Itaconic acid is an organic compound with the formula CH2=C(CO2H)CH2CO2H. With two carboxyl groups, it is classified as a dicarboxylic acid. It is a non-toxic white solid that is soluble in water and several organic solvents. It plays several roles in biology.
Reactions Upon heating, itaconic acid converts to its anhydride. As a dicarboxylic acid, itaconic acid has two pKa. At pH levels above 7, itaconic acid exists as its double negatively charged form, termed itaconate. As an α,β-unsaturated carbonyl compound, itaconic acid is a good Michael acceptor. Thus, nucleophiles add across the C=C bond.
CH2=C(CO2H)CH2CO2H + R2P(O)H → R2P(O)CH2−CHCH2(CO2H)2 (R = organic group). This reaction is the means by which the fire retarding chemical 9,10-dihydro-9-oxa-10-phosphaphenanthrene-10-oxide can be incorporated into polymers.
Production In 1836, Samuel Baup discovered itaconic acid as a by-product in a dry distillation of citric acid. In the late 1920s, itaconic acid was isolated from a fungus in the Aspergillus genus of fungi The dry distillation forms itaconic anhydride, which then is hydrolyzed. Since the 1960s, however, it has been produced commercially by fermenting glucose, molasses, or another abundant carbon sources by a fungus such as Aspergillus itaconicus, Aspergillus terreus, or Ustilago maydis have also been investigated. One generally accepted route by which fungi make itaconate is through the tricarboxylic acid cycle pathway. This pathway forms cis-aconitate which is converted to itaconate by cis-aconitate-decarboxylase. Animal cells also make itaconate by an enzyme-catalyzed reaction from cis-aconitate, an intermediate metabolite in the tricarboxylic acid cycle, (i.e., TCA cycle). The itaconate-producing reaction is stimulated when the TCA cycle is suppressed. Ustilago maydis makes itaconic acid from trans-aconitate, catalyzed by aconitate delta-isomerase. The trans-aconitate product is decarboxylated to itaconate by trans-aconitate decarboxylase (i.e., TAD1, an enzyme found in Ustilago maydis) Itaconate has also been obtained by fermenting the fungi Yarrowia lipolytica with glucose, various species of Candida fungi with glucose, Ustilago vetiveriae fungus with glycerol, and various species of Aspergillus niger fungi with glucose, sorbitol, or sorbitol plus xylose mixture. Fermenting Escherichia coli bacteria with glucose, xylose, glycerol, or starch and Corynebacterium glutamicum bacteria with glucose or urea also affords itaconic acid. Ustilago maydis has, however, been genetically engineered to increase its itaconic acid production,
History In the 1930s itaconate was shown to have bactericidal actions. In 2011, Strelko et al. reported that itaconate was produced by two mammalian immortalized cell lines, cultured mouse VM-M3 brain tumor cells and RAW 264.7 mouse macrophages, and by macrophages isolated from mice. This group also showed that stimulation of mouse macrophages with the bacterial toxin, lipopolysaccharide (i.e., LPS, also termed endotoxin), increased their production and secretion of itaconate. In 2013, Michelucci et al. revealed the biosynthesis pathway that makes itaconate in mammals. These publications were followed by numerous others focused on the biology of itaconate and certain itaconate-like compounds as regulars of various cellular responses in animals and possibly humans.
Biology of Itaconate Biological studies focus on itaconate's physiological and pathological functions.
Cellular sources of itaconate The major cell types that normally make itaconate in response to stressful conditions or inflammatory stimuli are phagocytes of the myeloid lineage. This includes macrophages, monocytes, dendritic cells, and neutrophils. Itaconate is also produced by certain myeloid-derived suppressor cells (MDSCs). In the absence of inflammatory stimuli (i.e., under homeostatic conditions) itaconate production is low. Phagocyte stimulation leads to upregulation of IRG1 (immune-responsive gene 1), which encodes the enzyme required to synthesize itaconate.
Itaconate-forming metabolic pathway Itaconate is a by-product of the tricarboxylic acid cycle, consisting of eight successive enzyme-catalyzed biochemical reactions that occur in the cell's mitochondria. When cis-aconitate, accumulates, aconitate decarboxylase (also termed ACOD1, cis-aconitate decarboxylase) metabolizes cis-aconitate to itaconate and carbon dioxide (CO2) in the following decarboxylation reaction:
cis-aconitate → itaconate + CO2 This itaconate is transported across the mitochondrial membrane into the cell's cytosol by the mitochondrial dicarboxylate carrier protein, mitochondrial 2-oxoglutarate/malate carrier protein, and citrate–malate shuttle. The cytosolic itaconate may then move form the cytosol through the patients' cells' surface membranes to the extracellular space (this trans-membrane movement may involve a specific transport protein such as the major facilitator superfamily transport protein (i.e., MfsA) in fungi.) This itaconate has mostly anti-inflammatory actions. It acts on its parent cell, other cells, and certain microorganism by stimulating or inhibiting the activity of various response-regulating pathways in its parent cell, other cells, and bacteria. Itaconate's actions on its parent and other cells were considered as entirely independent of any receptor. Itaconate stimulates certain mammalian cells by activating the OXGR1 receptor.
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