Shikimic acid
Encyclopedia
Shikimic acid, more commonly known as its anionic
form shikimate, is an important biochemical metabolite
in plants and microorganisms. Its name comes from the Japan
ese flower shikimi (シキミ, Illicium anisatum
), from which it was first isolated.
Shikimic acid is a precursor for:
In the pharmaceutical industry, shikimic acid from the Chinese star anise
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 fruit, 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.
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.
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.
DHQ is dehydrated to 3-dehydroshikimic acid by the enzyme dehydroquinase, which is reduced to shikimic acid by the enzyme shikimate dehydrogenase
, which uses nicotinamide adenine dinucleotide phosphate
(NADPH) as a cofactor.
Ion
An ion is an atom or molecule in which the total number of electrons is not equal to the total number of protons, giving it a net positive or negative electrical charge. The name was given by physicist Michael Faraday for the substances that allow a current to pass between electrodes in a...
form shikimate, is an important biochemical metabolite
Metabolite
Metabolites are the intermediates and products of metabolism. The term metabolite is usually restricted to small molecules. A primary metabolite is directly involved in normal growth, development, and reproduction. Alcohol is an example of a primary metabolite produced in large-scale by industrial...
in plants and microorganisms. Its name comes from the Japan
Japan
Japan is an island nation in East Asia. Located in the Pacific Ocean, it lies to the east of the Sea of Japan, China, North Korea, South Korea and Russia, stretching from the Sea of Okhotsk in the north to the East China Sea and Taiwan in the south...
ese flower shikimi (シキミ, Illicium anisatum
Japanese star anise
Illicium anisatum, commonly known as the Japanese star anise, is a tree similar to Chinese star anise. It is highly toxic, therefore it is not edible; instead, it has been burned as incense in Japan, where it is known as...
), from which it was first isolated.
Shikimic acid is a precursor for:
- the aromaticAromatic amino acidsAromatic amino acids are amino acids that include an aromatic ring.Examples include:* Among 20 standard amino acids: phenylalanine, tryptophan, and tyrosine* Others: thyroxine-See also:* Aromatic L-amino acid decarboxylase...
amino acidAmino acidAmino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s phenylalaninePhenylalaninePhenylalanine is an α-amino acid with the formula C6H5CH2CHCOOH. This essential amino acid is classified as nonpolar because of the hydrophobic nature of the benzyl side chain. L-Phenylalanine is an electrically neutral amino acid, one of the twenty common amino acids used to biochemically form...
and tyrosineTyrosineTyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group... - indoleIndoleIndole is an aromatic heterocyclic organic compound. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered nitrogen-containing pyrrole ring. Indole is a popular component of fragrances and the precursor to many pharmaceuticals. Compounds that contain an...
, indole derivatives and aromaticAromatic amino acidsAromatic amino acids are amino acids that include an aromatic ring.Examples include:* Among 20 standard amino acids: phenylalanine, tryptophan, and tyrosine* Others: thyroxine-See also:* Aromatic L-amino acid decarboxylase...
amino acidAmino acidAmino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
tryptophanTryptophanTryptophan is one of the 20 standard amino acids, as well as an essential amino acid in the human diet. It is encoded in the standard genetic code as the codon UGG... - many alkaloidAlkaloidAlkaloids are a group of naturally occurring chemical compounds that contain mostly basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Also some synthetic compounds of similar structure are attributed to alkaloids...
s and other aromatic metaboliteMetaboliteMetabolites are the intermediates and products of metabolism. The term metabolite is usually restricted to small molecules. A primary metabolite is directly involved in normal growth, development, and reproduction. Alcohol is an example of a primary metabolite produced in large-scale by industrial...
s - tanninTanninA tannin is an astringent, bitter plant polyphenolic compound that binds to and precipitates proteins and various other organic compounds including amino acids and alkaloids.The term tannin refers to the use of...
s, flavonoidFlavonoidFlavonoids , are a class of plant secondary metabolites....
s, and ligninLigninLignin or lignen is a complex chemical compound most commonly derived from wood, and an integral part of the secondary cell walls of plants and some algae. The term was introduced in 1819 by de Candolle and is derived from the Latin word lignum, meaning wood...
.
In the pharmaceutical industry, shikimic acid from the Chinese star anise
Star anise
Illicium verum, commonly called Star anise, star aniseed, or Chinese star anise, is a spice that closely resembles anise in flavor, obtained from the star-shaped pericarp of Illicium verum, a small native evergreen tree of northeast Vietnam and southwest China...
is used as a base material for production of oseltamivir
Oseltamivir
Oseltamivir INN , an antiviral drug, slows the spread of influenza virus between cells in the body by stopping the virus from chemically cutting ties with its host cell; median time to symptom alleviation is reduced by 0.5–1 day. The drug is sold under the trade name Tamiflu, and is taken orally...
(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
Oseltamivir
Oseltamivir INN , an antiviral drug, slows the spread of influenza virus between cells in the body by stopping the virus from chemically cutting ties with its host cell; median time to symptom alleviation is reduced by 0.5–1 day. The drug is sold under the trade name Tamiflu, and is taken orally...
. Shikimic acid can also be extracted from the seeds of the sweetgum fruit, 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
Escherichia coli
Escherichia coli is a Gram-negative, rod-shaped bacterium that is commonly found in the lower intestine of warm-blooded organisms . Most E. coli strains are harmless, but some serotypes can cause serious food poisoning in humans, and are occasionally responsible for product recalls...
have recently been enhanced to allow the organism to accumulate enough material to be used commercially.
A 2010 study released by the University of Maine
University of Maine
The University of Maine is a public research university located in Orono, Maine, United States. The university was established in 1865 as a land grant college and is referred to as the flagship university of the University of Maine System...
showed that shikimic acid can also be readily harvested from the needles of several varieties of pine
Pine
Pines are trees in the genus Pinus ,in the family Pinaceae. They make up the monotypic subfamily Pinoideae. There are about 115 species of pine, although different authorities accept between 105 and 125 species.-Etymology:...
tree.
Biosynthesis
PhosphoenolpyruvatePhosphoenolpyruvate
Phosphoenolpyruvic acid , or phosphoenolpyruvate as the anion, is an important chemical compound in biochemistry. It has the high-energy phosphate bond found in living organisms, and is involved in glycolysis and gluconeogenesis...
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
3-Dehydroquinic acid
3-Dehydroquinic acid is the first carbocyclic intermediate of the shikimate pathway. It is created from 3-deoxyarabinoheptulosonate 7-phosphate, a 7-carbon ulonic acid, by the enzyme DHQ synthase. The mechanism of ring closure is complex, but involves an aldol condensation at C-2 and C-7...
(DHQ), in a reaction catalyzed by DHQ synthase. Although this reaction requires nicotinamide adenine dinucleotide
Nicotinamide adenine dinucleotide
Nicotinamide adenine dinucleotide, abbreviated NAD, is a coenzyme found in all living cells. The compound is a dinucleotide, since it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine base and the other nicotinamide.In metabolism, NAD is involved...
(NAD) as a cofactor, the enzymic mechanism regenerates it, resulting in the net use of no NAD.
DHQ is dehydrated to 3-dehydroshikimic acid by the enzyme dehydroquinase, which is reduced to shikimic acid by the enzyme shikimate dehydrogenase
Shikimate dehydrogenase
In enzymology, a shikimate dehydrogenase is an enzyme that catalyzes the chemical reactionThus, the two substrates of this enzyme are shikimate and NADP+, whereas its 3 products are 3-dehydroshikimate, NADPH, and H+....
, which uses nicotinamide adenine dinucleotide phosphate
Nicotinamide adenine dinucleotide phosphate
Nicotinamide adenine dinucleotide phosphate, abbreviated NADP or TPN in older notation , is a coenzyme used in anabolic reactions, such as lipid and nucleic acid synthesis, which require NADPH as a reducing agent....
(NADPH) as a cofactor.
