Tryptophan Metabolism: A Versatile Area Providing Multiple Targets for Pharmacological Intervention

Abstract

The essential amino acid L-tryptophan (Trp) undergoes extensive metabolism along several pathways, resulting in production of many biologically active metabolites which exert profound effects on physiological processes. The disturbance in Trp metabolism and disposition in many disease states provides a basis for exploring multiple targets for pharmaco-therapeutic interventions. In particular, the kynurenine pathway of Trp degradation is currently at the forefront of immunological research and immunotherapy. In this review, I shall consider mammalian Trp metabolism in health and disease and outline the intervention targets. It is hoped that this account will provide a stimulus for pharmacologists and others to conduct further studies in this rich area of biomedical research and therapeutics.

Keywords: immunotherapy; indoleamine 2,3-dioxygenase; inflammation; kynurenine pathway; major depressive disorder; neurological disease; plasma free tryptophan; serotonin pathway; tryptophan 2,3-dioxygenase; tumoral immune escape.

Figure 1. The hydroxylation or serotonin pathway in brain and melatonin pathway in pineal.

Abbreviations used are: AANAT (arylalkylamine N-acetyltransferase), ALAAD (aromatic L-amino acid decarboxylase), ALDH (aldehyde dehydrogenase), BH₂ and BH₄ (dihydro- and tetrahydro-biopterin), HIOMT (hydoxyindole-O-methyltransferase), MAO (monoamine oxidase), PLP (pyridoxal 5’-phosphate), TPH (tryptophan hydroxylase).

Figure 2. The decarboxylation or tryptamine pathway.

Abbreviations used are: ALAAD (aromatic L-amino acid decarboxylase), ALDH (aldehyde dehydrogenase), MAO (monoamine oxidase), NAD(H) [oxidized and (reduced) nicotinamide-adenine dinucleotide], PLP (pyridoxal 5’-phosphate).

Figure 3. The transamination or indolepyruvic acid pathway.

Abbreviations used are: ALDH (aldehyde dehydrogenase), IPD (indole pyruvate decarboxylase) ILDH (indole lactate dehydrogenase), ROS (reactive oxygen species), TAT (tryptophan aminotransferase).

Figure 4. The oxidative or kynurenine pathway up to quinolinic acid and down to acetyl CoA.

Adapted from Figure 1 in ref [6] (A. A.-B. Badawy. Kynurenine pathway of tryptophan metabolism: regulatory and functional aspects. Int J Tryptophan Res. 10, 1-20, 2017 doi: 10.1177/1178646917691938. Abbreviations used are: ACMS (2-Amino-3-carboxymuconic acid-6-semialdehyde), AMS (2-Aminomuconic acid -6-semialdehyde), IDO (indoleamine 2,3-dioxygenase), TDO (tryptophan 2,3-dioxygenase).

Figure 5. NAD⁺ synthesis from quinolinic acid and via the salvage pathway.

Adapted from Figure 1 in ref [6] (A. A.-B. Badawy. Kynurenine pathway of tryptophan metabolism: regulatory and functional aspects. Int J Tryptophan Res. 10, 1-20, 2017 doi: 10.1177/1178646917691938.