Big Paper on C. elegans and mouse aging published in Nature Communications
On the benefits of the tryptophan metabolite 3-hydroxyanthranilic acid in Caenorhabditis elegans and mouse aging published in Nature Communications
Physiological tryptophan (TRP) has a variety of potential fates in eukaryotic cells, including incorporation into proteins, conversion to serotonin or melatonin, conversion to tryptamine, or conversion to nicotinamide adenine dinucleotide (NAD+) through the kynurenine pathway (Fig. 1a). The majority (>90%) of ingested tryptophan is catabolized by the kynurenine pathway in mammals1. Altered kynurenine pathway activity has been implicated in a range of age-associated diseases in humans, including cardiovascular disease, kidney disease, cancer, and neurodegeneration2,3. The structure of the kynurenine pathway is evolutionarily conserved from bacteria through mammals, with a few notable exceptions. The initial, rate-limiting conversion of TRP to N-formylkynurenine (NFK) is carried out by the enzyme tryptophan 2,3-dioxygenase (TDO2) across species. Vertebrate genomes encode a second cytokine-responsive enzyme, IDO1, that catalyzes this reaction, and vertebrate kynurenine pathway initiation is largely segregated between immune cells (IDO1) and liver (TDO2)4. A duplication event in the mammalian lineage produced IDO2, which is more ubiquitously expressed and less active than IDO1 and does not respond to cytokines. IDO2’s function is currently less well-defined4. Arylformamidase (AFMID) catabolizes NFK to kynurenine (KYN), which is in turn processed to either kynurenic acid (KA) or NAD+ through the two major branches of the kynurenine pathway. The NAD+ branch converts KYN to NAD+ through a series of metabolic steps catalyzed by the enzymes kynurenine 3-monooxygenase (KMO), kynureninase (KYNU), and 3-hydroxyanthranilic acid dioxygenase (HAAO).