Indole-3-carbaldehyde

Indole-3-carbaldehyde (I3A), also known as indole-3-aldehyde and 3-formylindole, is a metabolite of dietary L-tryptophan which is synthesized by human gastrointestinal bacteria, particularly species of the Lactobacillus genus.[2][3] I3A is a biologically active metabolite which acts as a receptor agonist at the aryl hydrocarbon receptor in intestinal immune cells, in turn stimulating the production of interleukin-22 which facilitates mucosal reactivity.[4][3][2]

Indole-3-carbaldehyde
Names
IUPAC name
1H-Indole-3-carbaldehyde
Other names
3-Formylindole; Indole-3-carboxaldehyde; Indole-3-aldehyde
Identifiers
CAS Number
3D model (JSmol)
Beilstein Reference
 5-21-08-00246
ChEMBL
ChemSpider
ECHA InfoCard 100.006.969
EC Number
  • 207-665-8
PubChem CID
UNII
InChI
  • InChI=1S/C9H7NO/c11-6-7-5-10-9-4-2-1-3-8(7)9/h1-6,10H
    Key: OLNJUISKUQQNIM-UHFFFAOYSA-N
SMILES
  • C1=CC=C2C(=C1)C(=CN2)C=O
Properties
Chemical formula
 C9H7NO
Molar mass 145.161 g·mol−1
Melting point 198 °C (388 °F; 471 K)
Structure
Crystal structure
 Orthorhombic
Space group
 Pca21
Lattice constant
a = 14.076, b = 5.8059, c = 8.6909[1]
Lattice volume (V)
 710.3
Formula units (Z)
 4
Hazards
GHS labelling:
Pictograms
Signal word
 Warning
Hazard statements
 H315, H319, H335
Precautionary statements
 P261, P264, P271, P280, P302+P352, P304+P340, P305+P351+P338, P312, P321, P332+P313, P337+P313, P362, P403+P233, P405, P501
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

Biosynthesis in humans and cellular effects
Tryptophan metabolism by human gastrointestinal microbiota ()
Tryptophan
Tryptophanase-
expressing
bacteria
Indole
Indole
AhR
Intestinal
immune
cells
PXR
Mucosal homeostasis:
↓TNF-α
↑Junction protein-
coding mRNAs
L cell
Neuroprotectant:
↓Activation of glial cells and astrocytes
↓4-Hydroxy-2-nonenal levels
↓DNA damage
–Antioxidant
–Inhibits β-amyloid fibril formation
Maintains mucosal reactivity:
↑IL-22 production
Associated with vascular disease:
↑Oxidative stress
↑Smooth muscle cell proliferation
↑Aortic wall thickness and calcification
This diagram shows the biosynthesis of bioactive compounds (indole and certain other derivatives) from tryptophan by bacteria in the gut.[2] Indole is produced from tryptophan by bacteria that express tryptophanase.[2] Clostridium sporogenes metabolizes tryptophan into indole and subsequently 3-indolepropionic acid (IPA),[5] a highly potent neuroprotective antioxidant that scavenges hydroxyl radicals.[2][6][7] IPA binds to the pregnane X receptor (PXR) in intestinal cells, thereby facilitating mucosal homeostasis and barrier function.[2] Following absorption from the intestine and distribution to the brain, IPA confers a neuroprotective effect against cerebral ischemia and Alzheimer's disease.[2] Lactobacillus 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.[2] Indole itself triggers the secretion of glucagon-like peptide-1 (GLP-1) in intestinal L cells and acts as a ligand for AhR.[2] 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.[2] 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.[2]

Chemistry

Indole-3-carbaldehyde has reactivity typical of aromatic aldehydes. It can is easily oxidized to indole-3-carboxylic acid. It condenses with nitromethane in a Henry reaction to give 3-nitrovinyl indole.

Antifungal properties

Indole-3-carbaldehyde has antifungal properties, and partially accounts for the protection from chytridiomycosis seen in amphibian species which carry Janthinobacterium lividum on their skin.[8]

References
  1. Dileep, C. S; Abdoh, M. M. M; Chakravarthy, M. P; Mohana, K. N; Sridhar, M. A (2012). "1H-Indole-3-carbaldehyde". Acta Crystallographica Section E. 68 (11): o3135. doi:10.1107/S1600536812040573. PMC 3515237. PMID 23284457.
  2. 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
  3. "Indole-3-carboxaldehyde". PubChem Compound. United States National Library of Medicine – National Center for Biotechnology Information. 11 November 2017. Retrieved 17 November 2017.
  4. ROMANI LUIGINA, TERESA ZELANTE (2013). "Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22". Immunity. 39 (2): 372–385. doi:10.1016/j.immuni.2013.08.003. PMID 23973224.
  5. Wikoff WR, Anfora AT, Liu J, Schultz PG, Lesley SA, Peters EC, Siuzdak G (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.
    IPA metabolism diagram
  6. "3-Indolepropionic acid". Human Metabolome Database. University of Alberta. Retrieved 12 June 2018.
  7. Chyan YJ, Poeggeler B, Omar RA, Chain DG, Frangione B, Ghiso J, Pappolla MA (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.
  8. Brucker, Robert M.; Harris, Reid N.; Schwantes, Christian R.; Gallaher, Thomas N.; Flaherty, Devon C.; Lam, Brianna A.; Minbiole, Kevin P. C. (2008-11-01). "Amphibian chemical defense: antifungal metabolites of the microsymbiont Janthinobacterium lividum on the salamander Plethodon cinereus". Journal of Chemical Ecology. 34 (11): 1422–1429. doi:10.1007/s10886-008-9555-7. ISSN 0098-0331. PMID 18949519. S2CID 9712168.
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