Kynurenine pathway and links to cell senescence (Homo sapiens)

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The kynurenine pathway is the major path for Tryptophan (Trp) breakdown (Castro-Portuguez & Sutphin, 2020; Dalton et al.,2020; Kondrikov et al., 2020; Li, Oxenkrug & Yang, 2017; Lindquist et al., 2020; Lugo-Huitron et al., 2013; Oxenkrug, 2011; Platten et al., 2019; Savitz, 2019; Soegdrageret al., 2019; Tan & Guillemin, 2019). The kynurenine (Kyn)/Trp ratio is proposed to be an accurate indicator of biological age as well as an indicator of risk for age-related diseases (Castro-Portuguez & Sutphin, 2020; Li et al., 2017; Lindquist et al., 2020; Oxenkrug, 2011; Platten et al., 2019; Savitz, 2019; Soegdrageret al., 2019).

The first and also rate-limiting enzymes that determine rate of Trp conversion into N-formylkynurenine and further on into Kyn are tryptophan-2,3-dioxygenase (TDO) and indoleamine-2,3-dioxygenase (IDO), out of which the IDO isoform IDO1 is the most important (Castro-Portuguez & Sutphin, 2020; Dalton et al.,2020; Li et al., 2017; Lindquist et al., 2020; Lugo-Huitron et al., 2013; Minhas et al., 2018; Oxenkrug, 2011; Platten et al., 2019; Savitz, 2019; Soegdrageret al., 2019; Tan & Guillemin, 2019). This catalytic enzyme is activated by pro-inflammatory cytokines such as interleukins, interferons gamma and beta or the aryl hydrocarbon receptor (AhR) (Castro-Portuguez & Sutphin, 2020; Dalton et al.,2020; Kondrikov et al., 2020; Li et al., 2017; Lindquist et al., 2020; Lugo-Huitron et al., 2013; Oxenkrug, 2011; Platten et al., 2019; Savitz, 2019; Soegdrageret al., 2019; Tan & Guillemin, 2019).

Next, N-formylkynurenine is converted either into kynurenic acid by a kynurenine aminotransferase (KAT), anthranilic acid by kynureninase or, into Kyn by formidase (AFMID) (Castro-Portuguez & Sutphin, 2020). Kyn can alter the regulation of cell cycle and proliferation and induce oxidative stress through by inducing the transcription of multiple miRNAs (Dalton et al., 2020), activating the p53/p21 pathway (Kondrikov et al., 2020) and binding to AhR, resulting in a positive feedback loop, while further promoting oxidative stress (Castro-Portuguez & Sutphin, Dalton et al., 2020; 2020, Kondrikov et al., 2020).

Kyn is further converted into 3-hydroxykynurenine (3HK) by kynurenine monooxygenase (KMO), then Kynureninase converts 3HK into 3-hydroxyanthranilic acid (3HAA) and then into 2-amino-3-carboxymuconate-6-semialdehyde (ACMSA) (Castro-Portuguez & Sutphin, 2020, Lindquist et al., 2020; Lugo-Huitron et al., 2013; Platten et al., 2019; Savitz, 2019; Tan & Guillemin, 2019). 3-HK can alternatively be converted into xanthurenic acid, a metabolite that modulates the tetrahydrobiopterin (BH4) pathway,(Tan & Guillemin, 2019). 3HAA can be converted either into quinolinic acid and from there enter the de novo NAD synthesis due to the enzymatic action of nicotinate-nucleotide pyrophosphorylase (QPRT), or it can be converted into 2-aminomuconate-6-semialdehyde (AMSA) which can be converted into glutaryl-CoA and enter the TCA cycle and glycolysis (Castro-Portuguez & Sutphin, 2020; Lindquist et al., 2020; Lugo-Huitron et al., 2013; Platten et al., 2019; Savitz, 2019; Tan & Guillemin, 2019).

Kynurenine Pathway Library (https://enamine.net/hit-finding/focused-libraries/view-all/immuno-oncology-library/kynurenine-pathway-library) was also used as a reference for this pathway.

 

Most studies were done on C. elegans and mice or in vitro on human/ mouse cells