Background
Kynurenine (KYN) is a metabolite of tryptophan, as well as a direct precursor of Kynurenic acid, o-aminobenzoic acid, and 3-hydroxykynurenine (3-HK), and more than 95% of tryptophan in mammals is degraded via the KYN pathway. The first rate-limiting step of the KYN pathway is the generation of KYN from tryptophan, mediated by indoleamine 2,3-dioxygenase (IDO)1, IDO2, and tryptophan 2,3-dioxygenase (TDO). The three enzymes are distributed in different tissues and are activated by different stimuli. IDO1 is activated by inflammatory and immune-related stimuli and is inhibited by NO and high levels of tryptophan. Compared with IDO1, IDO2 is mainly distributed in the kidney and liver, and its catalytic activity is lower. Under normal physiological conditions, the body primarily utilizes TDO, which is preferentially activated by glucocorticoids and can also be activated by low concentrations of reactive oxygen species. In addition, it is regulated by substrate availability and inhibits the final product by reducing nicotinamide adenine dinucleotide (NAD). KYN can cross the blood-brain barrier, and 60% of the KYN in the central nervous system comes from the periphery. The metabolism of KYN in the brain depends on the type of brain cells. It is generally believed that the metabolic response plays a neuroprotective role in astrocytes, while it is neurotoxic in microglia and macrophages.
Figure 1. The kynurenine pathway
(Source: Brown SJ, et al. 2021)
There are two sources of KYN in mammals, including endogenous and exogenous sources. Endogenous KYN comes from the above-mentioned KYN metabolic pathway and is synthesized by IDO and TDO using tryptophan as raw materials. Numerous foods are important external sources of kynurenic acid, such as potatoes, honey, coffee, tea, and alcoholic beverages. Among them, KYN is abundant in honey, on the contrary, KYN is very low in plant foods such as sesame seeds and cyanobacteria. In addition, low concentrations of KYN ranging from 0.008 mg/L to 0.015 mg/L were detected in white wine and red wine during non-yeast fermentation, but not in large-scale production.
Since KYN was found to be an agonist of aromatic hydrocarbon receptor (AhR), the research on the role of KYN in the central and peripheral nervous system has gradually increased. AhR is widely expressed in human tissues, mainly involved in metabolic functions, and its activation plays an important role in many pathological processes such as inflammation and carcinogenesis, so KYN acting on AhR may affect a variety of physiological and pathological conditions. Kynurenic acid and quinolinic acid significantly promote glutamatergic signaling in the brain, and abnormal production of these metabolites has been linked to neurodegenerative and other neurological disorders as well as psychiatric disorders such as depression, bipolar disorder, addiction, and schizophrenia.
Alternative Names
Human KYN ELISA kit
References
- 1. Brown SJ, et al. The kynurenine pathway in major depression: What we know and where to next. Neurosci Biobehav Rev. 2021 Aug;127:917-927.
- 2. Marszalek-Grabska M, et al. Kynurenine emerges from the shadows - Current knowledge on its fate and function. Pharmacol Ther. 2021 Sep;225:107845.
References
Tumor cell-released kynurenine biases MEP differentiation into megakaryocytes in individuals with cancer by activating AhR-RUNX1
Nat Immunol
Authors: Zhou L, Wu D, Zhou Y, Wang D, Fu H, Huang Q, Qin G, Chen J, Lv J, Lai S, Zhang H, Tang K, Ma J, Fiskesund R, Zhang Y, Zhang X, Huang B.
Abstract
Tumor-derived factors are thought to regulate thrombocytosis and erythrocytopenia in individuals with cancer; however, such factors have not yet been identified. Here we show that tumor cell-released kynurenine (Kyn) biases megakaryocytic-erythroid progenitor cell (MEP) differentiation into megakaryocytes in individuals with cancer by activating the aryl hydrocarbon receptor-Runt-related transcription factor 1 (AhR-RUNX1) axis. During tumor growth, large amounts of Kyn from tumor cells are released into the periphery, where they are taken up by MEPs via the transporter SLC7A8. In the cytosol, Kyn binds to and activates AhR, leading to its translocation into the nucleus where AhR transactivates RUNX1, thus regulating MEP differentiation into megakaryocytes. In addition, activated AhR upregulates SLC7A8 in MEPs to induce positive feedback. Importantly, Kyn-AhR-RUNX1-regulated MEP differentiation was demonstrated in both humanized mice and individuals with cancer, providing potential strategies for the prevention of thrombocytosis and erythrocytopenia.
Advances in kynurenine analysis
Clin Chim Acta
Authors: Mrštná K, Krčmová LK, Švec F.
Abstract
Kynurenine, the first product of tryptophan degradation via the kynurenine pathway, has become one of the most frequently mentioned biomarkers in recent years. Its levels in the body indicate the state of the human physiology. Human serum and plasma are the main matrixes used to evaluate kynurenine levels and liquid chromatography is the dominant technique for its determination. However, their concentrations in blood do not always correspond to the levels in other matrixes obtained from the affected individuals. It is therefore important to decide when it is appropriate to analyse kynurenine in alternative matrices. However, liquid chromatography may not be the best option for the analysis. This review presents alternatives that can be used and summarizes the features that need to be considered prior to kynurenine determination. Possible approaches to kynurenine analysis in a variety of human matrixes, their challenges, and limitations are critically discussed.
COA
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