Itaconic acid

Source: Wikipedia, the free encyclopedia.
Itaconic acid
Skeletal formula
Ball-and-stick model
Names
Preferred IUPAC name
Methylidenebutanedioic acid
Other names
2-Methylenesuccinic acid
Methylenesuccinic acid[1]
1-Propene-2,3-dicarboxylic acid
Identifiers
3D model (
JSmol
)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard
 100.002.364 Edit this at Wikidata
KEGG
UNII
  • InChI=1S/C5H6O4/c1-3(5(8)9)2-4(6)7/h1-2H2,(H,6,7)(H,8,9) checkY
    Key: LVHBHZANLOWSRM-UHFFFAOYSA-N checkY
  • InChI=1/C5H6O4/c1-3(5(8)9)2-4(6)7/h1-2H2,(H,6,7)(H,8,9)
    Key: LVHBHZANLOWSRM-UHFFFAOYAS
  • O=C(O)C(=C)CC(=O)O
Properties
C5H6O4
Molar mass 130.099 g·mol−1
Appearance White solid
Density 1.63 g/cm3[1]
Melting point 162 to 164 °C (324 to 327 °F; 435 to 437 K) (decomposes)[1]
1 g/12 mL[1]
Solubility in ethanol 1 g/5 mL[1]
-57.57·10−6 cm3/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
checkY verify (what is checkY☒N ?)

Itaconic acid (also termed methylidenesuccinic acid and 2-methylidenebutanedioic acid

carboxyl groups (notated as -CO2H) and two others which are double bonded together (i.e., C=C). (itaconic acid's chemical formula is C5H6O4, see adjacent figure and dicarboxylic acids). At the strongly acidic pH levels below 2, itaconic acid is electrically neutral because both of its carboxy residues are bound to hydrogen (notated as H); at the basic
pH levels above 7, it is double negatively charged because both of its carboxy residues are not bound to H, i.e., CO2 (its chemical formula is C5H4O42-); and at
fungi but not animals[4]
) is here termed trans-itaconate (trans-itaconic acid is not further mentioned here).

Animal cells make itaconate by an

bactericidal agent, i.e., an agent that acts directly on certain types of bacteria to inhibit their viability and/or disease-causing abilities.[8][9]

In 1836, Samuel Baup discovered a previously unknown

bacterial toxin, lipopolysaccharide (i.e., LPS, also termed endotoxin), increased their production and secretion of itaconate.[7] In 2013, Michelucci et al.[12] 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.[7][13]

The following section, titled "Biology of Itaconate," details

pathological functions as well as its mechanisms of action in health and disease; b) define the actions and mechanisms of action of various itaconate-like compounds; and c) determine which actions of itaconate and itaconate-like compounds support conducting further studies to determine if it or they would be useful therapeutic agents in humans.[6][7][14] The last section, titled "Commercial production and uses of itaconic acid," reports on the changing methods for making large amounts, and the many commercial uses, of itaconic acid.[3][15]

Biology of Itaconate

Cells making itaconate

While many cell types can be manipulated to produce itaconate, the major

phagocytes, i.e., cells that ingulf microorganisms, dead or seriously injured cells, and foreign particles all of which cause inflammatory responses.[14] Itaconate is also produced by certain myeloid-derived suppressor cells[16] such as highly mature neutrophils[17][18][19] which are often termed granulocyte myeloid-derived suppressor cells or granulocyte MDSCs.[16] Unlike other types of itaconate-forming cells, however, these neutrophils, which are phagocytes, tend to retain rather than release itaconate to the extracellular space.[18]

Itaconate-forming metabolic pathway

Itaconate is a by-product of the tricarboxylic acid cycle. This cycle consists of eight successive enzyme-catalyzed

biochemical reactions
that occur in the cell's mitochondria. These reactions sequentially metabolize (indicated by →) citrate through eight intermediate metabolites and then converts the eighth intermediate metabolite, i.e. oxaloacetate, back to citate:

citrate

This cyclical metabolic pathway serves the vital function of releasing the energy stored in nutrients to its cell of origin and in multicellular organisms' other cells throughout the body.[6][20] Recent studies have found that some of the metabolites in the tricarboxylic acid cycle stimulate physiological and pathological responses, i.e., they are bioactive metabolites. For example, cells undergoing stress suppress the tricarboxylic acid cycle's operation. This causes succinate to accumulate.[20][21][22] The accumulating succinate stimulates a wide range of mostly pathological (e.g., cardiac ventricular hypertrophy)[22]) and pro-inflammatory[23] (e.g., Crohn's disease)[24] disorders. High levels of succinate do have some beneficial actions such as promoting the neovascularization of tissues suffering vascular occlusions.[25] Succinate produces these effects by activating its G protein-coupled receptor, i.e., SUCNR1, in cells bearing this receptor but also by stimulating cells not bearing SUCNR1 as well as SUCNR1-bearing cells by receptor-independent mechanisms.[21][26] Itaconate is also a bioactive metabolite. When operation of the tricarboxylic acid cycle is suppressed, one of its metabolites, cis-aconitate, accumulates. Aconitate decarboxylase (also termed ACOD1, cis-aconitate decarboxylase, immune-responsive gene 1, immune response gene 1, immunoregulatory gene 1, and IRG1[27][28][29][30]) metabolizes cis-aconitate to itaconate and carbon dioxide (CO2) in the following decarboxylation reaction:[14][24]

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.[31] The cytosolic itaconate may then move form the cytosol through the patents cells surface membrane 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.[32]) This itaconate has mostly anti-inflammatory actions.[19][23] It acts on its parent cell, other cells, and certain microorganism[6] 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. Very recently, however, itaconate has been reported to stimulate certain mammalian cells by activating the OXGR1 receptor.[33][34]

OXGR1 receptor

OXGR1 (also known as GPR99) is a G protein-coupled receptor that was identified in 2004 as a receptor for the tricarboxylic cycle intermediate, α-ketoglutarate.[33] In 2013, it was found to also be a receptor for leukotriene E4 and to lesser extents leukotriene C4 and D4.[35][36] AZeng et al.[33] reported in 2023 that: a) among a set of cultured human embryonic kidney HEK 293 cells made to express any one of 351 different human G protein-coupled receptors, only cells expressing OXGR1 responded to itaconate by raising their cytosolic Ca2+ levels; b) HEK 293 cells expressing any of the other 350 receptors did not consistently alter their cytosolic Ca2+ levels in response to itaconate; c) respiratory epithelium cells isolated from control mice (i.e., these cells naturally express OXGR1) but not from Oxgr1 gene knockout mice (i.e., these cells lacked OXRG1) responded to itaconic acid by raising their cytosolic Ca2+ levels and stimulating their mucociliary clearance (equivalent to stimulating the secretion of mucus); d) application of itaconate in the noses of control mice but not Oxgr1 gene knockout mice stimulated nasal secretion of mucus; e) Oxgr1 gene knockout mice and Irg1 gene knockout mice (mice lacking the itaconate-producing protein, IRG1) that were intranasally infected with Pseudomonas aeruginosa had increased numbers of these bacteria in their lung tissue and bronchoalveolar lavage fluid (i.e., airway washing) than control mice that respectively expressed OXGR1 and IRG1 and f) α-ketoglutarate and itaconate, which have similar structures, activated OXGR1-exressing HEK293 cells at similar concentrations, i.e., between 200–300 μM/liter.[33][34] These findings ate the first to indicate that itaconate stimulates human HEK 293 and mouse respiratory epithelial cells by activating their OXGR1 receptors. Since OXGP1 is expressed in a wide range of tissues and mediates the allergic and inflammatory responses to the cited leukotrienes,[34] it may be involved in the inflammatory responses detailed in the following "Actions of itaconate and its analogs" section. That is, itaconate, like succinate (see previous paragraph), may stimulate cells by receptor-dependent and receptor independent mechanisms. Future studies need to determine the extent to which OXGR1 contributes to the various actions of itaconate and itaconate-like compounds (see next section) as well as the potencies of each of these agents in activating OXGR1.[23][33][34]

Itaconate and itaconate-like compounds

4-Octyl itaconate, dimethyl itaconate,[9] and 4-ethyl itaconate[6] have been used to mimic the biological effects of itaconate. These functional analogs of itaconate are often used in place of itaconate because of their presumed greater ability to pass through the surface membranes of, and thereby enter, cells. In should be noted that many studies have examined the actions of itaconate analogs rather than itaconate itself and that itaconate and these three analogs have on occasion shown significantly different biological activities.[7][14][19][37][38]

The anionic forms of

interleukin-23. The itaCORMs require further study.[41] Analyses of itaconate as well as each of the itaconate analogs, itaconate isomers, and itaCORM may be useful for selecting the agent(s) best suited to treat the human disorders which preclinical studies suggest are improved by itaconate or an itaconate-like compound(s).[6]

Dietary sources of itaconate and its isomers

Itaconic acid and its two isomers, mesaconic and citraconic acids, were found in rye and wheat breads with appreciably higher concentrations of itaconic and citraconic acids in their crusts (i.e., outer bread layer) than crumbs (i.e., soft inner part of the bread). Based on the average consumption of bread and bread-related baked goods in Germany, the daily intake of itaconate plus its two isomers was estimated to be from 7 to 20 micrograms. Rats have been shown to absorb the itaconic acid that was added to their diet. Further studies are needed to determine the levels of these compounds in other foods, the extent to which itaconic acid and itaconic acid-like compounds are absorbed by humans, and the usefulness of treating itaconate-suppressing disorders with oral itaconic acid or the acidic forms of the itaconic acid-like compounds.[39]

Actions of itaconate and its analogs

Itaconate and its analogs can operate concurrently through multiple pathways to induce their effects.[42][43][44] Relevant to this, future studies must determine the role of the newly defined receptor for itaconate, OXGR1, in contributing to the mediation of the following actions of itaconate and itaconate-like compounds.[33]

Inhibit succinate dehydrogenase

Succinate dehydrogenase (i.e., SDH) is an enzyme complex of six proteins in the mitochondrial tricarboxylic acid cycle that metabolizes succinate to fumarate.[27] (Although bacteria generally lack mitochondria,[45] their surface membranes have a similar SDH system.[46]) Itaconate inhibits SDH's activity thereby blocking succinate's oxidation to fumarate and causing succinate levels to increase. Itaconate has been reported to increase succinate levels in a wide variety of cells including cultured mouse RAW264.7 macrophages, macrophages differentiated from human monocytes,[37] Huh7 human liver carcinoma cells, human MCF-7 breast cancer cells, human A549 lung adenocarcinoma cells, and the brain neurons and astrocytes generated from rat embryo brain tissue.[47] This succinate stimulates various responses in its parent and other cells as detailed elsewhere (see SUCNR1 and succinic acid).[20][21][48]

Inactivate KEAP1

T cells, and neutrophils;[51] and c) increases the cellular and tissue levels of pro-inflammatory reactive oxygen species. 4-Octyl itaconate, dimethyl itaconate, and itaconate inactivate KEAP1 thereby increasing Nrf2's entry into the cell nucleus and inhibiting production of the cited pro-inflammatory cytokines and various reactive oxygen species.[6][31][50][52]

In a model of intracellular inflammation, LPS stimulated mouse bone marrow-derived macrophages to increase their levels of IL-1β, tumor necrosis factor, hypoxia-inducible factor 1-alpha, and reactive oxygen species. 4-Octyl itaconate suppressed all of these LPS-induced responses. It also reduced the production of IL-1β and tumor necrosis factor in LPS-stimulated human peripheral blood monocytes. And, in a model of LPS-induced septic shock, mice injected intraperitoneally with LPS plus 4-octyl itaconate had fewer physical symptoms of shock, lower serum levels of the pro-inflammatory cytokines, IL-1β and tumor necrosis factor, unchanged levels of the anti-inflammatory cytokine interleukin 10, and longer survival times compared to mice treated with LPS but not 4-octyl itaconate. Thus, the inhibitory effects of 4-octyl itaconate, dimethyl itaconate, and itaconate on cells appear due to their inactivation of KEAP1 and resulting movement of cytosolic Nrf2 into the cell nucleus where it inhibits its target genes from producing reactive oxygen species and the cited inflammation-promoting proteins. This mechanism may also underlie 4-octyl itaconate's ability to reduce the severity of LPS-induced shock in mice.[31]

Inhibit NLRP3

The

gasdermin D (also termed GSDMD) into its active form that triggers its parent cell's pyroptosis response. Pyroptosis is a form of programmed cell death which causes parent cell swelling, Lysis (i.e., the breakdown of their surface membranes), and the release of IL-1β and interleukin 18 into the extracellular space where they stimulate other cells to mount inflammatory responses.[14][49][53]

In one study,

autoinflammatory disease due to any one of several different mutations in the NLRP3 gene; these mutations cause cells to release excessive amounts of IL-1β. 4-Octyl itaconate inhibited the release of IL-1β from LPS- or Pam3CSK4-stimulated (Pam3CSK4a mimics LPS's actions[54]), nigericin-activated mononuclear cells isolated from the blood of persons who did or did not have CAPS.[55] Finally, the injection of monosodium urate crystals (a form of uric acid that activates the NLRP3 inflammasome) into the peritoneum of mice caused peritonitis (i.e., inflammation of the serous membrane that lines the abdominal cavity and the cavity's organs (e.g., intestines, liver, etc.). Injection of 4-octyl itaconate along with the uric acid crystals significantly reduced this inflammation response as indicated by the lower levels of IL-1β and another pro-inflammatory cytokine, interleukin 6 (i.e., IL-6), and fewer inflammation-inducing neutrophils in the peritoneum compared to 4-octyl itaconate-untreated mice. These studies indicate that itaconate, dimethyl itaconate, and 4-octyl itaconate inhibit NLRP3 and thereby the formation of the active NLRP3 inflammasome. This inhibition appears responsible for the ability of itaconate, dimethyl itaconate, and 4-octyl itaconate to suppress the pro-inflammatory responses of mouse macrophages and human mononuclear cells to LPS as well as the ability of 4-octyl itaconate to suppress the peritoneal inflammatory response of mice to urate crystals.[14][55]

Increase ATF3 levels

ATF3 (i.e., cyclic AMP-dependent transcription factor ATF-3) is a transcription factor that inhibits the NFKBIZ gene's expression of NF-kappa-B inhibitor zeta (i.e., IκBζ), a protein located in the cell nucleus that promotes the production of certain pro-inflammatory cytokines such as IL-6,[14][43] interferon gamma, and granulocyte-macrophage colony-stimulating factor.[43][44] Itaconate and dimethyl itaconate stimulate the production of ATF3 thereby suppressing the cellular levels of IκBζ and IL-6 as well as IL-6-promoted inflammatory responses.[7][14][56]

Studies have shown that: a) Atf3 gene knockout embryonic mouse

left anterior descending coronary artery or by intraperitoneal injections of the heart-injuring drug, doxorubicin, developed greater levels of cardiac tissue inflammation, larger cardiac infarction (i.e., dead tissue) sizes, more cardiac fibrosis, poorer cardiac function, and higher blood serum levels of IL-6 than ATF3-expressing control mice; and e) 4-octyl itaconate reduced the IL-6 serum levels, cardiac inflammation, cardiac fibrosis, infarction size, and cardiac dysfunction caused by myocardial infarction or doxorubicin in Atf3 gene knockout mice.[58] These findings suggest that 4-octyl itaconate and dimethyl itaconate have anti-inflammatory actions in these cited models of inflammation and do so by increasing ATF3 and/or decreasing IκBζ levels which in turn reduces the levels of inflammation-promoting cytokines.[6][59][56]

Inhibit Tet methylcytosine dioxygenase 2

dendritic cells and macrophages.[40][60][61][62]

Studies have shown that: a) itaconate blocked α-ketoglutarate from binding to and thereby activating the isolated TET2 protein in a cell-free system; 2) TET2 gene knockout bone marrow-derived macrophages (i.e., BMDMs) had far lower levels of hydroxymethylcytosine in their DNA than control macrophages; c) itaconate and 4-octyl itaconate lowered the amount of hydroxymethylcytosine in the DNA of control but not in TET2 gene knockout BMDMs; d) LPS stimulation of mouse macrophage RAW264.7 cells (these cells express TET2) caused increases in their levels of the

chemokines (i.e., proteins that among other functions mobilize inflammation-promoting leukocytes), CXCL9, CXCL10, and CXCL11, but did not do so in Tet2 gene knockout RAW264.7 cells; e) itaconate reduced the ability of LPS to stimulate rises in the messenger RNA levels for IL-6 and IL-1β in RAW264.7 cells; f) 4-octyl itaconate reduced the ability of LPS to raise the messenger RNA levels of IκBζ, Il-6, CXCL9, CXCL10, and CXCL11 in the RAW264 cells; g) in a model of LPS-induced septic shock, LPS-treated Irg1 gene knockout mice (i.e., mice lacking the itaconate-forming protein, IRG1), had higher serum levels of IL-6, greater lung damage, and poorer survival times than control (i.e. IRG1-expressing) LPS-treated mice; h) compared to LPS-treated control mice, LPS-treated mice that were made to express an inactive TET2 protein (termed Tet2HxD) in place of active TET2 protein had lower serum levels of pro-inflammatory cytokines IL-6 and tumor necrosis factor, lower serum levels of the proinflammatory chemokine CXCL9, lower serum levels of alanine transaminase and aspartate transaminase (i.e., liver proteins that are released in the circulation by damaged livers), less severe pulmonary edema and lung tissue injury, and longer survival times; and i) the intraperitoneal injection of itaconate 12 hours before LPS treatment of in mice expressing active TET2 likewise had lower serum levels of IL-6, tumor necrosis factor, CXCL9, alanine transaminase, and aspartate transaminase, less severe pulmonary edema and lung tissue injury, and longer survival times.[7][63] These findings indicate that 4-octyl itaconate and itaconate inhibit the activation of TET2 and thereby the production of various proinflammatory cytokines and chemokines. At least some of these itaconate and 4-octyl itaconate actions appear to suppress the sepsis shock-like actions of LPS in mice. Further studies are needed to determine in itaconate and/or itaconate-like compounds suppress other inflammatory conditions.[7][63] (Since TET2 inactivating gene mutations in humans have been associated the development of various cancers such as acute myeloid leukemia, the possibility that itaconate's inhibition of TET2's catalytic activity may lead to these cancers requires investigation.[7]
)

Inhibit interleukin 17A

Interleukin 17 (i.e., IL-17) refers to any one of 6 different but closely related subtypes, IL-17A to IL17F. IL-17A is a pro-inflammatory cytokine that is commonly elevated in cells undergoing inflammatory responses.[59] (Some studies used the term IL-17 when referring to IL-17A or when the subtype of IL-17 measured was undefined.) Excessive IL-17A production appears to contribute to the development of various autoimmune diseases[64] by stabilizing the messenger RNA for IκBζ and thereby increasing cellular levels of IκBζ protein and IL-6.[42][59]

A study focusing on models of the skin autoimmune disease

Sjögren’s syndrome.[42][43] The effects of itaconate or one of its analogs in animal models of these autoimmune diseases should be examined in a manner similar to the studies in psoriasis.[59]

Antibacterial actions

Itaconate can act directly on certain types of bacteria to limit their growth and disease-causing abilities. The enzyme

Mycobacterium avium, Salmonella enterica, Coxiella burnetii, Francisella tularensis, and Acinetobacter baumannii.[8][14][19][40][48][71]

Studies examining the effects of itaconate and itaconate-like compounds on phagocytosed bacterial have reported that: a) mouse bone marrow-derived macrophages exposed to live or heat-killed Staphylococcus aureus rapidly (i.e., within 1 hour) developed increases in their levels of IRG1 and IRG1's metabolite, itaconate; b ) human

aqueous humor developed increased retina tissue levels of the itaconate-forming enzyme, IRG1, as well as itaconate; b) Irg1 gene knockout mice (i.e., mice lacking IRG1 protein) that had interocular injections of these bacteria developed severer disease than control (i.e., IRG1-exressing) mice receiving these bacteria injections; c) Mice intraocularly injected with these bacteria plus itaconate, 4-octyl itaconate, or dimethyl itaconate developed less severe eye damage and fewer interocular bacteria than mice injected with these bacteria without getting injected with itaconate or the itaconate analogs; d) adding antibiotics to the itaconate treatment further reduced the severity of these eye infections; and e) analysis of the aqueous humor in the eyes of 22 patients with bacterial eye infections (i.e., 12 gram-positive and 10 gram-negative bacteria) found significantly higher levels of itaconate than those in the eyes of 10 patients with non-infectious eye problems (e.g., retinal detachment). These findings suggest that itaconate functions to suppress the growth of the cited bacteria in mice and may also do so in humans. They also support studies to determine if itaconate or itaconate-like compounds are useful for treating human Staphylococcus aureus eye infections, other types of bacterial eye infections in animals and humans, and animal and human infections in other tissue sites besides the eye.[14][28] It should be noted, however, that Staphylococcus aureus and at least one other bacterial species, Pseudomonas aeruginosa, can use host cell-derived itaconate to form a biofilm that covers their surfaces and thereby increases their survival and pathogenicity.[40][73]

Antiviral actions

Itaconate suppresses the growth of certain disease-causing viruses.

strokes. As of 2023, there were no vaccines or antiviral medications available to treat Zika fever.[74] In cell culture studies, human A549 lung adenocarcinoma cells and Huh7 human hepatocyte-derived cancer cells were treated with buffer or 4-octyl itaconate for 2 days and then infected with Zika virus for 4 days. 4-Octyl itaconate suppressed the growth of this virus in both cancer cell types.[75] In a model of neurological Zika disease, mice were injected intracranially with Zika virus plus or minus 4-octyl itaconate. 4-Ocyl itaconate significantly reduced the number of brain tissue Zika viruses. This study also indicated that the antiviral action of 4-octyl itaconate was associated with its inhibition of the succinate dehydrogenase enzyme and the resulting rises in brain tissue levels of succinate. Further studies are needed to determine if itaconate and/or its analogs will prove useful for treating Zika fever in humans.[14][76]

4-Octyl itaconate also suppresses the proliferation of

vesicular stomatitis virus in cultured 4T1 mouse breast cancer and 786-O human kidney carcinoma cells; it also reduced the inflammatory response to, and improved the survival of, influenza A virus but did not inhibit this virus's growth in mice.[29]

Anti-cancer actions

Individuals with

hyperplastic colons; b) fewer inflammatory cells in their colons; c) lower colon tissue levels of the proinflammatory cytokines, IL-1β and IL-6 as well as the proinflammatory chemokines, CCL2, CCL17, and Interleukin 8; and d) far fewer colon tumors. These findings indicate that dimethyl itaconate inhibited colon inflammatory responses to dextran sodium sulfate and presumably thereby colon cancer responses to azomethane in mice. They also support further preclinical studies to determine if itaconate-like compounds suppress human inflammation-related colon cancers.[7][78]

nude mice (i.e., immunodefient mice) were implanted with Y79-CR or Y79 cells in the subcutaneously issue of their flanks; one week later were interperitoneally injected with 4-octyl itaconate or the vehicle used to dissolve 4-octyl itaconate once every other day for 2 weeks; and were euthanized 21 days later. Tumor masses in mice given Y79-CL cells were far less in 4-octyl itaconate-treated than vehicle-treated mice. Also, the differences in tumor masses between 4-octyl itaconate-treated and vehicle-treated mice transplanted with Y79 cells were much less than that in mice transplanted with Y19-CR cells. These results indicate that 4-octyl itaconate selectively kills multiple drug resistant Y79-CR cells that are cultured or implanted in mice and does so by triggering ferroptosis. They also support studies to learn if itaconate and itaconate-like compounds would be useful for treating humans with carboplatin-resistant or other forms of multiple drug resistant retinoblastomas and perhaps other multiple drug resistant cancers.[7][79][80]

thymus gland cancer. In more advanced cases, it is commonly treated with platinum-based antineoplastic drugs and lenvatinib, an inhibitor of vascular endothelial growth factor receptors. However, patients often are or develop resistant to these drugs. Consequently, other agents are being evaluated as treatments for thymic carcinomas. A recent preclinical study reported that dimethyl itaconate decreased the proliferation of cultured Ty82 human thymic carcinoma cells but had relatively little effect on the proliferation of cultured non-cancerous human fibroblasts. Dimethyl itaconate treatment of the Ty82 cells decreased the activity of their mTOR protein as well as PI3K/AKT/mTOR pathway (This pathway promotes the development and/or progression of many cancers including some thymus gland cancers.) Temsirolimus, a specific inhibitor of mTOR, mimicked the action of dimethyl itaconate in suppressing the proliferation of Ty82 cells.[7][82][83][84] These findings suggest that dimethyl itaconate inhibits the proliferation of Ty82 mouse cells by suppressing the activity of their mTOR protein and I3K/AKT/mTOR pathway. Further studies are needed to determine the effects of dimethyl itaconate, other itaconate-like compounds, and/or itaconate treating animals models of thymic carcinomas.[7][82]

Varying actions of itaconate and its analogs

One study

IFN-β as well as to secrete IL-6, interleukin 10, and IFN-β whereas itaconate and 4-ethyl itaconate had far less ability to or did not stimulate these responses. This result suggests that future studies should examine the actions of itaconate along with those of each of its analogs.[14][38]

Commercial production and uses of itaconic acid

Itaconic acid is a non-toxic

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 and b) fermenting Escherichia coli bacteria with glucose, xylose, glycerol, or starch and Corynebacterium glutamicum bacteria with glucose or urea.[91] Among the fungi, Aspergillus terreus has been the organism of choice for industrial itaconic acid production in part because it gives relatively high yields of itaconic acid. Recently, however, Ustilago maydis has been genetically engineered to increase its itaconic acid production and is being studied for its usefulness in mass-producing itaconic acid.[92]

Itaconic acid's chemical structure consists of one unsaturated

organic materials such as itaconic acid).[94] It is also converted to methyl methacrylate,[91] a product that has many commercial and some medical applications (see uses of methyl methacrylate). Fields using the products of itaconate include those that manufacture paint, lacquers (i.e., coatings for covering the surfaces of various objects), plasticizers, plastics, chemical fibers, hygienic materials, construction materials,[3] and environmentally-friendly fuels that can be substituted for pollution-causing, non-renewable fuels such as coal, oil, and natural gas.[94] Itaconic acid itself may be mass-produced if it or any of the analogs synthesized from it are found to be useful for treating medical disorders.[3]

Recently, the demand for itaconic acid has grown to such an extent that it is projected to reach a market value of 177 million dollars per year in United States of American currency by 2028. Consequently, alternate methods for making products with properties similar or identical to those made from itaconic acid by using less costly substitutes for itaconic acid and/or methods that are more productive, less expensive, and/or more environmental-friendly than those used for itaconic acid are being evaluated.[15] Betulin, for example, is an abundant, naturally occurring diol triterpene that is readily isolated from the bark of birch trees. Betulin forms polymers that have some of the biochemical properties found in itaconate polymers. Consequently, botulin is being studied to determine if it can be used in place of itaconic acid to form products with properties similar to those made from itaconic acid but doing so in economically and/or environmentally more favorable ways.[15]

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  49. ^
    PMID 36750315
    .
  50. ^
    PMID 33391283
    .
  51. PMID 32853548
    .
  52. PMID 31032474
    .
  53. PMID 35513901
    .
  54. PMID 31508424
    .
  55. ^
    PMID 32791101
    .
  56. ^
    PMID 29670287
    .
  57. PMID 16688168
    .
  58. PMID 37209857
    .
  59. ^
    PMID 36245291
    .
  60. ^
    PMID 33085059
    .
  61. PMID 26287468
    .
  62. PMID 28826859
    .
  63. ^
    PMID 35256775
    .
  64. PMID 31718798
    .
  65. PMID 32070069
    .
  66. PMID 33692806
    .
  67. ^
    PMID 26565676
    .
  68. PMID 32899140
    .
  69. PMID 34079536
    .
  70. PMID 36327660
    .
  71. PMID 26829557
    .
  72. PMID 31672889
    .
  73. PMID 32428444
    .
  74. PMID 38157877
    .
  75. ^
    PMID 33009401
    .
  76. PMID 30635240
    .
  77. PMID 35643170
    .
  78. PMID 32840638
    .
  79. ^
    PMID 37417104
    .
  80. ^
    PMID 35654783
    .
  81. PMID 10507539
    .
  82. ^
    PMID 34293399
    .
  83. PMID 32272379
    .
  84. PMID 37596643
    .
  85. doi:10.15227/orgsyn.011.0070
    .
  86. PMID 23727192
    .
  87. doi:10.1039/C3GC41935E
    .
  88. PMID 23420787
    .
  89. PMID 26639528
    .
  90. PMID 26639528
    .
  91. ^
    PMID 31212656
    .
  92. PMID 31689647
    .
  93. PMID 32974742
    .
  94. ^
    PMID 30065845
    .
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