Shikimic acid

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Shikimic acid
Chemical structure of shikimic acid 3D model of shikimic acid
Identifiers
CAS number 138-59-0 YesY
PubChem 8742
ChemSpider 8412 YesY
EC number 205-334-2
KEGG C00493 N
ChEBI CHEBI:16119 YesY
ChEMBL CHEMBL290345 YesY
Jmol-3D images Image 1
Properties
Molecular formula C7H10O5
Molar mass 174.15 g mol−1
Melting point 185–187 °C
Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
 N (verify) (what is: YesY/N?)
Infobox references

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]

It appears in the list of Group 3 carcinogens of the International Agency for Research on Cancer. Group 3 means that the agent is not classifiable as to its carcinogenicity to humans. Nevertheless, it is recommended to roast tree fern fronds, a speciality called fiddlehead (furled fronds of a young tree fern in the order Cyatheales, harvested for use as a vegetable). These fronds are edible, but must be roasted first to remove shikimic acid.[3]

Shikimic acid is also the glycoside part of some hydrolysable tannins.

Biosynthesis[edit]

Phosphoenolpyruvate and erythrose-4-phosphate react 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 phosphoenolpyruate 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[edit]

Main article: Shikimic acid pathway

Biosynthesis of the aromatic amino acids[edit]

The shikimate pathway 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 represent essential amino acids that must be obtained from the animal's diet (animals can synthesise tyrosine from phenylalanine, and therefore is not an essential amino acid except for individuals unable to hydroxylate phenylalanine to tyrosine).

The first enzyme involved is shikimate kinase, an enzyme that catalyzes the ATP-dependent phosphorylation of shikimate to form shikimate 3-phosphate.[4] Shikimate 3-phosphate is then coupled with phosphoenol pyruvate to give 5-enolpyruvylshikimate-3-phosphate via the enzyme 5-enolpyruvylshikimate-3-phosphate (EPSP) synthase.

Chorismate pathway 1.png

Then 5-enolpyruvylshikimate-3-phosphate is transformed into chorismate by a chorismate synthase.

Chorismate pathway 2.png

Prephenic acid is then synthesized by a Claisen rearrangement of chorismate by Chorismate mutase.[5][6]

Prephenate biosynthesis.png

Prephenate is oxidatively decarboxylated with retention of the hydroxyl group to give p-hydroxyphenylpyruvate, which is transaminated using glutamate as the nitrogen source to give tyrosine and α-ketoglutarate.

Tyrosine biosynthesis.svg

Starting point in the biosynthesis of some phenolics[edit]

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 uses L-phenylalanine to products, trans-cinnamic acid and ammonia.

Gallic acid biosynthesis

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.[7]

Other compounds[edit]

Shikimic acid is a precursor for:

Mycosporine-like amino acids[edit]

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

Uses[edit]

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 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.[8][9][10] A 2010 study released by the University of Maine showed that shikimic acid can also be readily harvested from the needles of several varieties of pine tree.[11]

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 e.g. 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,[12] an antibiotic which inhibits the aromatic biosynthetic pathway.[13]

Glyphosate, the active ingredient in the herbicide Roundup, kills plants by interfering with the shikimate pathway in plants. More specifically, glyphosate inhibits the enzyme 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS). "Roundup Ready" genetically modified crops overcome that inhibition.

See also[edit]

Books[edit]

  • The shikimate pathway, E. Haslam, 2 editions - first published in 1974
  • Shikimic acid, E. Haslam, 1 edition - first published in 1993

References[edit]

  1. ^ The Botanical Relations of Illicium Religiosum, Sieb., Illicium Anisatum, Lour. J. F. Eykman, American Journal of Pharmacy, 1881, volume 53, Number 8 (article)
  2. ^ a b Liquidambar styraciflua: a renewable source of shikimic acid. Liza B. Enrich, Margaret L. Scheuermann, Ashley Mohadjer, Kathryn R. Matthias, Chrystal F. Eller, M. Scott Newman, Michael Fujinaka and Thomas Poon, Tetrahedron Letters, 2008, volume 49, pages 2503–2505, doi:10.1016/j.tetlet.2008.02.140
  3. ^ Carcinogenicity of bracken and shikimic acid. I. A. Evans and M. A. Osman, Nature, 26 July 1974, volume 250, pages 348 - 349, doi:10.1038/250348a0
  4. ^ Herrmann, K. M.; Weaver, L. M. (1999). "The Shikimate Pathway". Annual Review of Plant Physiology and Plant Molecular Biology 50: 473–503. doi:10.1146/annurev.arplant.50.1.473. PMID 15012217.  edit
  5. ^ Helmut Goerisch (1978). "On the mechanism of the chorismate mutase reaction". Biochemistry 17 (18): 3700. doi:10.1021/bi00611a004. 
  6. ^ Peter Kast, Yadu B. Tewari, Olaf Wiest, Donald Hilvert, Kendall N. Houk, and Robert N. Goldberg (1997). "Thermodynamics of the Conversion of Chorismate to Prephenate: Experimental Results and Theoretical Predictions". J. Phys. Chem. B 101 (50): 10976–10982. doi:10.1021/jp972501l. 
  7. ^ Gallic acid pathway on metacyc.org
  8. ^ Bradley, David (December 2005). "Star role for bacteria in controlling flu pandemic?". Nature Reviews Drug Discovery 4 (12): 945–946. doi:10.1038/nrd1917. PMID 16370070. Retrieved 2007-03-07. 
  9. ^ Marco Krämer, Johannes Bongaertsa, Roel Bovenberga, Susanne Kremera, Ulrike Müllera, Sonja Orfa, Marcel Wubboltsa, Leon Raevena. (2003). "Metabolic engineering for microbial production of shikimic acid". Metabolic Engineering 5 (4): 277–283. doi:10.1016/j.ymben.2003.09.001. PMID 14642355. 
  10. ^ Johansson Louise, Lindskog Anna, Silfversparre Gustav, Cimander Christian, Nielsen Kristian Fog, Liden Gunnar (2005). "Shikimic acid production by a modified strain of E. coli (W3110.shik1) under phosphate-limited and carbon-limited conditions". Biotechnology and Bioengineering 92 (5): 541–552. doi:10.1002/bit.20546. PMID 16240440. 
  11. ^ Maine pine needles yield valuable Tamiflu material, Boston.com, November 7, 2010
  12. ^ http://jiang.tju.edu.cn/pdfs/6flufull.pdf
  13. ^ http://aac.asm.org/content/38/2/403.full.pdf

External links[edit]