kynurenine {90000122}

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- In humans, kynurenine is primarily synthesised endogenously from tryptophan.
- The kynurenine pathway produces several neuroactive products within the brain – both neuroprotective and neurotoxic
- Patients with Alzheimer’s disease (AD) will have lower levels of tryptophan and kynurenic acid and increased levels of quinolinic acid in their plasma.
- Patients with Parkinson’s disease (PD) will have increased ratios of kynurenic acid and kynurenic acid/kynurenine, with lower ratios of quinolinic acid and quinolinic acid/kynurenine acid.
- Kynurenine can also limit the tryptophan available for serotonin synthesis in the brain, though most serotonin is produced before dietary tryptophan is absorbed into the circulatory system in the intestine.
- Intestinal microbiota affect the kynurenine pathway by influencing the absorption of tryptophan before it reaches the liver, where most kynurenine synthesis takes place.
- In the intestinal lumen, bacteria can convert tryptophan to indole, sending dietary tryptophan to the indole pathway.
- Indole itself serves as a signalling molecule for bacteria such as E. coli and can send warning signals for signs of inflammation in the gut.

Shared Reference Notes

  • [1.1
    - The kynurenine metabolites can participate in numerous neurodegenerative disorders (Alzheimer disease, amyotrophic lateral sclerosis, Huntington disease, and Parkinson disease) or other diseases such as AIDS, cancer, cardiovascular diseases, inflammation, and irritable bowel syndrome.
  • [1.2] [#Cancer
    - Kynurenine—a tryptophan metabolite that blocks antitumour immunity—inhibits T cell proliferation in a manner that can be rescued by BH4.
  • [1.3] [#Crohn’s disease, #Inflamatory bowel disease
    - The blood–brain barrier allows the access of #Tryptophan. - In IBD, especially in CD patients, TRP metabolism increases; consequently, the amino acid levels are reduced with respect to normal healthy individuals, and these changes correlate with the gravity of the disease. - TRP undergoes two major metabolic host pathways, the kynurenine (KYN) and #Serotonin (5-HT) biosynthetic pathways, and one microbial pathway to produce #Indole and its derivatives.
  • - The blood–brain barrier allows the access of kynurenines. - changes in KYN and SCFAs brain levels may underlay the development of mood disorders and anxiety, while KYN may be involved in visceral hypersensitivity by modulating visceral pain along the gut–brain axis.
  • [1.4] [#Amyotrophic lateral sclerosis
    - Greater abundance of #Ruminococcus, at genus level > related to higher risk of ALS. - Kynurenine > risk factor of ALS.
  • [1.5
    - kynurenic acid > signaling through GPR35, expressed on IECs and immune cells > immunoregulatory effects > protects the intestine. - Gut-derived kynurenines and 5-HT are additionally implicated in the pathogenesis of chronic inflammatory, metabolic and neuropsychiatric diseases.
  • [1.6
    - #Tryptophan > Excessive Kyn levels in the tumor microenvironment is one of the adaptive mechanism for the tumors to escape immune surveillance and metastasize. Most individuals with #Cancer, including hepatocellular carcinoma, CRC, kidney #Cancer, lung #Cancer often exhibit increased Kyn levels and decreased serum Trp levels, or increased kyn/Trp ratio.
  • [1.7] [#Gestational diabetes mellitus (GDM)
    - Metabolomics revealed elevated plasma kynurenine at G15/19 in all mouse strains. - indoleamine-2,3-dioxygenase, or IDO1, the rate limiting enzyme for kynurenine production, had increased intestinal expression at G15, which was associated with mild systemic and gut inflammation. - Pharmacologic and genetic inhibition of IDO1 inhibited kynurenine levels and reversed pregnancy-associated Insulin Rsistance.
  • [1.8] [#Pancreatic Cancer
  • [1.9] [#Multiple Sclerosis
    - The enhanced conversion of tryptophan into kynurenine is associated with MS occurrence and worse outcomes.
  • [#Irritable bowel syndrome] -IBS > the level of neuroprotective #kynurenic acid (KynA) and the ratio of KynA/Kyn were reduced
  • [1.11
    - kynurenine and #Indole derivatives might be associated with neurogenic #Depression
  • [#Diabetes Type 2] - #Dimethylglycine, #Imidazole propionate, #Tryptophan, kynurenine and #Indolelactate associated with increased risk of T2D
  • [#Short Chain Fatty Acid] - SCFAs, #Serotonin, kynurenine, #Indole and its derivatives, and #Tryptamine, can bridge the gut and nervous system.
  • [1.12
    - Trp metabolite Kyn is present in higher amounts in the plasma of advanced-stage #Cancer patients.
  • [#Inflamatory bowel disease] [#Tryptophan] - patients with inflammatory bowel diseases (IBD) have lower levels of Trp in both their serum and feces than healthy subjects. - active IBD > increased Kyn or Kyn/Trp ratios in IBD patients, indicating the promoted Trp metabolism along the Kyn pathway.
  • - The #Ginseng polysaccharides decreased L-kynurenine, as well as the ratio of Kyn/Trp
  • [#Tryptophan] - A high-serum Kyn/Trp ratio is also correlated with a poor prognosis after a PD-1 blockade in #Lung cancer, #Melanoma and #renal cell carcinomas
  • [1.13] [#Depression
    - Depressed individuals receiving the #Probiotic had ↓ circulating CRP. - #Probiotic treatment, but not prebiotic treatment, decreased depressive symptoms. #Probiotic treatment resulted in ↓ circulating kynurenine/#Tryptophan ratio, when adjusting for #Isoleucine
  • [#Limosilactobacillus (Lactobacillus) reuteri] [#Condition of chronic stress] - chronic stress was connected with increased #Depression-like behavior (as measured by the forced swim test), reduced Lactobacillus spp. in the fecal microbiome, as well as increased circulating levels of kynurenine, a direct metabolite of #Tryptophan via the enzyme IDO1. - supplemented the diet of the mice with L. reuteri ATCC 23272 for an additional 4 weeks, which was sufficient to reverse behavior and kynurenine concentrations. - The reversal of #Depression-like behaviors was diminished if kynurenine levels were artificially elevated during probiotic supplementation, suggesting a link between kynurenine signaling and #Depression-like behavior.
  • [1.14] [#Colorectal cancer
    - Kyn acts as an endogenous ligand for AhR and can be secreted by cancer cells into the tumor microenvironment, suppressing anti-tumor immunity and promoting tumor cell survival through AhR via autocrine and paracrine signaling.
  • - #Tryptophan metabolites are produced via four different pathways: The #Serotonin pathway, the #Tryptamine pathway, the kynurenine pathway, and the bacterial #Indole pathway.
  • - The host Kyn and bacterial #Indole pathways each process ~90% and ~5% of the available #Tryptophan, respectively.
  • [1.15
    - Kyn can be metabolized either to #kynurenic acid (KYNA), with neuroprotective properties, or to the neurotoxic components #Quinolinic acid (QA) and #3-hydroxykynurenine (3-HK)
  • [#Bipolar disorder, #Major depressive disorder, #Schizophrenia] [#Quinolinic acid] - shift in the #Tryptophan metabolism from #Serotonin to the kyn pathway is associated with BD, MDD and SZ, but only in mood disorders (BD and MDD) there was a preferential metabolism of Kyn to the potentially neurotoxic QA.
  • [#Bipolar disorder] [#3-hydroxykynurenine, #Quinolinic acid, #kynurenic acid] - individuals with BD present lower peripheral blood levels of #Tryptophan, Kyn, KYNA, xanthurenic acid (a component derived from 3-HK), KYNA/Kyn and KYNA/QA ratio
  • [#Bipolar disorder] - Kyn pathway seems to be abnormally activated in BD patients.
  • [#Indole] - #Tryptophan can be metabolized via the indoleamine 2,3-dioxygenase (IDO) or through the enzyme #Tryptophan-2,3-dioxygenase (TDO) to form N-formylkynurenine (Kyn) > Kyn pathway, and accounts for ~95% of dietary #Tryptophan degradation. - The indoles and their derivates can also be transformed into Kyn. - Many components of the Kyn pathway are neuroactive.
  • [1.16] [#Indole-3-propionic acid
    - The GM metabolism of #Tryptophan also leads to the production of six neuroactive compounds altogether called TRYP-6 affecting the Gut-Brain Axis (GBA). - These six metabolites include #Indole-3-acetic acid, quinolinate, kynurenine, indole, #Tryptamine and indole propionic acid
  • [1.17] [#Ceramides, #Para-cresol] [#Aging
    - Among metabolites that were positively associated with age, seven were common in all four groups (aconitic acid, #Choline, #Citrulline, #Cysteine, cystine, kynurenine, and symmetric dimethylarginine (SDMA)) and 10 were common in three out of four groups (aspartic acid, asymmetric dimethylarginine (ADMA), butyrylcarnitine, ceramide d18:1/24:1, ceramide d18:1/25:0, ceramide d18:2/24:1, hippuric acid, homocysteine, methionine sulfoxide, and p-cresol #Sulfate)
  • [1.18
    - kynurenine is an effective agonist and the #Tryptophan photo-oxidation product 6-formylindolo[3,2-b]carbazole (FICZ) is one of the most potent endogenous #AHR agonists
  • [1.19] [#kynurenic acid, #Picolinic acid, #Quinolinic acid
    - The kynurenine pathway, > production of the bioactive compounds quinolinic, picolinic, kynurenic, and #Anthranilic acid
  • - #Tryptophan is mostly shunted into the kynurenine pathway but is also the primary metabolite for #Serotonin production and the bacterial #Indole pathway.
  • [#Tryptophan] - Digestion of Trp results in the well-known neuroactive compounds, #Serotonin and #Melatonin, and is a starting point for the NAD+ -producing kynurenine pathway in human
  • [#Tryptophan] - #Small intestinal bacterial overgrowth (SIBO), can shift Trp metabolism in the small intestine, driving an increase in locally produced kynurenine
  • - T-cell differentiation and activation is reduced when #AHR is activated on the T cells by KYN
  • [#Breast cancer] - ~50% of patients with BrCa have higher rates of KP metabolism as compared to controls
  • - #Cancer patients were shown to have lower concentrations of #Tryptophan and higher concentrations of kynurenine pathway metabolites in their blood and urine. - TRP is one of the critical components required for T-cell survival, a first mechanism involves the overactivation of IDO1 and/or TDO to deplete TRP within the local tumour microenvironment rapidly. - a TRP-stripped tumour microenvironment mediated by an overactive tumoral IDO1/TDO will induce mid-G1 phase arrest in T cells. - three KP metabolites 3HK, 3HAA and QUIN were shown to suppress anti-tumour immune cell populations.
  • [1.21
    - increased levels of kynurenine, and a trend towards normalization in #Tryptophan and the kynurenine/#Tryptophan ratio in long #Covid-19 patients.
  • [1.22] [#Multiple Sclerosis] [#kynurenic acid
    - the small-intestinal microbes in EAE mice enhanced the KYN pathway, resulting in increased KYNA in the SI; - increased KYNA contributed to the accumulation of Th17-inducing GPR35+ Ly6C+ macrophages in the SI of EAE mice before inflammation in the SC; - microbiota-induced Th17 cells were not retained in the intestines and migrated toward the SC to induce EAE.
  • [1.23] [#Alzheimer’s disease
    - #Tryptophan depletion increases cognitive deficits among people with AD and the bioavailability of metabolites in the #Serotonin and kynurenine pathways are altered in both the urine and serum of AD patients
  • [1.24
    - Specific bacterial genera, including #Catenibacterium, #Prevotellaceae, and #Enterobacteriaceae, enriched in PLWH > were strongly associated with accelerated biological #Aging. - These bacterial taxa can catabolize #Tryptophan and were correlated with elevated levels of the metabolic byproducts of #Tryptophan catabolism. Increased #Tryptophan catabolism leads to an accumulation of toxic metabolic byproducts such as kynurenine and #Quinolinic acid. - These byproducts have been linked with adverse outcomes in chronic #HIV infection
  • - elevated kynurenine levels are associated with neurological deficits in the #Aging population
  • [1.25] [#Collagen-induced arthritis , #Rheumatoid Arthritis
    - kynurenine supplementation, or inhibition of kynurenine production with the IDO1 inhibitor 1-methyl-#Tryptophan (1-MT) have shown conflicting effects on arthritis severity:
  • - elevated levels of serum kynurenine appear to impair Treg function. - kynurenine is thought to be primarily produced by host metabolism of Trp via indoleamine-2,3-dioxygenase (IDO1), the microbiota can also produce kynurenine via #Tryptophan-2,3-dioxygenase (TDO2)
  • [#Rheumatoid Arthritis] - Intra-articular injection of #Indole, but not kynurenine, into rabbit knees induced RA-like synovitis
  • [1.26] [#Alzheimer’s disease, #Parkinson’s Disease] [#Tryptophan
    - Part of kynurenine can also be converted to #3-hydroxykynurenine (3-HK) by the kynurenine-3-monooxygenase (KMO). 3-HK is further converted to 3-hydroxyanthranilic (3-HAA) via the enzyme kynureninase. Both 3-HK and 3-HAA are neurotoxic and oxidative mediators. - 3-HK has been shown to induce endogenous oxidative stress and neuronal cell apoptosis and has been linked to a series of neurodegenerative disorders
  • - kynureninase converts kynurenine to #Anthranilic acid (AA), a metabolite generally accepted as biologically inactive
  • [#Inflamatory bowel disease] [#Tryptophan] - IBD exhibit decreased Trp absorption, enhanced kynurenine pathway, altered #Indole pathway along, and altered #Indole pathway with decreased Trp plasma levels.
  • [#Inflamatory bowel disease] - dysbiosis can alter the kynurenine pathway and promote inflammation in IBD
  • [#Irritable bowel syndrome] - IBS patients’ blood had more kynurenine than the control group, and that there was a positive link between the severity of IBS symptoms and the kynurenine/#Tryptophan (Kyn/Trp) ratio
  • - Kynurenine aminotransferase (KAT) converts kynurenine into #kynurenic acid (KA). - KA is an N-methyl-D-aspartate (NMDA) receptor antagonist and α7 nicotinic acetylcholine receptor and it exhibits immunosuppressive, anti-oxidative, and neuroprotective roles
  • [1.27] [#Tryptophan
    - serum Trp levels across the majority of Chronic inflammatory diseases (CIDs), and a prevailing negative relationship between Trp and systemic inflammatory marker #C-reactive protein (CRP). - serum Trp was low in several CIDs even in the absence of measurable systemic inflammation. - Increases in the kynurenine-to-Trp ratio (Kyn:Trp) suggest that these changes result from increased degradation along the kynurenine pathway.
  • [1.28] [#Alzheimer’s disease
    - microbial-derived #Tryptophan degradation as one of the primary microbial sources of #Formate. - #Tryptophan depletion increases cognitive deficits among people with AD and the bioavailability of metabolites in the #Serotonin and kynurenine pathways are altered in both the urine and serum of AD patients

References Notes

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Common References

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