Itaconic acid

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[2]) is a fatty acid containing five carbons (carbon notated as C), two of which are in 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 acidic pH's between 2 and 7, it exists as a mixture with none, one, or both of its carboxy residues bound to hydrogen. In the cells and most fluids of living animals, which generally have pH levels above 7, itaconic acid exists almost exclusively in its double negatively charged form; this form of itaconic acid is termed itaconate.[3] Itaconic acid and itaconate exist as cis and trans isomers (see cis–trans isomerism). Cis-itaconic acid and cis-itaconate isomers have two H's bound to one carbon and two residues (noted as R) bound to the other carbon in the double bound (i.e., H2C=CR2) whereas trans-itaconic acid and trans-itaconate have one H and one R residue bound to each carbon of the double bound. The adjacent figure shows the cis form of itaconic acid. Cis-aconitic acid spontaneously converts to its thermodynamically more stable (see chemical stability) isomer, trans-aconitic acid, at pH levels below 7.[4] The medical literature commonly uses the terms itaconic acid and itaconate without identifying them as their cis isomers. This practice is used here, i.e., itaconic acid and itaconate refer to their cis isomers while the trans isomer of itaconate (which has been detected in fungi but not animals[4]) is here termed trans-itaconate (trans-itaconic acid is not further mentioned here).

Animal cells make itaconate by an enzyme-catalyzed reaction from cis-aconitate (see aconitic acid), an intermediate metabolite in the tricarboxylic acid cycle, (i.e., TCA cycle). This cycle operates in the mitochondria of virtually all the cells of animals, plants, fungi, and some microorganisms.[5] The itaconate-producing reaction is stimulated when cells undergo stressful conditions that suppress the TCA cycle's operation.[6] Studies examining the actions of itaconate and/or itaconate-like compounds suggest that the itaconate formed in this reaction acts on its cell of origin and other cells to regulate the potentially deleterious inflammation responses caused by various microorganisms, viruses, autoimmune diseases, oxidative stress, and other types of tissue injury.[6] They also suggest that it may inhibit the development and/or progression of certain cancers.[7] Itaconate is also a 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 by-product in a distillate of citric acid; this by-product was later named itaconic acid.[6] In the late 1920s, itaconic acid was isolated from a fungus in the Aspergillus genus of fungi[6] and in the 1930s itaconate was shown to have bactericidal actions.[8][9] During this time, itaconic acid proved to be useful for synthesizing a wide range of products required by agricultural, textile, and other industries. Since then, the use of itaconic acid for industrial and manufacturing purposes has grown.[10] In 2011, Strelko et al.[11] 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.[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 preclinical studies that analyzed the effects of itaconate and itaconate-like compounds on human cells, animal cells, and animals used as models of specific diseases. These studies sought to a) define itaconate's physiological and 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]

  1. ^ a b c d e Merck Index, 11th Edition, 5130
  2. ^ Tretter L, Patocs A, Chinopoulos C (August 2016). "Succinate, an intermediate in metabolism, signal transduction, ROS, hypoxia, and tumorigenesis". Biochimica et Biophysica Acta (BBA) - Bioenergetics. 1857 (8): 1086–1101. doi:10.1016/j.bbabio.2016.03.012. PMID 26971832.
  3. ^ a b Kuenz A, Krull S (May 2018). "Biotechnological production of itaconic acid-things you have to know". Applied Microbiology and Biotechnology. 102 (9): 3901–3914. doi:10.1007/s00253-018-8895-7. PMID 29536145.
  4. ^ a b Nie Z, Wang L, Zhao P, Wang Z, Shi Q, Liu H (November 2023). "Metabolomics reveals the impact of nitrogen combined with the zinc supply on zinc availability in calcareous soil via root exudates of winter wheat (Triticum aestivum)". Plant Physiology and Biochemistry. 204: 108069. Bibcode:2023PlPB..20408069N. doi:10.1016/j.plaphy.2023.108069. PMID 37852066.
  5. ^ Xie LY, Xu YB, Ding XQ, Liang S, Li DL, Fu AK, Zhan XA (November 2023). "Itaconic acid and dimethyl itaconate exert antibacterial activity in carbon-enriched environments through the TCA cycle". Biomedicine & Pharmacotherapy. 167: 115487. doi:10.1016/j.biopha.2023.115487. PMID 37713987.
  6. ^ a b c d e Shi X, Zhou H, Wei J, Mo W, Li Q, Lv X (December 2022). "The signaling pathways and therapeutic potential of itaconate to alleviate inflammation and oxidative stress in inflammatory diseases". Redox Biology. 58: 102553. doi:10.1016/j.redox.2022.102553. PMC 9713374. PMID 36459716.
  7. ^ a b c d Yang W, Wang Y, Tao K, Li R (December 2023). "Metabolite itaconate in host immunoregulation and defense". Cellular & Molecular Biology Letters. 28 (1): 100. doi:10.1186/s11658-023-00503-3. PMC 10693715. PMID 38042791.
  8. ^ a b Michelucci A, Cordes T, Ghelfi J, Pailot A, Reiling N, Goldmann O, Binz T, Wegner A, Tallam A, Rausell A, Buttini M, Linster CL, Medina E, Balling R, Hiller K (May 2013). "Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production". Proceedings of the National Academy of Sciences of the United States of America. 110 (19): 7820–5. Bibcode:2013PNAS..110.7820M. doi:10.1073/pnas.1218599110. PMC 3651434. PMID 23610393.
  9. ^ a b Murphy MP, O'Neill LA (August 2018). "Krebs Cycle Reimagined: The Emerging Roles of Succinate and Itaconate as Signal Transducers". Cell. 174 (4): 780–784. doi:10.1016/j.cell.2018.07.030. PMID 30096309.
  10. ^ Boondaeng A, Suwanruji P, Vaithanomsat P, Apiwatanapiwat W, Trakunjae C, Janchai P, Apipatpapha T, Chanka N, Chollakup R (July 2021). "Bio-synthesis of itaconic acid as an anti-crease finish for cellulosic fiber fabric". RSC Advances. 11 (42): 25943–25950. Bibcode:2021RSCAd..1125943B. doi:10.1039/d1ra05037k. PMC 9037204. PMID 35479465.
  11. ^ Strelko CL, Lu W, Dufort FJ, Seyfried TN, Chiles TC, Rabinowitz JD, Roberts MF (October 2011). "Itaconic acid is a mammalian metabolite induced during macrophage activation". Journal of the American Chemical Society. 133 (41): 16386–9. doi:10.1021/ja2070889. PMC 3216473. PMID 21919507.
  12. ^ Lewis RN, Sykes BD, McElhaney RN (June 1987). "Thermotropic phase behavior of model membranes composed of phosphatidylcholines containing dl-methyl anteisobranched fatty acids. 1. Differential scanning calorimetric and 31P NMR spectroscopic studies". Biochemistry. 26 (13): 4036–44. doi:10.1021/bi00387a044. PMID 3651434.
  13. ^ Wu R, Chen F, Wang N, Tang D, Kang R (August 2020). "ACOD1 in immunometabolism and disease". Cellular & Molecular Immunology. 17 (8): 822–833. doi:10.1038/s41423-020-0489-5. PMC 7395145. PMID 32601305.
  14. ^ Peace CG, O'Neill LA (January 2022). "The role of itaconate in host defense and inflammation". The Journal of Clinical Investigation. 132 (2). doi:10.1172/JCI148548. PMC 8759771. PMID 35040439.
  15. ^ Lehman-Chong AM, Cox CL, Kinaci E, Burkert SE, Dodge ML, Rosmarin DM, Newell JA, Soh L, Gordon MB, Stanzione JF (September 2023). "Itaconic Acid as a Comonomer in Betulin-Based Thermosets via Sequential and Bulk Preparation". ACS Sustainable Chemistry & Engineering. 11 (38): 14216–14225. doi:10.1021/acssuschemeng.3c04178. PMC 10526528. PMID 37771764.