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Carminic acid (C22H20O13) is a red glucosidal hydroxyanthrapurin that occurs naturally in some
scale insects Scale insects are small insects of the order Hemiptera, suborder Sternorrhyncha. Of dramatically variable appearance and extreme sexual dimorphism, they comprise the infraorder Coccomorpha which is considered a more convenient grouping than the ...
, such as the
cochineal The cochineal ( , ; ''Dactylopius coccus'') is a scale insect in the suborder Sternorrhyncha, from which the natural dye carmine is derived. A primarily sessility (motility), sessile parasitism, parasite native to tropical and subtropical Sout ...
, Armenian cochineal, and Polish cochineal. The insects produce the acid as a deterrent to predators. An aluminum salt of carminic acid is the coloring agent in
carmine Carmine ()also called cochineal (when it is extracted from the cochineal insect), cochineal extract, crimson lake, or carmine lake is a pigment of a bright-red color obtained from the aluminium complex derived from carminic acid. Specific code n ...
, a
pigment A pigment is a colored material that is completely or nearly insoluble in water. In contrast, dyes are typically soluble, at least at some stage in their use. Generally dyes are often organic compounds whereas pigments are often inorganic compo ...
. Natives of
Peru , image_flag = Flag of Peru.svg , image_coat = Escudo nacional del Perú.svg , other_symbol = Great Seal of the State , other_symbol_type = Seal (emblem), National seal , national_motto = "Fi ...
had been producing cochineal dyes for textiles since at least 700 CE. Synonyms are C.I. 75470 and C.I. Natural Red 4. The chemical structure of carminic acid consists of a core
anthraquinone Anthraquinone, also called anthracenedione or dioxoanthracene, is an aromatic organic compound with formula . Isomers include various quinone derivatives. The term anthraquinone however refers to the isomer, 9,10-anthraquinone (IUPAC: 9,10-dioxo ...
structure linked to a
glucose Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, using ...
sugar unit. Carminic acid was first synthesized in the laboratory by organic chemists in 1991. In 2018, researchers genetically engineered the microbe ''
Aspergillus nidulans ''Aspergillus nidulans'' (also called ''Emericella nidulans'' when referring to its sexual form, or teleomorph) is one of many species of filamentous fungi in the phylum Ascomycota. It has been an important research organism for studying eukaryo ...
'' to produce carminic acid. It was previously thought that it contains α-D-glucopyranosyl residue, which was later redetermined to be the β-D-glucopyranosyl anomer.


Harvesting from cochineals

Carminic acid is commonly harvested from an American species scaled insects called ''
Dactylopius coccus The cochineal ( , ; ''Dactylopius coccus'') is a scale insect in the suborder Sternorrhyncha, from which the natural dye carmine is derived. A primarily sessile parasite native to tropical and subtropical South America through North America ( ...
'' (or cochineals). Cochineals are parasitic scaled insects which are abundantly found on their host plants, the
prickly pear cactus ''Opuntia'', commonly called prickly pear or pear cactus, is a genus of flowering plants in the cactus family Cactaceae. Prickly pears are also known as ''tuna'' (fruit), ''sabra'', ''nopal'' (paddle, plural ''nopales'') from the Nahuatl word f ...
native to Mexico and South America. The insects are either cultivated or harvested from wild populations, mainly for the wingless females of the species which attach themselves to the cactus and outnumber the winged males of the species two hundred to one. Classically, cultivated species were grown from eggs placed by workers onto the cactus leaves and left to grow. There the female cochineals would remain immobile for about 3 months until being brushed off, collected, and dried for shipping. Females possess concentrations of about 1.5% bodyweight of carminic acid and newborns about 3.0%. The carminic acid is then extracted by soaking the dried cochineals in water, and additives are then added to alter dye colour and enable the dye to adhere to objects.


Use as a deterrent

For many scaled insects of the genus ''
Dactylopius ''Dactylopius'' is a genus of insect in the superfamily Coccoidea, the scale insects. It is the only genus in the family Dactylopiidae.Van Dam, A. R. and B. May. (2012)A new species of ''Dactylopius'' Costa (''Dactylopius gracilipilus'' sp. nov.) ...
,'' carminic acid, thoroughly documented by
Thomas Eisner Thomas Eisner (June 25, 1929 – March 25, 2011) was a German-American entomologist and ecologist, known as the "father of chemical ecology." He was a Jacob Gould Schurman Professor of Chemical Ecology at Cornell University, and Director of the ...
, has been shown to be a highly potent feeding deterrent against ants. In Eisner's 1980 paper, he notes that the red colour of the carminic acid released when the cochineals are crushed could also be a visual
aposematic Aposematism is the advertising by an animal to potential predators that it is not worth attacking or eating. This unprofitability may consist of any defences which make the prey difficult to kill and eat, such as toxicity, venom, foul taste o ...
deterrent for predators as well. However, he notes that tests have not been done on vertebrates to provide any support to that theory. In the same paper however, Eisner mentions that cochineals were bitter when tasted by humans. Like other compounds housed in various plants, predators which are able to overcome the deterrent are able to sequester carminic acid in their flesh and utilize the deterrent for their own defense. The pyralid moth (''
Laetilia coccidivora ''Laetilia coccidivora'', the scale-feeding snout moth, is a species of snout moth The Pyralidae, commonly called pyralid moths, snout moths or grass moths, are a family of Lepidoptera in the ditrysian superfamily Pyraloidea. In many (particul ...
'') is one such predator which feeds on cochineals, sequestering their prey's carminic acid in their own body for defense against predators.The ability to sequester carminic acid has also been seen in several other larval bearing species (''Hyperaspis'', ''Leucopis'', etc.). Eisner remarks that the ability to sequester the compound likely arose due to ants being a common predator amongst larvae


Biosynthesis of carminic acid

Carminic acid is a
polyketide Polyketides are a class of natural products derived from a precursor molecule consisting of a chain of alternating ketone (or reduced forms of a ketone) and methylene groups: (-CO-CH2-). First studied in the early 20th century, discovery, biosynth ...
secondary metabolite Secondary metabolites, also called specialised metabolites, toxins, secondary products, or natural products, are organic compounds produced by any lifeform, e.g. bacteria, fungi, animals, or plants, which are not directly involved in the norm ...
produced by the scale insect '' Dacylopius coccus''. In terms of its biosynthetic origin, the structure of carminic acid was speculated to be either from type ll polyketide or shikimate pathways. This claim was not disputed until a key intermediate exclusive to the polyketide pathway was isolated. Until then, a detailed
biosynthetic Biosynthesis is a multi-step, enzyme-Catalysis, catalyzed process where substrate (chemistry), substrates are converted into more complex Product (chemistry), products in living organisms. In biosynthesis, simple Chemical compound, compounds are mo ...
mechanism Mechanism may refer to: * Mechanism (engineering), rigid bodies connected by joints in order to accomplish a desired force and/or motion transmission *Mechanism (biology), explaining how a feature is created *Mechanism (philosophy), a theory that ...
had not been formally proposed. The biosynthesis of carminic acid can be divided into three stages. The initiation stage involves
transferases A transferase is any one of a class of enzymes that catalyse the transfer of specific functional groups (e.g. a methyl or glycosyl group) from one molecule (called the donor) to another (called the acceptor). They are involved in hundreds of d ...
that load acetyl (AT) and malonyl-CoA (MCAT) to the
acyl carrier protein The acyl carrier protein (ACP) is a cofactor of both fatty acid and polyketide Polyketides are a class of natural products derived from a precursor molecule consisting of a chain of alternating ketone (or reduced forms of a ketone) and methylene ...
(ACP) forming acetyl and malonyl-ACP, respectively. The acetyl-ACP acts as a priming unit for the decarboxylative
condensation Condensation is the change of the state of matter from the gas phase into the liquid phase, and is the reverse of vaporization. The word most often refers to the water cycle. It can also be defined as the change in the state of water vapor to ...
with
malonyl-CoA Malonyl-CoA is a coenzyme A derivative of malonic acid. Functions It plays a key role in chain elongation in fatty acid biosynthesis and polyketide biosynthesis. Fatty acid biosynthesis Malonyl-CoA provides 2-carbon units to fatty acids and commi ...
catalyzed by a
ketoacyl synthase Ketoacyl synthases (KSs) catalyze the condensation reaction of acyl-CoA or acyl-acyl ACP with malonyl-CoA to form 3-ketoacyl-CoA or with malonyl-ACP to form 3-ketoacyl-ACP. This reaction is a key step in the fatty acid synthesis cycle, as the result ...
(KS) protein. The resulting acetoacetyl ACP is the simplest polyketide produced by this pathway, and it is subsequently condensed with six more malonyl-ACP units before cyclizing. The elongation stage consists of the repeated decarboxylative condensation by a ketoacyl synthase/chain length factor
heterodimer In biochemistry, a protein dimer is a macromolecular complex formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ''dimer'' has ...
that monitors the length of the growing polyketide. The resulting octaketide is then
aromatized Aromatization is a chemical reaction in which an aromaticity, aromatic system is formed from a single nonaromatic precursor. Typically aromatization is achieved by dehydrogenation of existing cyclic compounds, illustrated by the conversion of cycl ...
by a cyclase domain which catalyzes an
aldol In organic chemistry, an aldol describes a structural motif consisting of a 3-hydroxy ketone or 3-hydroxyaldehyde. Aldols are usually the product of aldol addition. When used alone, the term "aldol" may refer to 3-hydroxybutanal. Stereochemistry ...
-like cyclization reaction resulting in the formation of a flavokermesic acid anthrone (FKA). In any polyketide-based pathway, flavokermesic acid anthrone is the first cyclic intermediate. It was the successful isolation and characterization of FKA in wild type coccids that strengthened the evidence of a polyketide mediated biosynthetic pathway. The reactions that follow the formation of FKA consist of the
aromatization Aromatization is a chemical reaction in which an aromatic system is formed from a single nonaromatic precursor. Typically aromatization is achieved by dehydrogenation of existing cyclic compounds, illustrated by the conversion of cyclohexane int ...
and functionalization stages. FKA is subjected to two rounds of
hydroxylation In chemistry, hydroxylation can refer to: *(i) most commonly, hydroxylation describes a chemical process that introduces a hydroxyl group () into an organic compound. *(ii) the ''degree of hydroxylation'' refers to the number of OH groups in a ...
catalyzed by two distinct
P450 Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various compo ...
monooxygenases forming flavokermesic acid and kermesic acid, respectively. Whether these monooxygenases are oxygen or flavin dependent is to be determined. The first monooxygenation occurs in the central aromatic ring carbon, C10 while the second occurs in the C4 position. The final attachment of a carbohydrate onto the C2 position C-glycosylation reaction is catalyzed by a UDP-glucose dependent membrane bound
glucosyltransferase Glucosyltransferases are a type of glycosyltransferase that enable the transfer of glucose. Examples include: * glycogen synthase * glycogen phosphorylase Glycogen phosphorylase is one of the phosphorylase enzymes (). Glycogen phosphorylase c ...
. The order of the last two steps has not been determined due to lack of experimental kinetic data.


References

{{Glycosides Anthraquinone dyes Anthraquinone glucosides Hydroxyquinols