The Plasma [Kynurenine]/[Tryptophan] Ratio and Indoleamine 2,3-Dioxygenase: Time for Appraisal

Abstract

The plasma kynurenine to tryptophan ([Kyn]/[Trp]) ratio is frequently used to express or reflect the activity of the extrahepatic Trp-degrading enzyme indoleamine 2,3-dioxygenase (IDO). This ratio is increasingly used instead of measurement of IDO activity, which is often low or undetectable in immune and other cells under basal conditions, but is greatly enhanced after immune activation. The use of this ratio is valid in in vitro studies, eg, in cell cultures or isolated organs, but its ‘blanket’ use in in vivo situations is not, because of modulating factors, such as supply of nutrients; the presence of multiple cell types; complex structural and functional tissue arrangements; the extracellular matrix; and hormonal, cytokine, and paracrine interactions. Determinants other than IDO may therefore be involved in vivo. These are hepatic tryptophan 2,3-dioxygenase (TDO) activity and the flux of plasma-free Trp down the Kyn pathway. In addition, conditions leading to accumulation of Kyn, eg, inhibition of activities of Kyn monooxygenase and kynureninase, could lead to elevation of the aforementioned ratio. In this review, the origin of use of this ratio will be discussed, variations in extent of its elevation will be described, evidence against its indiscriminate use will be presented, and examining determinants other than IDO activity and their correlates will be proposed for future studies.

Quinolinate as a Marker for Kynurenine Metabolite Formation and the Unresolved Question of NAD+ Synthesis During Inflammation and Infection

“…Also, tryptophan and kynurenine loading in rats increased Quin-IR differentially in distinct cell types demonstrating selective uptake and utilization systems for these closely related metabolites (29). The plasma kynurenine to tryptophan ratio (Kyn/Trp) is often used as an indicator of IDO action and kynurenine pathway flux, despite its complications and limitations (65). Quin-IR provides a unique method for looking at kynurenine pathway throughput up to the point of Quin synthesis.…”

Tracking Hidden Binding Pockets Along the Molecular Recognition Path of l‐Trp to Indoleamine 2,3‐Dioxygenase 1

“…l ‐Tryptophan ( l ‐Trp, 1 ) is an essential amino acid in mammals and its metabolic fate is accurately controlled by a number of metabolic pathways, leading to the formation of many biologically active compounds . Large part of l ‐Trp taken from diet is metabolized along the kynurenine pathway (KP), wherein the first and rate limiting step consists in the oxidative cleavage of the indole ring to form N‐formyl‐kynurenine ( 2 ) (Figure ) …”

“…[1,2] Large part of l-Trp taken from diet is metabolized along the kynurenine pathway (KP), wherein the first and rate limiting step consists in the oxidative cleavage of the indole ring to form N-formyl-kynurenine (2) (Figure 1). [3] This biochemical reaction is carried out by heme-containing dioxygenases, including tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase 1 (IDO1). Despite catalyzing the same reaction, these enzymes have several structural and biochemical differences.…”

Metabolic analysis of amino acids and vitamin B6 pathways in lymphoma survivors with cancer related chronic fatigue

“…Metabolites of the kynurenine pathway also serve as precursors for nicotinamide adenine dinucleotide synthesis and thereby play a role in energy homeostasis. The hepatic enzyme tryptophan-2,3-dioxygenase (TDO) and the more widely expressed indolamine 2,3-dioxygenases (IDO) 1 and 2 catalyze the oxidative cleavage of Trp to Kyn, the first and rate limiting step of the pathway [41,42]. The ratio of Kyn to Trp has been proposed as a marker of these enzymatic reactions, but other factors, especially the activity of downstream enzymes metabolizing Kyn are also important in determining the Kyn/Trp ratio [41].…”