3-Indolepropionic acid explained

Verifiedrevid:685380927
Drug Name:3-indolepropionic acid
Iupac Name:3-(1H-Indol-3-yl)propanoic acid
Tradename:Oxigon[1]
Legal Us:Unscheduled
Legal Un:unscheduled
Cas Number:830-96-6
Atc Prefix:none
Pubchem:3744
Iuphar Ligand:4709
Chemspiderid:3613
Unii:JF49U1Q7KN
Chebi:43580
Synonyms:Conjugate acid:


Conjugate base:
C:11
H:11
N:1
O:2
Smiles:C1=CC=C2C(=C1)C(=CN2)CCC(=O)O
Stdinchi:1S/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)
Stdinchikey:GOLXRNDWAUTYKT-UHFFFAOYSA-N
Melting Point:134
Melting High:135

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[2] 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.[3]

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. Similar to melatonin but unlike other antioxidants, it scavenges radicals without subsequently generating reactive and pro-oxidant intermediate compounds.[4]

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.[5], 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.

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.[6]

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.[7]

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.[8]

Metabolism

IPA can be converted in the liver or kidneys to 3-indoleacrylic acid, which is subsequently conjugated with glycine, forming indolylacryloyl glycine.[9]

History

The neuroprotective, antioxidant, and anti-amyloid properties of IPA were first reported in 1999.[10] [11] [12]

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.[13]

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.[14] [15] 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.[6]

IPA is active in vitro against Mycobacterium tuberculosis and other Mycobacterium species. It works as an allosteric inhibitor of tryptophan biosynthesis.[16]

See also

Notes and References

  1. Bendheim PE, Poeggeler B, Neria E, Ziv V, Pappolla MA, Chain DG . Development of indole-3-propionic acid (OXIGON) for Alzheimer's disease . Journal of Molecular Neuroscience . 19 . 1–2 . 213–217 . October 2002 . 12212784 . 10.1007/s12031-002-0036-0 . 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. . 31107810 .
  2. Jiang H, Chen C, Gao J . Extensive Summary of the Important Roles of Indole Propionic Acid, a Gut Microbial Metabolite in Host Health and Disease . Nutrients . 15 . 1 . 151 . December 2022 . 36615808 . 9824871 . 10.3390/nu15010151 . free .
  3. Web site: How Alzheimer's drugs help manage symptoms . 2023-11-03 . Mayo Clinic . en.
  4. Reiter RJ, Guerrero JM, Garcia JJ, Acuña-Castroviejo D . Reactive oxygen intermediates, molecular damage, and aging. Relation to melatonin . Annals of the New York Academy of Sciences . 854 . 1 . 410–424 . November 1998 . 9928448 . 10.1111/j.1749-6632.1998.tb09920.x . 29333394 . 1998NYASA.854..410R .
  5. Attwood G, Li D, Pacheco D, Tavendale M . Production of indolic compounds by rumen bacteria isolated from grazing ruminants . Journal of Applied Microbiology . 100 . 6 . 1261–1271 . June 2006 . 16696673 . 10.1111/j.1365-2672.2006.02896.x . 35673610 . free .
  6. Galligan JJ . Beneficial actions of microbiota-derived tryptophan metabolites . Neurogastroenterology and Motility . 30 . 2 . e13283 . February 2018 . 29341448 . 10.1111/nmo.13283 . 39904059 .
  7. 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 . Indoleacrylic Acid Produced by Commensal Peptostreptococcus Species Suppresses Inflammation . Cell Host & Microbe . 22 . 1 . 25–37.e6 . July 2017 . 28704649 . 10.1016/j.chom.2017.06.007 . 5672633 .
  8. Sun Y, Yang Z, Zhang C, Xia J, Li Y, Liu X, Sun L, Tan S . Indole-3-propionic acid regulates lateral root development by targeting auxin signaling in Arabidopsis . iScience . 27 . 7 . 110363 . July 2024 . 39071891 . 10.1016/j.isci.2024.110363 . 11278081 .
  9. Keszthelyi D, Troost FJ, Masclee AA . Understanding the role of tryptophan and serotonin metabolism in gastrointestinal function . Neurogastroenterology and Motility . 21 . 12 . 1239–1249 . December 2009 . 19650771 . 10.1111/j.1365-2982.2009.01370.x . 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 . 23568813 .
  10. Poeggeler B, Sambamurti K, Siedlak SL, Perry G, Smith MA, Pappolla MA . A novel endogenous indole protects rodent mitochondria and extends rotifer lifespan . PLOS ONE . 5 . 4 . e10206 . April 2010 . 20421998 . 2858081 . 10.1371/journal.pone.0010206 . free . 2010PLoSO...510206P .
  11. Karbownik M, Reiter RJ, Garcia JJ, Cabrera J, Burkhardt S, Osuna C, Lewiński A . 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 . 2001 . 11255233 . 10.1002/1097-4644(20010601)81:3<507::AID-JCB1064>3.0.CO;2-M . 27462000 .
  12. Reiter RJ, Tan DX, Osuna C, Gitto E . Actions of melatonin in the reduction of oxidative stress. A review . Journal of Biomedical Science . 7 . 6 . 444–458 . 2000 . 11060493 . 10.1007/bf02253360 .
  13. Behr C, Kamp H, Fabian E, Krennrich G, Mellert W, Peter E, Strauss V, Walk T, Rietjens IM, van Ravenzwaay B . Gut microbiome-related metabolic changes in plasma of antibiotic-treated rats . Archives of Toxicology . 91 . 10 . 3439–3454 . October 2017 . 28337503 . 10.1007/s00204-017-1949-2 . 2017ArTox..91.3439B .
  14. 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 . 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 . 46337 . April 2017 . 28397877 . 5387722 . 10.1038/srep46337 . 2017NatSR...746337D .
  15. Tuomainen M, Lindström J, Lehtonen M, Auriola S, Pihlajamäki J, Peltonen M, Tuomilehto J, Uusitupa M, de Mello VD, Hanhineva K . 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 . May 2018 . 29795366 . 5968030 . 10.1038/s41387-018-0046-9 .
  16. Negatu DA, Gengenbacher M, Dartois V, Dick T . Indole Propionic Acid, an Unusual Antibiotic Produced by the Gut Microbiota, With Anti-inflammatory and Antioxidant Properties . Frontiers in Microbiology . 11 . 575586 . 27 October 2020 . 33193190 . 7652848 . 10.3389/fmicb.2020.575586 . free .

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