Tryptophan metabolites, kynurenines

What is measured?

Kynurenine (Kyn), kynurenic acid (KA), quinaldic acid (Qld), anthranilic acid (AA), 3-hydroxykynurenine (HK), xanthurenic acid (XA) and 3-hydroxyanthranilic acid (HAA), picolinic acid (Pic), quinolinic acid (QA), nicotinic acid (NA), nicotinamide (NAM), N1-methylnicotinamide (mNAM).
Method(s): LC-MS/MS (1).

Tryptophan metabolites of the kynurenine pathway

The amino acid tryptophan is catabolized mainly through the kynurenine pathway, forming metabolites collectively referred to as kynurenines. Some kynurenines are neuroactive compounds with immunomodulatory effects.
The intial step in this pathway, the conversion of Trp to formylkynurenine (fKyn), is catalyzed by indoleamine 2,3-dioxygenase (IDO), which is activated by pro-inflammatory cytokines, like INFγ and TNFα. fKyn is converted to Kyn, wich in turn is metabolized to HK by the FAD-dependent kynurenine mono-oxygenase (KMO), and then cleaved to HAA by the pyridoxal 5´-phosphate (PLP)-dependent enzyme, kynureninase (KYNU), which also catalyzes the conversion of Kyn to AA. The PLP-dependent enzyme kynurenine transaminase (KAT) catalyzes the formation of two end-stage metabolites, KA (from Kyn) and XA (from HK) (2) (Figure 1).
The downstream metabolite, QA, is converted to nicotinic acid mononucleotide, which is a precursor of niacin and nicotinamide dinucleotide (NAD), i.e. B3 vitamers. NAM in plasma and mNAM in urine are potential markers of vitamin B3 status.
Kynurenic acid (KA) and picolinic acid (Pic) are considered as neuroprotective, whereas 3-hydroxykynurenine (HK) and in particular quinolinic acid (QA) have neuroexcitatory effects (Figure 1). These kynurenines are suggested to be involved in the pathogenesis of some neurodegenerative and neuropsychiatric diseases (2).
The CSF levels of neuroactive kynurenines, KA and HK, show no change (KA) or decrease (HK) with age, whereas the neurotoxic kynurenine, QA, in CSF shows a remarkably strong positive associations with age, but also with markers of neuroinflammation, like neopterin and KTR. These age-related changes may be associated with increasing incidence of neurodegenerative diseases with age (3).
A composite index involving five kynurenines, HKr (HK:(KA+AA+XA+HAA)), is a functional marker of B6 status.

Indication(s)

Investigating risk and pathogenesis of neuropsychiatric, neurodegenerative, cardiovascular, dysmetabolic diseases, cancer and other common chronic conditions.

Specimen, collection and processing

Matrix: EDTA plasma (preferred) or serum. 3-Hydroxykynurenine (HK) and 3-hydroxyanthranilic acid (HAA) decrease (up to 40-70%) whereas anthranilic acid (AA) and in particular nicotinamide (NAM) increase (AA, up to 30%; NAM, up to 300 %) in samples with hemolysis.
Volume: Minimum volume is 60 µL, but 200 µL is optimal and allows reanalysis.
Preparation and stability: The kynurenines have different stability. Kyn and KA are stable, whereas HK and HAA decrease while AA increases during storage of serum/plasma samples. Samples should be put on ice immediately after collection and stored at -80 °C.

Transportation

Frozen, on dry ice. (for general instruction on transportation, click here)

Reported values, interpretation

Reported values: Kyn: 1.0-3.3 µmol/L; KA: 20-100 nmol/L; Qld: 0.2-20nmol/L; AA: 7-30 nmol/L; HK: 25-80 nmol/L; XA: 2-35 nmol/L; HAA: 10-80 nmol/L; Pic: 20-100 nmol/L; QA: 150-700 nmol/L; NA: < 20 nmol/L; NAM: 100-600 nmol/L; mNAM: 20-250 nmol/L.
Intraclass correlation coefficient (ICC): Kyn: 0.68; KA: 0.68; Qld: na; AA: 0.64; HK: 0.62; XA: 0.58; HAA: 0.54; Pic, na; QA: na; NA: na; NAM: na; mNAM: na.

Literature

1. Midttun, O., Hustad, S., and Ueland, P.M. (2009). Quantitative profiling of biomarkers related to B-vitamin status, tryptophan metabolism and inflammation in human plasma by liquid chromatography/tandem mass spectrometry. Rapid Commun Mass Sp 23, 1371-79.
2. Ueland, P.M., McCann, A., Midttun, Ø., and Ulvik, A. (2017). Inflammation, vitamin B6 and related pathways. Mol Aspects Med 53, 10-27.
3. de Bie, J., Guest, J., Guillemin, G.J., and Grant, R. (2016). Central kynurenine pathway shift with age in women. J Neurochem 136, 995-1003.

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