3-Indolepropionic acid
Verifiedrevid685380927
Drug name3-indolepropionic acid
Iupac name3-(1H-Indol-3-yl)propanoic acid
TradenameOxigon[1]
Legal usUnscheduled
Legal ununscheduled
Cas number830-96-6
Cas supplemental[2]
Atc prefixnone
Pubchem3744
Iuphar ligand4709
Chemspiderid3613
UniiJF49U1Q7KN
Chebi43580
SynonymsConjugate acid:
• 1H-Indole-3-propanoic acid
• Indole-3-propionic acid
Conjugate base:
• 3-Indolepropionate
• Indole-3-propionate
C11
H11
N1
O2
SmilesC1=CC=C2C(=C1)C(=CN2)CCC(=O)O
Stdinchi1S/C11H11NO2/c13-11(14)6-5-8-7-12-10-4-2-1-3-9(8)10/h1-4,7,12H,5-6H2,(H,13,14)
StdinchikeyGOLXRNDWAUTYKT-UHFFFAOYSA-N
Melting point134
Melting high135
Melting notes[2]

3-Indolepropionic acid (IPA), or indole-3-propionic acid, has been studied for its therapeutic value in the treatment of Alzheimer's disease. As of 2022[3] IPA shows potential in the treatment of this disease, though the therapeutic effect of IPA depends on dose and time of therapy initiation.

Though promising in some historical clinical trials, IPA is not clinically listed as a useful therapeutic in managing Alzheimer's as of 2023.[4]

IPA is an even more potent scavenger of hydroxyl radicals than melatonin, the most potent scavenger of hydroxyl radicals that is synthesized by human enzymes.[2][5] Similar to melatonin but unlike other antioxidants, it scavenges radicals without subsequently generating reactive and pro-oxidant intermediate compounds.[2][5][6]

Occurrence

Biosynthesis in humans and cellular effects

This compound is endogenously produced by human microbiota and has only been detected in vivo when the species Clostridium sporogenes is present in the gastrointestinal tract.[7][8][9] As of April 2016, C. sporogenes, which uses tryptophan to synthesize IPA, is the only species of bacteria known to synthesize IPA in vivo at levels which are subsequently detectable in the blood plasma of the host.[7][8][9][5]

C. sporogenes produces IPA via a two step process. Tryptophanse (TnaA) first converts tryptophan into indole. Tryptophan amino transferase (Tam1) then converts indole into IPA.[10]

Peptostreptococcus species with a full fldAIBC gene cluster convert tryptophan into IPA and 3-indoleacrylic acid (IA) in vitro and protects against colitis in mice. IA differs from IPA only by a double bond and both enhance IL-10 secretion after LPS stimulation. However, IA does not reduce TNF production after LPS stimulation. It also activates the NRF2 antioxidant pathway and induces the expression of AhR target genes, unlike IPA.[11]

Biosynthesis by soil microbes

IPA is structurally similar to the phytohormone auxin (indole-3-acetic acid, IAA). Plants may encounter the substance when soil bacteria that produces IPA is present (Clostridium is known to reside in soil). Like auxin, IPA increases the growth of lateral roots and root hairs. However, it seems to inhibit some auxin-related processes such as root gravitation, probably by interfering with the plant's own auxin signaling and/or transport.[12]

Metabolism

IPA can be converted in the liver or kidneys to 3-indoleacrylic acid, which is subsequently conjugated with glycine, forming indolylacryloyl glycine.[13]

History

The neuroprotective, antioxidant, and anti-amyloid properties of IPA were first reported in 1999.[5][14][15][16]

Research

A study that assessed the effects of broad-spectrum antibiotics – specifically aminoglycosides, fluoroquinolones, and tetracyclines – on the metabolome of rats found that only aminoglycosides reduced plasma concentrations of IPA in rats.[17]

In 2017, elevated concentrations of IPA in human blood plasma were found to be correlated with a lower risk of type 2 diabetes and higher consumption of fiber-rich foods.[2][18][19] A separate study found that Roux-en-Y gastric bypass surgery increases the amount of IPA and indole sulfuric acid (ISA) in obese T2D patients.[10]

IPA is active in vitro against Mycobacterium tuberculosis and other Mycobacterium species. It works as an allosteric inhibitor of tryptophan biosynthesis.[20]

See also

References

  1. ^ Bendheim PE, Poeggeler B, Neria E, Ziv V, Pappolla MA, Chain DG (October 2002). "Development of indole-3-propionic acid (OXIGON) for Alzheimer's disease". Journal of Molecular Neuroscience. 19 (1–2): 213–217. doi:10.1007/s12031-002-0036-0. PMID 12212784. S2CID 31107810 The accumulation of amyloid-beta and concomitant oxidative stress are major pathogenic events in Alzheimer's disease. Indole-3-propionic acid (IPA, OXIGON) is a potent anti-oxidant devoid of pro-oxidant activity. IPA has been demonstrated to be an inhibitor of beta-amyloid fibril formation and to be a potent neuroprotectant against a variety of oxidotoxins. This review will summarize the known properties of IPA and outline the rationale behind its selection as a potential disease-modifying therapy for Alzheimer's disease.
  2. ^ Human metabolome IPA
  3. ^ Jiang H, Chen C, Gao J (December 2022). "Extensive Summary of the Important Roles of Indole Propionic Acid, a Gut Microbial Metabolite in Host Health and Disease". Nutrients. 15 (1): 151. doi:10.3390/nu15010151. PMC 9824871. PMID 36615808
  4. ^ "How Alzheimer's drugs help manage symptoms". Mayo Clinic. Retrieved 2023-11-03.
  5. ^ Indolepropionic acid scavenging
  6. ^ Reiter RJ, Guerrero JM, Garcia JJ, Acuña-Castroviejo D (November 1998). "Reactive oxygen intermediates, molecular damage, and aging. Relation to melatonin". Annals of the New York Academy of Sciences. 854 (1): 410–424. Bibcode:1998NYASA.854..410R. doi:10.1111/j.1749-6632.1998.tb09920.x. PMID 9928448. S2CID 29333394
  7. ^ Microbiome IPA
  8. ^ Microbial biosynthesis of bioactive compounds
  9. ^ Attwood G, Li D, Pacheco D, Tavendale M (June 2006). "Production of indolic compounds by rumen bacteria isolated from grazing ruminants". Journal of Applied Microbiology. 100 (6): 1261–1271. doi:10.1111/j.1365-2672.2006.02896.x. PMID 16696673. S2CID 35673610
  10. ^ Galligan JJ (February 2018). "Beneficial actions of microbiota-derived tryptophan metabolites". Neurogastroenterology and Motility. 30 (2). doi:10.1111/nmo.13283. PMID 29341448. S2CID 39904059
  11. ^ Wlodarska M, Luo C, Kolde R, d'Hennezel E, Annand JW, Heim CE, Krastel P, Schmitt EK, Omar AS, Creasey EA, Garner AL, Mohammadi S, O'Connell DJ, Abubucker S, Arthur TD, Franzosa EA, Huttenhower C, Murphy LO, Haiser HJ, Vlamakis H, Porter JA, Xavier RJ (July 2017). "Indoleacrylic Acid Produced by Commensal Peptostreptococcus Species Suppresses Inflammation". Cell Host & Microbe. 22 (1): 25–37.e6. doi:10.1016/j.chom.2017.06.007. PMC 5672633. PMID 28704649
  12. ^ Sun Y, Yang Z, Zhang C, Xia J, Li Y, Liu X, Sun L, Tan S (July 2024). "Indole-3-propionic acid regulates lateral root development by targeting auxin signaling in Arabidopsis". iScience. 27 (7). Bibcode:2024iSci...27k0363S. doi:10.1016/j.isci.2024.110363. PMC 11278081. PMID 39071891
  13. ^ Keszthelyi D, Troost FJ, Masclee AA (December 2009). "Understanding the role of tryptophan and serotonin metabolism in gastrointestinal function". Neurogastroenterology and Motility. 21 (12): 1239–1249. doi:10.1111/j.1365-2982.2009.01370.x. PMID 19650771. S2CID 23568813 Indolylpropionic acid can be further converted in the liver or kidney into indolyl acrylic acid (IAcrA) and conjugated with glycine to produce indolylacryloyl glycine (IAcrGly). ... Also, indolyl propionic acid has been shown to be a powerful antioxidant, and is currently being investigated as a possible treatment for Alzheimer's disease.40
  14. ^ Poeggeler B, Sambamurti K, Siedlak SL, Perry G, Smith MA, Pappolla MA (April 2010). "A novel endogenous indole protects rodent mitochondria and extends rotifer lifespan". PLOS ONE. 5 (4). Bibcode:2010PLoSO...510206P. doi:10.1371/journal.pone.0010206. PMC 2858081. PMID 20421998
  15. ^ Karbownik M, Reiter RJ, Garcia JJ, Cabrera J, Burkhardt S, Osuna C, Lewiński A (2001). "Indole-3-propionic acid, a melatonin-related molecule, protects hepatic microsomal membranes from iron-induced oxidative damage: relevance to cancer reduction". Journal of Cellular Biochemistry. 81 (3): 507–513. doi:10.1002/1097-4644(20010601)81:3<507::AID-JCB1064>3.0.CO;2-M. PMID 11255233. S2CID 27462000
  16. ^ Reiter RJ, Tan DX, Osuna C, Gitto E (2000). "Actions of melatonin in the reduction of oxidative stress. A review". Journal of Biomedical Science. 7 (6): 444–458. doi:10.1007/bf02253360. PMID 11060493
  17. ^ Behr C, Kamp H, Fabian E, Krennrich G, Mellert W, Peter E, Strauss V, Walk T, Rietjens IM, van Ravenzwaay B (October 2017). "Gut microbiome-related metabolic changes in plasma of antibiotic-treated rats". Archives of Toxicology. 91 (10): 3439–3454. Bibcode:2017ArTox..91.3439B. doi:10.1007/s00204-017-1949-2. PMID 28337503
  18. ^ de Mello VD, Paananen J, Lindström J, Lankinen MA, Shi L, Kuusisto J, Pihlajamäki J, Auriola S, Lehtonen M, Rolandsson O, Bergdahl IA, Nordin E, Ilanne-Parikka P, Keinänen-Kiukaanniemi S, Landberg R, Eriksson JG, Tuomilehto J, Hanhineva K, Uusitupa M (April 2017). "Indolepropionic acid and novel lipid metabolites are associated with a lower risk of type 2 diabetes in the Finnish Diabetes Prevention Study". Scientific Reports. 7. Bibcode:2017NatSR...746337D. doi:10.1038/srep46337. PMC 5387722. PMID 28397877
  19. ^ Tuomainen M, Lindström J, Lehtonen M, Auriola S, Pihlajamäki J, Peltonen M, Tuomilehto J, Uusitupa M, de Mello VD, Hanhineva K (May 2018). "Associations of serum indolepropionic acid, a gut microbiota metabolite, with type 2 diabetes and low-grade inflammation in high-risk individuals". Nutrition & Diabetes. 8 (1): 35. doi:10.1038/s41387-018-0046-9. PMC 5968030. PMID 29795366
  20. ^ Negatu DA, Gengenbacher M, Dartois V, Dick T (27 October 2020). "Indole Propionic Acid, an Unusual Antibiotic Produced by the Gut Microbiota, With Anti-inflammatory and Antioxidant Properties". Frontiers in Microbiology. 11. doi:10.3389/fmicb.2020.575586. PMC 7652848. PMID 33193190