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3-Indolepropionic acid

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3-indolepropionic acid
Clinical data
Trade namesOxigon[1]
Other namesConjugate acid:
 • 1H-Indole-3-propanoic acid
 • Indole-3-propionic acid
Conjugate base:
 • Indole-3-propionate
ATC code
  • none
Legal status
Legal status
  • US: Unscheduled
  • UN: Unscheduled
Identifiers
  • 3-(1H-Indol-3-yl)propanoic acid
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
ChEBI
CompTox Dashboard (EPA)
ECHA InfoCard100.011.455 Edit this at Wikidata
Chemical and physical data
FormulaC11H11NO2
Molar mass189.214 g·mol−1
3D model (JSmol)
Melting point134 to 135 °C (273 to 275 °F) [2]
  • C1=CC=C2C(=C1)C(=CN2)CCC(=O)O
  • InChI=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)
  • Key:GOLXRNDWAUTYKT-UHFFFAOYSA-N
  (verify)

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

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Biosynthesis in humans and cellular effects

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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]

Tryptophan metabolism by human gut microbiota (
)
The image above contains clickable links
This diagram shows the biosynthesis of bioactive compounds (indole and certain other derivatives) from tryptophan by bacteria in the gut.[8] Indole is produced from tryptophan by bacteria that express tryptophanase.[8] Clostridium sporogenes metabolizes tryptophan into indole and subsequently 3-indolepropionic acid (IPA),[7] a highly potent neuroprotective antioxidant that scavenges hydroxyl radicals.[8][2][5] IPA binds to the pregnane X receptor (PXR) in intestinal cells, thereby facilitating mucosal homeostasis and barrier function.[8] Following absorption from the intestine and distribution to the brain, IPA confers a neuroprotective effect against cerebral ischemia and Alzheimer's disease.[8] Lactobacillaceae (Lactobacillus s.l.) species metabolize tryptophan into indole-3-aldehyde (I3A) which acts on the aryl hydrocarbon receptor (AhR) in intestinal immune cells, in turn increasing interleukin-22 (IL-22) production.[8] Indole itself triggers the secretion of glucagon-like peptide-1 (GLP-1) in intestinal L cells and acts as a ligand for AhR.[8] Indole can also be metabolized by the liver into indoxyl sulfate, a compound that is toxic in high concentrations and associated with vascular disease and renal dysfunction.[8] AST-120 (activated charcoal), an intestinal sorbent that is taken by mouth, adsorbs indole, in turn decreasing the concentration of indoxyl sulfate in blood plasma.[8]

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

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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

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

History

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

Research

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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

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References

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  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. ^ a b c d e f "3-Indolepropionic acid". Human Metabolome Database. University of Alberta. Retrieved 12 June 2018.
  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 3 November 2023.
  5. ^ a b c d e Chyan YJ, Poeggeler B, Omar RA, Chain DG, Frangione B, Ghiso J, et al. (July 1999). "Potent neuroprotective properties against the Alzheimer beta-amyloid by an endogenous melatonin-related indole structure, indole-3-propionic acid". J. Biol. Chem. 274 (31): 21937–21942. doi:10.1074/jbc.274.31.21937. PMID 10419516. S2CID 6630247. [Indole-3-propionic acid (IPA)] has previously been identified in the plasma and cerebrospinal fluid of humans, but its functions are not known. ... In kinetic competition experiments using free radical-trapping agents, the capacity of IPA to scavenge hydroxyl radicals exceeded that of melatonin, an indoleamine considered to be the most potent naturally occurring scavenger of free radicals. In contrast with other antioxidants, IPA was not converted to reactive intermediates with pro-oxidant activity.
  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. ^ a b c Wikoff WR, Anfora AT, Liu J, Schultz PG, Lesley SA, Peters EC, et al. (March 2009). "Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites". Proc. Natl. Acad. Sci. U.S.A. 106 (10): 3698–3703. Bibcode:2009PNAS..106.3698W. doi:10.1073/pnas.0812874106. PMC 2656143. PMID 19234110. Production of IPA was shown to be completely dependent on the presence of gut microflora and could be established by colonization with the bacterium Clostridium sporogenes. ... Conversely, a different set of enteric bacteria has been implicated in the metabolic transformation of indole to indole-3-propionic acid (IPA) (27). IPA, also identified only in the plasma of conv mice, has been shown to be a powerful antioxidant (28) ... Although the presence of IPA in mammals has long been ascribed in the literature to bacterial metabolic processes, this conclusion was based on either the production of IPA in ex vivo cultures of individual bacterial species (31) or observed decreases in IPA levels in animals after administration of antibiotics (32). In our own survey of IPA production by representative members of the intestinal flora, only Clostridium sporogenes was found to produce IPA in culture (Table S2). Based on these results, individual GF mice were intentionally colonized with C. sporogenes strain ATCC 15579, and blood samples were taken at several intervals after colonization. IPA was undetectable in the samples taken shortly after introduction of the microbes, and was first observed in the serum 5 days after colonization, reaching plateau values comparable with conv mice by day 10. These colonization studies demonstrate that the introduction of enteric bacteria capable of IPA production in vivo into the gastrointestinal tract is sufficient to introduce IPA into the bloodstream of the host. Also, other GF animals were injected i.p. with either IPA (at 10, 20, or 40 mg/kg) or sterile PBS vehicle, and their serum concentrations of IPA were measured over time. As seen in Table S3, the high serum levels of IPA observed 1 h after injection decreased more than 90% within 5 h, showing that IPA is rapidly cleared from the blood, and that its presence in the serum of conv animals must result from continuous production from 1 or more bacterial species associated with the mammalian gut.
    IPA metabolism diagram
  8. ^ a b c d e f g h i j k Zhang LS, Davies SS (April 2016). "Microbial metabolism of dietary components to bioactive metabolites: opportunities for new therapeutic interventions". Genome Med. 8 (1): 46. doi:10.1186/s13073-016-0296-x. PMC 4840492. PMID 27102537. Lactobacillus spp. convert tryptophan to indole-3-aldehyde (I3A) through unidentified enzymes [125]. Clostridium sporogenes convert tryptophan to IPA [6], likely via a tryptophan deaminase. ... IPA also potently scavenges hydroxyl radicals
    Table 2: Microbial metabolites: their synthesis, mechanisms of action, and effects on health and disease
    Figure 1: Molecular mechanisms of action of indole and its metabolites on host physiology and disease
  9. ^ a b 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. ^ a b Galligan JJ (February 2018). "Beneficial actions of microbiota-derived tryptophan metabolites". Neurogastroenterology and Motility. 30 (2): e13283. doi:10.1111/nmo.13283. PMID 29341448. S2CID 39904059.
  11. ^ Wlodarska M, Luo C, Kolde R, d'Hennezel E, Annand JW, Heim CE, et al. (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, et al. (July 2024). "Indole-3-propionic acid regulates lateral root development by targeting auxin signaling in Arabidopsis". iScience. 27 (7): 110363. 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): e10206. 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, et al. (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, et al. (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, et al. (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: 46337. Bibcode:2017NatSR...746337D. doi:10.1038/srep46337. PMC 5387722. PMID 28397877.
  19. ^ Tuomainen M, Lindström J, Lehtonen M, Auriola S, Pihlajamäki J, Peltonen M, et al. (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: 575586. doi:10.3389/fmicb.2020.575586. PMC 7652848. PMID 33193190.
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