Table 5. Pharmacological targeting of the kynurenine pathway.
| Target | Condition | Mechanisms and effectors |
|---|---|---|
| Trp and metabolites: | ||
| Trp | tumoral immune escape | Decrease tumoral uptake by α-MT |
| Decrease plasma free Trp by albumin infusions | ||
| Decreased plasma free Trp by antilipolytic agents | ||
| Nicotinic acid | cancer | Decreased plasma free Trp by inhibition of lipolysis in host |
| Nicotinamide | cancer | TDO inhibition in tumors and hosts |
| Kynurenic acid | Alcoholism | Aversion to alcohol by ALDH inhibition |
| Schizophrenia | KAT inhibition | |
| Inflammatory diseases | KA analogues | |
| Retinal degeneration | Increasing KA formation by Trp? | |
| GIT diseases | Increasing KA formation by Trp | |
| Enzymes: | ||
| TDO | Depression | Increased serotonin synthesis by TDO inhibition (antidepressants, others) |
| Neurodegeneration | Increased KA formation | |
| Anxiety | Increased brain serotonin by TDO inhibition | |
| Hepatic porphyrias | Decreased haem utilisation by TDO inhibitors (glucose, others?) | |
| Cancer, immune escape | Decreased immunosuppressive kynurenines by TDO inhibitors | |
| IDO | cancer, immune escape | Decreased immunosuppressive kynurenines by IDO inhibitors |
| Formamidase | Neurological diseases | Decreasing neurotoxic Kyn metabolites by formamidase inhibition |
| Cancer and infections | Decreasing immunosuppressive Kyn metabolites by formamidase inhibition | |
| KAT | Schizophrenia | Improved glutamatergic activity by KAT II inhibition |
| Malaria infection | Decreasing XA by KAT inhibition | |
| KMO | anxiety, cerebral malaria, Inflammatory and neurodegenerative diseases, pancreatitis | Decreased 3-HK, 3-HAA and QA and increased Kyn and KA by KMO inhibitors |
| Kynureninase | Neurodegenerative diseases | Decreased 3-HAA and QA formation by kynureninase inhibition |
| 3-HAAO | Neurodegenerative diseases | Decreased QA formation by 3-HAAO inhibition |
| ACMSD | No definite views | Inhibition could be controversial |
| QPRT | neurodegenerative Diseases |
Stimulation to lower QA |
| Cancer | Inhibition to decrease NAD+ to undermine tumor viability | |
| And suppression of cell death by inhibition of caspase production | ||
| NAD synthetase | Mycobacterium tuberculosis | Inhibition to limit NAD+ availability |
| NMPRT | Cancer | Inhibition to suppress colorectal tumors |
| NMNAT-NAMNAT | Neurological and neuro-degenerative diseases | Activation to increase NAD+ synthesis to combat oxidative damage |
| NNMT | Obesity, type 2 diabetes | Inhibition undermines processes related to glucose metabolism and fat deposition |
| NADase | Streptococcal virulence | Inhibition of NADase |
| PARP | Cancer, stroke, myocardial infarction, neurotrauma | Inhibition of PARP activity |
Abbreviations used: ACMSD (2-amino-3-carboxymuconic acid-6-semialdehyde; also known as acroleyl aminofumarate), 3-HAA (3-hydroxyanthranilic acid), 3-HAAO (3-hydroxyanthranilic acid 3,4-dioxygenase), 3-HK (3-hydroxykynurenine), IDO (indoleamine 2,3-dioxygenase), KA (kynurenic acid), Kyn (kynurenine), KAT (kynurenine aminotransferase), KMO (kynurenine monooxygenase or kynurenine hydroxylase), α-MT (α-methyltryptophan), NAMNAT/NMNAT (nicotinamide mononucleotide/nicotinic acid mononucleotide adenylyl transferases), NMPRT (nicotinamide phosphoribosyltransferase), NNMT (nicotinamide N-methyltransferase), PARP [poly (ADP-ribose) polymerase], QPRT (quinolinate phosphoribosyltransferase), QA (quinolinic acid), Trp (tryptophan), TDO (tryptophan 2,3-dioxygenase), XA (xanthurenic acid).