Chorismic acid

Chorismic acidMain

Community hub

Chorismic acid

8 pages, 0 posts

0 subscribers

Recent from talks

Be the first to start a discussion here.

Recent from talks

Be the first to start a discussion here.

Contribute something

About hubMembersContent overviewUpdatesRules

Main reference articles

Chorismic acid

View on Wikipedia

from Wikipedia

Chorismic acid
Names
Chemical structure of chorismic acid

IUPAC name (3R,4R)-3-[(1-carboxyvinyl)oxy]-4-hydroxycyclohexa-1,5-diene-1-carboxylic acid
Identifiers
CAS Number	617-12-9^Y
3D model (JSmol)	Interactive image
ChEBI	CHEBI:17333^Y
ChemSpider	11542^Y
ECHA InfoCard	100.164.204
PubChem CID	12039
UNII	GI1BLY82Y1
CompTox Dashboard (EPA)	DTXSID50210697
InChI InChI=1S/C10H10O6/c1-5(9(12)13)16-8-4-6(10(14)15)2-3-7(8)11/h2-4,7-8,11H,1H2,(H,12,13)(H,14,15)/t7-,8-/m1/s1^Y Key: WTFXTQVDAKGDEY-HTQZYQBOSA-N^Y InChI=1/C10H10O6/c1-5(9(12)13)16-8-4-6(10(14)15)2-3-7(8)11/h2-4,7-8,11H,1H2,(H,12,13)(H,14,15)/t7-,8-/m1/s1 Key: WTFXTQVDAKGDEY-HTQZYQBOBD
SMILES O=C(O)C1=C/[C@@H](O/C(C(=O)O)=C)[C@H](O)/C=C1
Properties
Chemical formula	C₁₀H₁₀O₆
Molar mass	226.184 g·mol⁻¹
Melting point	140 °C (284 °F; 413 K)
Hazards
GHS labelling:
Pictograms
Signal word	Danger
Hazard statements	H302, H312, H315, H319, H332, H335, H350, H361
Precautionary statements	P201, P202, P261, P264, P270, P271, P280, P281, P301+P312, P302+P352, P304+P312, P304+P340, P305+P351+P338, P308+P313, P312, P321, P322, P330, P332+P313, P337+P313, P362, P363, P403+P233, P405, P501
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). Y verify (what is ^YN ?) Infobox references

Chorismic acid, more commonly known as its anionic form chorismate, is an important biochemical intermediate in plants and microorganisms. It is a precursor for:

The aromatic amino acids phenylalanine, tryptophan, and tyrosine
Indole, indole derivatives and tryptophan
2,3-Dihydroxybenzoic acid (DHB) used for enterobactin biosynthesis
The plant hormone salicylic acid^[1]
Many alkaloids and other aromatic metabolites.
The folate precursor para-aminobenzoate (pABA)
The biosynthesis of vitamin K and folate in plants and microorganisms.

The name chorismic acid derives from a classical Greek word χωρίζω meaning "to separate",^[2] because the compound plays a role as a branch-point in aromatic amino acid biosynthesis.^[3]

Biosynthesis

[edit]

Shikimate → shikimate-3-phosphate → 5-enolpyruvylshikimate-3-phosphate (5-O-(1-carboxyvinyl)-3-phosphoshikimate)

Chorismate synthase is an enzyme that catalyzes the final chemical reaction:

5-O-(1-carboxyvinyl)-3-phosphoshikimate → chorismate + phosphate.

Metabolism

[edit]

Chorismate is transformed into para-aminobenzoic acid by the enzymes 4-amino-4-deoxychorismate synthase and 4-amino-4-deoxychorismate lyase.^[4]

Chorismate lyase is an enzyme that transforms chorismate into 4-hydroxybenzoate and pyruvate. This enzyme catalyses the first step in ubiquinone biosynthesis in Escherichia coli and other Gram-negative bacteria.^{[citation needed]}

References

[edit]

^ Wildermuth MC, Dewdney J, Wu G, Ausubel FM (2001). "Isochorismate synthase is required to synthesize salicylic acid for plant defence". Nature. 414 (6863): 562–5. Bibcode:2001Natur.414..562W. doi:10.1038/35107108. PMID 11734859.
^ Henry George Liddell; Robert Scott; Henry Stuart Jones & Roderick McKenzie (1996). A Greek-English Lexicon. Clarendon Press. ISBN 0-19-864226-1.
^ Gibson, F. (1999). "The elusive branch-point compound of aromatic amino acid biosynthesis". Trends in Biochemical Sciences. 24 (1): 36–38. doi:10.1016/S0968-0004(98)01330-9. PMID 10087921.
^ Folate Synthesis (Abstract)

External links

[edit]

Shikimate and chorismate biosynthesis

Revisions and contributors Edit on Wikipedia Read on Wikipedia

View on Grokipedia

from Grokipedia

Chorismic acid, more commonly known in its deprotonated anionic form as chorismate, is a pivotal branch-point intermediate in the shikimate pathway, essential for the biosynthesis of aromatic amino acids and other vital compounds in plants, bacteria, and fungi.^[1]^[2] With the molecular formula C₁₀H₁₀O₆, it exists as the (3R,4R)-stereoisomer of 3-[(1-carboxyethenyl)oxy]-4-hydroxycyclohexa-1,5-diene-1-carboxylic acid, featuring a cyclohexadiene ring with enolpyruvyl ether and carboxylic acid functionalities that confer instability and reactivity.^[1] Discovered in 1963 through isolation from bacterial extracts via ion-exchange chromatography, it was identified as a crucial precursor in aromatic biosynthesis using infrared spectroscopy and nuclear magnetic resonance.^[3] In biochemical pathways, chorismic acid partitions into multiple routes: chorismate mutase catalyzes its rearrangement to prephenate, which leads to phenylalanine and tyrosine via the Claisen rearrangement; anthranilate synthase directs it toward tryptophan; and additional enzymes like 4-amino-4-deoxychorismate synthase (PabA/PabB) and lyase (PabC) produce p-aminobenzoic acid, a folate precursor.^[2] It also serves as a precursor for ubiquinone (directly from chorismate), menaquinones (vitamin K, via isochorismate), and siderophores such as enterobactin (via isochorismate by EntC).^[2]^[4] Absent in mammals, which cannot synthesize aromatic amino acids de novo, the shikimate pathway's reliance on chorismic acid makes it a prime target for antibiotics (e.g., against bacterial infections) and herbicides (e.g., glyphosate, which inhibits upstream enzymes).^[2] Its production has been engineered in microorganisms like Klebsiella pneumoniae, yielding up to 800 mg/L, highlighting its industrial potential for bioproduction of aromatics.^[2]

Chemical Characteristics

Molecular Structure

Chorismic acid has the molecular formula C

_{10}

_{10}

_{6}

and possesses a seven-carbon cyclohexadienyl core derived from the initial condensation of phosphoenolpyruvate and erythrose-4-phosphate, extended by a three-carbon enolpyruvyl unit.^[5] This structure positions chorismic acid as a pivotal branch-point intermediate in the biosynthesis of aromatic compounds via the shikimate pathway.^[6] The IUPAC name of chorismic acid is (3R,4R)-5-[(1-carboxyethenyl)oxy]-6-hydroxycyclohexa-1,3-diene-1-carboxylic acid.^[1] The core features a cyclohexadiene ring with nonconjugated double bonds between carbons 1-2 and 4-5, a carboxylic acid substituent at C1, a hydroxy group at C6, and an enol ether linkage at C5 to a 1-carboxyethenyl side chain (-O-C(COOH)=CH

_{2}

). The side chain consists of a vinyl group bearing a carboxylic acid, forming an allylic enol ether that imparts instability to the molecule. At physiological pH, both carboxylic acid groups are typically deprotonated, yielding the dianionic chorismate form predominant in biological systems. SMILES: OC1=C(O)C(OC(=C)C(O)=O)=CC=C1C(O)=O^[1] The molecule has two chiral centers at C5 and C6, with the absolute configuration designated as (5R,6R), established through ozonolysis of enzymatically derived chorismic acid yielding D-(-)-tartaric acid.^[7] Chorismic acid exists primarily in the enol form but can undergo tautomerism to a minor keto tautomer involving migration of the enol ether double bond.^[8]

Physical and Chemical Properties

Chorismic acid exists as a colorless to pale yellow solid at room temperature and has a molecular weight of 230.18 g/mol.^[1] It is typically isolated as a powder and requires storage at −20°C to maintain integrity, reflecting its sensitivity to environmental conditions.^[9] The compound demonstrates high solubility in water, attributable to its polar carboxylic acid and enol functional groups, allowing concentrations suitable for optical rotation measurements (e.g., [α]_D²¹ = −274° at c = 0.16 in water).^[10] It exhibits moderate solubility in polar organic solvents such as methanol but is insoluble in nonpolar solvents, consistent with its hydrophilic nature.^[10] Chorismic acid displays instability in neutral or basic aqueous environments, where it spontaneously undergoes decarboxylation or a Claisen rearrangement to form prephenate.^[11] This reactivity underscores the need for acidic conditions (pH < 6) during purification and handling to minimize decomposition.^[11] Spectroscopically, chorismic acid absorbs ultraviolet light at 273 nm with an extinction coefficient (ε) of 8,300 M⁻¹ cm⁻¹, arising from its diene and enol ether systems.^[11] In ¹H NMR spectra, characteristic signals appear for the vinyl protons (around δ 5.5–6.5 ppm) and the ring protons (δ 6.8–7.2 ppm), aiding in structural confirmation.^[11] The acidity profile features two carboxylic acid groups that ionize under physiological conditions (pH ~7), leading to the predominant dianionic chorismate form and enhancing its water solubility and biological interactions.^[12]

Biosynthesis

Shikimate Pathway Overview

The shikimate pathway represents a seven-step anabolic metabolic route essential for the biosynthesis of chorismate, the central precursor to aromatic compounds including the amino acids phenylalanine, tyrosine, and tryptophan, as well as numerous secondary metabolites. This pathway operates in bacteria, fungi, and plants, where it integrates carbohydrate metabolism with the production of essential aromatics, but it is entirely absent in animals, rendering it a unique target for biochemical interventions such as antibiotic and herbicide development.^[5] The pathway initiates through the convergence of two key substrates derived from central metabolism: phosphoenolpyruvate (PEP), which originates from glycolysis, and erythrose-4-phosphate (E4P), produced via the pentose phosphate pathway. These molecules provide the carbon skeleton necessary for chorismate formation, with PEP contributing enolpyruvyl units and E4P supplying an aldose moiety in the initial condensation reaction.^[13]^[5] The overall stoichiometry of the pathway reflects its biosynthetic efficiency, summarized by the balanced equation:

2 \, \ce{PEP} + \ce{E4P} + \ce{ATP} + \ce{NADPH} \rightarrow \ce{chorismate} + \ce{ADP} + 3 \, \ce{P_i} + \ce{NADP+}

This equation accounts for the incorporation of two PEP molecules to build the C

_{10}

framework of chorismate while consuming ATP and NADPH and releasing inorganic products.^[14] Evolutionarily, the shikimate pathway is an ancient and highly conserved process, likely originating in early prokaryotes and retained across diverse domains of life due to its indispensable role in aromatic biosynthesis. In microorganisms and plants, it directs a substantial portion of cellular carbon flux—estimated at 20–30% in plants and significant in microbes—toward the production of aromatics critical for growth, defense, and structural integrity.^[15] Regulation of the pathway occurs primarily through allosteric feedback inhibition by downstream end products, such as phenylalanine and tyrosine, which bind to and inhibit the first committed enzyme, 3-deoxy-D-arabino-heptulosonate 7-phosphate (DAHP) synthase, thereby modulating flux in response to cellular needs and preventing metabolic imbalance.^[5]^[13]

Enzymatic Formation

The enzymatic formation of chorismic acid, also known as chorismate, occurs through a series of seven sequential reactions in the shikimate pathway, each catalyzed by specific enzymes that transform phosphoenolpyruvate (PEP) and erythrose 4-phosphate (E4P) into chorismate. The pathway begins with the condensation of PEP and E4P to form 3-deoxy-D-arabino-hept-2-ulosonate 7-phosphate (DAHP), catalyzed by DAHP synthase (EC 2.5.1.54), a rate-limiting enzyme that exists in multiple isozymes in organisms like Escherichia coli (encoded by aroF, aroG, and aroH).^[14] This step commits precursors to aromatic biosynthesis and is feedback-regulated, though the core reaction proceeds via an aldol-type condensation without cofactors beyond Mg²⁺.^[5] Subsequent cyclization of DAHP to 3-dehydroquinate is mediated by 3-dehydroquinate synthase (EC 4.6.1.3), which rearranges the linear substrate into a cyclic ketone through a series of dehydration and reduction steps, requiring NAD⁺ as a cofactor that is recycled during the reaction.^[16] Dehydration to 3-dehydroshikimate (EC 4.2.1.10) and reduction to shikimate (EC 1.1.1.25, using NADPH) follow, setting up the core cyclohexene structure, before shikimate kinase (EC 2.7.1.71, encoded by aroK or aroL in E. coli) phosphorylates shikimate at the 3-position using ATP to yield shikimate 3-phosphate.^[17] This kinase step enhances substrate solubility and prepares for the next addition.^[15] The penultimate step involves EPSP synthase (EC 2.5.1.19, encoded by aroA), which transfers the enolpyruvyl moiety from PEP to shikimate 3-phosphate, forming 5-enolpyruvylshikimate 3-phosphate (EPSP) in a protonated addition-elimination mechanism that avoids free enolpyruvate intermediates and requires no cofactors beyond divalent cations.^[14] This enzyme is a prominent herbicide target due to its specificity. The final step is catalyzed by chorismate synthase (EC 4.2.3.5, encoded by aroC in E. coli), which performs an anti-1,4-elimination of the 3-phosphate and the proR hydrogen at C-6 from EPSP to produce chorismate and inorganic phosphate:

\text{5-enolpyruvylshikimate 3-phosphate} \rightarrow \text{chorismate} + \text{P}_\text{i}

This lyase reaction requires reduced flavin mononucleotide (FMNH₂) as a cofactor, which binds tightly but is not stoichiometrically consumed; it likely stabilizes the transition state through hydrogen bonding or subtle electronic effects without redox involvement.^[18] The mechanism proceeds via a chair-like conformation of EPSP, ensuring stereospecific elimination, and is unique among pathway enzymes for its flavin dependence. In bacteria such as E. coli, all shikimate pathway enzymes, including chorismate synthase, are localized in the cytosol, facilitating rapid coordination with central metabolism.^[14] In contrast, plants and some fungi compartmentalize these enzymes, including chorismate synthase, within plastids (e.g., chloroplasts), linking chorismate production to photosynthetic carbon flow and enabling organelle-specific regulation.^[19] The aro gene cluster in E. coli exemplifies prokaryotic organization, with aroB (3-dehydroquinate synthase), aroA, and aroC forming an operon-like arrangement for efficient expression under aromatic demand.^[20] These enzymatic steps collectively yield chorismate as the branch-point intermediate, with high fidelity ensured by substrate specificity and cofactor roles.

Metabolism

Aromatic Amino Acid Production

Chorismate serves as the critical branch point in the biosynthesis of the three aromatic amino acids—phenylalanine (Phe), tyrosine (Tyr), and tryptophan (Trp)—in bacteria such as Escherichia coli, where the metabolic flux from the shikimate pathway diverges to support protein synthesis and other cellular needs. In E. coli, chorismate is partitioned among the pathways leading to Phe, Tyr, and Trp, as well as to aromatic compounds like ubiquinone, with the majority of flux typically directed toward Phe and Tyr due to their higher incorporation into proteins compared to Trp.^[21] The shared initial step for Phe and Tyr production involves the isomerization of chorismate to prephenate, catalyzed by chorismate mutase (EC 5.4.99.5), which proceeds through a pericyclic Claisen rearrangement mechanism. This reaction is represented as:

\text{chorismate} \xrightarrow{\text{chorismate mutase}} \text{prephenate}

chorismatechorismate mutase

prephenate In E. coli, chorismate mutase is part of bifunctional enzymes: PheA (chorismate mutase/prephenate dehydratase) directs flux toward Phe, while TyrA (chorismate mutase/prephenate dehydrogenase) channels it to Tyr. From prephenate, the Phe pathway continues with dehydration to phenylpyruvate by prephenate dehydratase (part of PheA), followed by transamination to Phe using an aromatic aminotransferase such as TyrB (EC 2.6.1.57). The Tyr pathway diverges with the NAD⁺-dependent oxidative decarboxylation of prephenate to 4-hydroxyphenylpyruvate by prephenate dehydrogenase (part of TyrA), then transamination to Tyr by TyrB. These steps ensure efficient conversion while maintaining pathway balance.^[21] The Trp branch initiates with anthranilate synthase (EC 4.1.3.27), a heterotetrameric complex of TrpE (anthranilate synthase component I) and the glutaminase subunit (TrpG, fused to phosphoribosylanthranilate isomerase in TrpD), which catalyzes the amination and decarboxylation of chorismate using glutamine as the ammonia donor: $\text{chorismate} + \text{L-glutamine} \xrightarrow{\text{anthranilate synthase}} \text{anthranilate} + \text{pyruvate} + \text{L-glutamate}$

anthranilate+pyruvate+L-glutamate Anthranilate is then activated by anthranilate phosphoribosyltransferase (TrpD, EC 2.4.2.18) through reaction with 5-phospho-α-D-ribosyl 1-pyrophosphate (PRPP): $\text{anthranilate} + \text{PRPP} \xrightarrow{\text{anthranilate phosphoribosyltransferase}} \text{N-(5'-phosphoribosyl)anthranilate} + \text{PP}_\text{i}$

N-(5’-phosphoribosyl)anthranilate+PPi Subsequent reactions, including isomerization, decarboxylation, and condensation with serine, yield indole-3-glycerol phosphate and ultimately Trp via tryptophan synthase (TrpBA). This branch commits chorismate exclusively to Trp production.^[21] Flux control at the chorismate branch is achieved through allosteric regulation of chorismate mutase by end-product inhibition from Phe and Tyr, which bind to distinct sites on the enzyme to reduce activity and prevent imbalance. Transcriptional control by the TyrR repressor modulates expression of genes like pheA, tyrA, and tyrB in response to Phe, Tyr, and ATP levels, while the TrpR repressor similarly regulates the trp operon (trpEDCBA) upon Trp binding. These mechanisms ensure coordinated production aligned with cellular demands.^[21]

Other Downstream Metabolites

Chorismate serves as a key branch point in the shikimate pathway for the biosynthesis of various non-amino acid aromatic compounds, including those involved in vitamin production and siderophores. In bacteria such as Escherichia coli, chorismate is converted to isochorismate by isochorismate synthase (EntC; EC 5.4.4.2), which catalyzes the reversible rearrangement of chorismate to isochorismate, the initial step in enterobactin biosynthesis, a catecholate siderophore essential for iron acquisition.^[22] This enzyme facilitates the production of isochorismate, which is then further processed by enzymes like EntB to form 2,3-dihydroxybenzoyl-serine units that assemble into the enterobactin macrocycle.^[23] Similarly, in folate biosynthesis, chorismate is aminated to 4-amino-4-deoxychorismate (ADC) by aminodeoxychorismate synthase (PabA/PabB), followed by decarboxylation and aromatization to p-aminobenzoate (PABA), a critical component of the folate cofactor in bacteria.^[24] Although anthranilate, derived from chorismate via anthranilate synthase, primarily supports tryptophan synthesis, structural similarities in the enzymatic machinery allow for occasional crosstalk in folate pathways in certain bacteria like Acinetobacter calcoaceticus.^[25] In ubiquinone (coenzyme Q) biosynthesis, chorismate is directly transformed into 4-hydroxybenzoate by chorismate pyruvate-lyase (UbiC; EC 4.1.3.40), releasing pyruvate in the process, which serves as the aromatic precursor for the benzoquinone ring in both prokaryotes and eukaryotic mitochondria.^[26] This step occurs in the cytosol of bacteria and yeast, with subsequent prenylation, hydroxylation, and decarboxylation steps assembling the polyisoprenoid-tailed ubiquinone in the inner mitochondrial membrane of eukaryotes, where it functions as an electron carrier in the respiratory chain.^[27] Unlike menaquinone biosynthesis, which proceeds via isochorismate, the ubiquinone pathway bypasses this intermediate, highlighting chorismate's versatile partitioning.^[4] In plants, chorismate-derived isochorismate plays a central role in salicylic acid (SA) biosynthesis, a phytohormone involved in defense responses. Isochorismate synthase (ICS; EC 5.4.4.2) converts chorismate to isochorismate in the plastid, which is then exported to the cytosol and conjugated with glutamate by PBS3 (an acyl-adenylate-forming enzyme) to form isochorismoyl-glutamate.^[28] This intermediate is subsequently processed by EPS1 to yield SA and N-pyruvoyl-L-glutamate, completing the two-step conversion from isochorismate.^[29] This pathway predominates in Arabidopsis and other dicots, accounting for the majority of pathogen-induced SA accumulation.^[30] Chorismate also contributes to secondary metabolite diversity in fungi, acting as a precursor for phenolics, naphthoquinones, and certain mycotoxins through extensions of the shikimate pathway. In fungal species like those in the genus Fusarium, chorismate-derived o-succinylbenzoate (from the isochorismate shunt) feeds into the biosynthesis of 1,4-naphthoquinones, such as phylloquinone analogs and other specialized quinones with antimicrobial properties, via a series of condensations and oxidations.^[31] Phenolic compounds, including simple phenols and more complex polyketide hybrids, arise indirectly from chorismate through flux diversion to aromatic precursors, supporting fungal pigmentation and stress responses.^[32] These metabolites underscore chorismate's role in fungal secondary metabolism, often elicited under environmental stress.

Biological Roles

In Microorganisms

Chorismate plays a central role in microbial physiology as the branch-point intermediate of the shikimate pathway, essential for synthesizing aromatic amino acids (phenylalanine, tyrosine, and tryptophan) in bacteria and fungi, which lack the capacity for de novo synthesis without this pathway. Mutations disrupting enzymes upstream or at chorismate formation, such as aroA encoding 5-enolpyruvylshikimate-3-phosphate (EPSP) synthase in Escherichia coli, result in aromatic auxotrophy, rendering cells unable to grow unless supplemented with phenylalanine, tyrosine, and tryptophan. Similarly, deletions in other aro genes like aroE (shikimate dehydrogenase) in E. coli lead to auxotrophic phenotypes that can be bypassed only by specific suppressors or supplementation, underscoring chorismate's indispensability for microbial viability.^[33]^[34] In bacteria, chorismate supports diverse secondary metabolism beyond amino acids; for instance, in Pseudomonas aeruginosa and other Pseudomonas species, it fuels high-flux production of phenazines, redox-active pigments that enhance biofilm formation, antibiotic resistance, and competition in polymicrobial environments. The phenazine pathway begins with chorismate amination by PhzE to form anthranilate, followed by conversion to phenazine-1-carboxylic acid (PCA) via PhzD isochorismatase and subsequent enzymes, with PCA serving as a precursor to pyocyanin and other derivatives critical for virulence. The shikimate pathway's vulnerability is exploited by glyphosate, which inhibits bacterial EPSP synthase (AroA), blocking chorismate formation and causing aromatic auxotrophy in glyphosate-sensitive strains, thereby impacting microbial ecology in agricultural settings.^[35]^[36]^[37] Chorismate-derived metabolites also bolster pathogenicity in bacteria; in Salmonella enterica, it is the precursor for enterobactin, a catecholate siderophore synthesized via the ent operon (starting with EntC isochorismate synthase converting chorismate to isochorismate), which chelates ferric iron with exceptional affinity to support replication in iron-scarce host tissues during infection. Enterobactin production enhances Salmonella virulence in mammalian models, as mutants deficient in this pathway exhibit reduced fitness and attenuation. In metabolic engineering, overexpression of shikimate pathway genes such as aroB (3-dehydroquinate synthase), aroD (3-dehydroshikimate dehydratase), and aroE in Corynebacterium glutamicum redirects carbon flux toward chorismate and shikimate accumulation, yielding up to 40 g/L shikimate in fed-batch fermentations and enabling scalable production of aromatic compounds.^[38]^[39]^[40]

In Plants and Fungi

In plants, chorismate serves as a critical precursor for secondary metabolites, including lignins, flavonoids, and alkaloids, which contribute to structural integrity, pigmentation, and chemical defense.^[14] The shikimate pathway, culminating in chorismate production, directs 20–30% of photosynthetically fixed carbon flux toward these compounds in vascular plants, underscoring its metabolic significance.^[15] Chorismate contributes to plant defense through the phenylpropanoid pathway, where it is converted to phenylalanine, leading to the synthesis of lignins and isoquinoline alkaloids that reinforce cell walls and deter herbivores or pathogens.^[41] Additionally, isochorismate, an isomer derived from chorismate, is the primary precursor for salicylic acid biosynthesis in the chloroplast, enabling systemic signaling for immune responses against biotic stresses.^[28] The biosynthesis of chorismate occurs in plant chloroplasts via the shikimate pathway, while downstream branches, such as those for phenylalanine and tyrosine, extend into the cytosol, allowing compartmentalized flux control.^[42] Expression of shikimate pathway enzymes is light-regulated, with upregulation under illumination to align aromatic compound production with photosynthetic carbon availability.^[43] Under pathogen attack, chorismate mutase activity increases in Arabidopsis thaliana, diverting flux toward defense-related phenylpropanoids and salicylic acid to bolster resistance.^[44] In fungi, chorismate supports essential processes, including the production of 4-aminobenzoate in Saccharomyces cerevisiae, which is required for folate biosynthesis and thereby sustains cellular metabolism, including ergosterol formation in membranes.^[45] Chorismate-derived pathways also contribute to spore pigmentation in various fungi, where aromatic intermediates form melanins that protect against environmental stresses and aid dispersal.^[46]

Research and Applications

Discovery and History

Chorismic acid, a pivotal intermediate in the biosynthesis of aromatic compounds, was first identified through studies on bacterial auxotrophs in the early 1950s. Bernard D. Davis and colleagues utilized penicillin-enriched techniques to isolate Escherichia coli mutants blocked in aromatic amino acid synthesis, revealing the accumulation of novel intermediates, including an enigmatic substance termed "compound X," which supported growth of certain auxotrophs but was not shikimic acid itself.^[47] These auxotroph studies established a linear biosynthetic sequence leading to phenylalanine, tyrosine, and tryptophan, with compound X positioned as a late-stage precursor just before branch-point divergence.^[48] The isolation and characterization of compound X as chorismic acid occurred in 1962, led by Frank Gibson's group at the Australian National University. Using a triple mutant of Aerobacter aerogenes (later reclassified as Enterobacter aerogenes), they extracted the compound via acidification and organic solvents, confirming its role as the branch-point intermediate through enzymatic conversions to anthranilate, prephenate, and p-aminobenzoate. The name "chorismic acid" derives from the Greek word chorisma, signifying "separation" or "junction," aptly reflecting its position as the common precursor diverging to multiple aromatic pathways. The full chemical structure—(3R,4R)-3-[(1-carboxyethenyl)oxy]-4-hydroxycyclohexa-1,5-diene-1-carboxylic acid—was elucidated shortly thereafter using nuclear magnetic resonance (NMR) spectroscopy by Lloyd Jackman and colleagues, with refinements in the 1970s confirming the enolpyruvyl ether configuration.^[1] By the mid-1960s, the shikimate pathway leading to chorismic acid had been outlined through collaborative efforts, notably by Ulrich Weiss and Charles Gilvarg, who identified key early intermediates like 3-dehydroquinate and shikimate using isotopic labeling and mutant accumulation in E. coli.^[48] Contributions from researchers such as Edwin Haslam advanced understanding in plants, demonstrating the pathway's conservation across kingdoms and its role in phenolic compound formation beyond amino acids.^[49] Klaus M. Herrmann further elucidated enzymatic steps through purification and kinetic studies in the 1970s and 1980s, solidifying chorismate's central enzymology. Milestones in the 1980s included the cloning of the chorismate synthase gene (aroC in E. coli) by White et al., enabling overexpression and detailed mechanistic studies of the final pathway step from 5-enolpyruvylshikimate-3-phosphate to chorismate. In the 1990s, crystal structures of chorismate mutase—the enzyme catalyzing chorismate's rearrangement to prephenate—were solved for Bacillus subtilis (at 2.0 Å resolution) and yeast, revealing dimeric architectures and active-site geometries that facilitated computational modeling of pericyclic rearrangements and allosteric regulation. These structural insights, from groups including those of Gregory Petsko and Dagmar Ringe, marked a shift toward integrating biochemistry with molecular dynamics simulations for pathway engineering.

Industrial Uses

Chorismic acid serves as a pivotal intermediate in the shikimate pathway, which is targeted for herbicide development due to its absence in mammals. Glyphosate, the active ingredient in the herbicide Roundup introduced by Monsanto in 1974, inhibits 5-enolpyruvylshikimate-3-phosphate (EPSP) synthase, an enzyme upstream of chorismate formation, thereby blocking the pathway and preventing the synthesis of essential aromatic amino acids in plants.^[50]^[51] This inhibition leads to plant death and has made glyphosate one of the most widely used herbicides globally, with applications in agriculture for weed control in crops like soybeans and corn.^[50] In pharmaceutical production, the shikimate pathway is leveraged for synthesizing oseltamivir (Tamiflu), an antiviral drug for influenza treatment, where shikimic acid—an upstream precursor to chorismate—is chemically converted to oseltamivir. To address supply limitations from natural sources like star anise, microbial fermentation in engineered Escherichia coli has been optimized, achieving yields of up to 101 g/L of shikimic acid in fed-batch processes.^[52]^[53] This biotechnological approach enhances scalability and reduces costs for large-scale drug manufacturing.^[53] Metabolic engineering of the chorismate pathway has enabled production of high-value compounds in microorganisms. In Saccharomyces cerevisiae, redirection of chorismate flux through the phenylpropanoid branch via overexpression of enzymes like phenylalanine ammonia-lyase and 4-coumarate:CoA ligase yields vanillin, a key flavor compound, reaching titers of 45-65 mg/L in de novo pathways from glucose. More recent engineering efforts have further improved de novo vanillin production in S. cerevisiae, achieving titers up to 533 mg/L as of 2025.^[54]^[55]^[56] Additionally, engineering chorismate-utilizing pathways in lactic acid bacteria, such as Lactococcus lactis, has led to folate overproduction, with patents covering strains that increase folate yields by up to 10-fold through targeted gene amplifications and feedback deregulation.^[57] The shikimate pathway's enzymes, including those handling chorismate, are explored as targets for antibiotics, particularly against pathogens like Mycobacterium tuberculosis, where inhibitors of chorismate synthase disrupt aromatic compound biosynthesis essential for bacterial survival.^[58] Chorismate analogs, such as azo-dyes and pyrazolo[4,3-d]pyrimidines, have been designed as potent inhibitors of chorismate mutase and synthase, showing micromolar IC₅₀ values and potential for novel drug development against tuberculosis and other infections.^[59]^[60] However, chorismic acid's inherent instability in vivo and during extraction limits its direct industrial application, prompting a focus on more stable upstream intermediates like shikimate for enhanced scalability in fermentation processes.^[61]^[62]

History

Media collections

Chorismic acid

Recent from talks

Recent from talks

Contribute something

Contribute something

Media Pages

Timelines

Articles

Notes collections

Notes

Notes

Days in Chronicle

Chorismic acid

Biosynthesis

Metabolism

See also

References

External links

Chorismic acid

Chemical Characteristics

Molecular Structure

Physical and Chemical Properties

Biosynthesis

Shikimate Pathway Overview

Enzymatic Formation

Metabolism

Aromatic Amino Acid Production

Add your contribution

Related Hubs

Contribute something