emmons olefination in the to generate the enone precursor, enabling high stereocontrol through subsequent and deprotection. These -based methods emphasize conceptual elegance in leveraging but often suffer from longer step counts (10–15) and overall yields below 20%. Diels-Alder cycloaddition from represents a concise strategy for constructing the ring, exploiting the diene's reactivity. Bartlett and McQuaid pioneered this in 1984, reacting with an activated dienophile to form the bicyclic , followed by and elimination to yield racemic shikimic acid in 50% overall yield. For enantioselective variants, Evans and Barnes employed chiral in the to favor the endo (67% ee initially, improvable to >95% ee with auxiliaries), addressing stereocontrol at C-4 and C-5. Koreeda et al. extended this in 1982 using Diels-Alder with derivatives, incorporating regioselective oxygenations for oxygenated analogs. These routes highlight the challenge of , often requiring auxiliary removal and epimerization corrections, with overall efficiencies limited to lab-scale (grams). Synthesis of analogs, such as 6-fluoroshikimic acid, builds on these frameworks to probe in the . This compound, a potent inhibitor of chorismate , is prepared via of protected quinic or shikimic acid derivatives. et al. detailed a 14-step sequence from in 1989, involving tosylation at C-6 followed by fluoride displacement, affording (6S)-6-fluoroshikimic acid in approximately 3% overall yield after deprotection. Improved protocols, such as those by Campbell et al. in the 1990s, enhanced using DAST-mediated fluorination, achieving 20–50% yields for the fluoro-introduction step while preserving the natural configuration.80092-0) Key challenges in these synthetic routes include precise stereocontrol amid multiple hydroxyl groups, which can lead to epimerization or elimination side products, and scalability beyond milligram quantities due to costly reagents and purifications. Post-2015 developments integrate with hybrid biocatalytic steps—such as enzymatic resolutions—for greener processes, reducing and improving enantiopurity to >99% ee, though purely chemical methods remain dominant for analog diversity. Overall, while lab-scale syntheses enable structure-activity studies, economic viability lags behind for bulk production.

Applications

Pharmaceutical Uses

Shikimic acid serves as a critical starting material in the synthesis of (Tamiflu), an antiviral medication used to treat and prevent A and B infections. The commercial production process, developed by and scaled by , involves a multi-step beginning with (−)-shikimic acid extracted from natural sources or produced via , culminating in oseltamivir phosphate after approximately 10-15 transformations that introduce key functional groups like the ring and neuraminidase-binding moieties. This route has been pivotal since the drug's approval in 2002, with global demand for shikimic acid surging during the 2005 threat and the 2009 H1N1 swine flu pandemic, driving production increases to meet stockpiling needs and generating over $1 billion in annual revenue for at its peak. Shikimic acid derivatives exhibit antibacterial potential, notably (6S)-6-fluoroshikimic acid, a fluorinated analog that inhibits the shikimate kinase enzyme in the aromatic pathway of . This compound demonstrates micromolar inhibitory activity against bacterial growth by disrupting chorismate production, positioning it as a lead for novel antibiotics targeting the , which is absent in humans. Additionally, 6-fluoroshikimic acid has shown efficacy against pathogens such as , protecting animal models from infection at low doses. The itself is a validated drug target, with serving as a prototype inhibitor of 5-enolpyruvylshikimate-3-phosphate (EPSPS), the fifth enzymatic step, forming a dead-end ternary complex that halts synthesis in and microbes. While primarily the basis for glyphosate's use as a broad-spectrum , this mechanism inspires pharmaceutical analogs for antibacterial and agents, as the pathway is essential in pathogens lacking mammalian equivalents. In Plasmodium falciparum, the causative agent of , the shikimate pathway supports and ubiquinone biosynthesis, making it a promising target for antimalarials; pathway inhibitors like glyphosate derivatives inhibit parasite growth at submicromolar concentrations, with potential for combination therapies against drug-resistant strains. Shikimic acid exhibits direct antiviral and antibacterial activities independent of its role as a synthetic precursor. It inhibits Staphylococcus aureus growth by altering cell membrane integrity and metabolic pathways, with minimum inhibitory concentrations around 2.5-5 mg/mL, and shows promise against viruses like Chikungunya through interference with viral replication in cell models. Pine needles, a natural source of shikimic acid, contribute to these antiviral properties, as the compound serves as the basis for oseltamivir (Tamiflu) against influenza. In neuroprotective contexts, post-2015 studies in inflammation models demonstrate that shikimic acid reduces neuroinflammation by suppressing NF-κB and MAPK signaling, attenuating microglial activation in LPS-induced mice, suggesting potential as an adjunct therapy though human trials remain pending. Furthermore, shikimic acid from pine needles exhibits anti-inflammatory and pain-relieving effects by inhibiting inflammatory pathways and demonstrating analgesic activity in experimental models. It also provides antioxidant benefits, combating oxidative stress and supporting nervous system health through activation of protective signaling pathways. Shikimic acid is incorporated into dietary supplements for its and properties, typically at doses below 1 g per day, with subchronic oral studies in indicating no major adverse effects up to 1 g/kg body weight, supporting its safety profile for human use when sourced purely and consumed in moderation. Recent studies as of 2024 have explored its synergistic effects with antibiotics like against methicillin-resistant S. aureus (MRSA) in experimental models.

Industrial and Other Uses

Shikimic acid plays a role in agricultural applications, particularly through its accumulation in treated with , which inhibits the and leads to elevated levels suitable for extraction as a chiral precursor. This glyphosate-induced production enhances yields from crops like carrots, providing a sustainable source for downstream industrial uses. Additionally, shikimic acid serves as a chiral in the synthesis of complex organic molecules, including analogs that mimic structures in development targeting aromatic pathways. In the food and cosmetics industries, shikimic acid contributes antioxidant properties to extracts from sources like star anise, helping to inhibit oxidation in proteins such as those in duck meat, thereby extending shelf life. In skincare formulations, shikimic acid, derived from sources such as star anise and pine needles, exhibits anti-inflammatory effects by regulating sebum production and alleviating redness, as well as exfoliation, hydration, and brightening properties, offering antibacterial and regenerative benefits. These properties make it a valuable ingredient in anti-aging and whitening cosmetics. As a research tool, isotopically labeled shikimic acid, such as with ¹⁴C or ³H at specific carbons, enables precise tracking of the in metabolic studies of . It also acts as a precursor for phenolic derivatives used in material science, where these aromatics form the basis for sustainable polymers through bio-based routes. Emerging applications include its role in production via aromatic derivatives from the , offering bio-replacements for petroleum-derived additives in fuels. In , shikimic acid shows potential as an adjuvant, enhancing efficacy against resistant like MRSA in animal models and supporting antiviral strategies for diseases such as . The global shikimic acid market was valued at approximately $40.5 million in 2024, with projections for growth to $63.9 million by 2033 driven by demand in for sustainable synthesis of aromatics and bioactives (as of 2024 estimates).

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