Systemic tryptophan homeostasis

Abstract

Tryptophan is an essential amino acid, which is not only a building block for protein synthesis, but also a precursor for the biosynthesis of co-enzymes and neuromodulators, such as NAD/NADP(H), kynurenic acid, melatonin and serotonin. It also plays a role in immune homeostasis, as local tryptophan catabolism impairs T-lymphocyte mediated immunity. Therefore, tryptophan plasmatic concentration needs to be stable, in spite of large variations in dietary supply. Here, we review the main checkpoints accounting for tryptophan homeostasis, including absorption, transport, metabolism and elimination, and we discuss the physiopathology of disorders associated with their dysfunction. Tryptophan is catabolized along the kynurenine pathway through the action of two enzymes that mediate the first and rate-limiting step of the pathway: indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO). While IDO1 expression is restricted to peripheral sites of immune modulation, TDO is massively expressed in the liver and accounts for 90% of tryptophan catabolism. Recent data indicated that the stability of the TDO protein is regulated by tryptophan and that this regulation allows a tight control of tryptophanemia. TDO is stabilized when tryptophan is abundant in the plasma, resulting in rapid degradation of dietary tryptophan. In contrast, when tryptophan is scarce, TDO is degraded by the proteasome to avoid excessive tryptophan catabolism. This is triggered by the unmasking of a degron in a non-catalytic tryptophan-binding site, resulting in TDO ubiquitination by E3 ligase SKP1-CUL1-F-box. Deficiency in TDO or in the hepatic aromatic transporter SLC16A10 leads to severe hypertryptophanemia, which can disturb immune and neurological homeostasis.

Tryptophan Metabolism in Postmenopausal Women with Functional Constipation

“…Most TRP (over 90%) is metabolized in the digestive tract in the serotonin (1–2%), kynurenine (approximately 95%) and indole (2–3%) pathways, and their initiating enzymes are TRP hydroxylase (TPH-1), indoleamine 2,3-diooxygenase (IDO-1), and bacterial TRPase (TNA), respectively. These enzymes compete for access to ingested TRP [ 13 ]. In healthy people, the balance of these pathways is maintained, but it can be disturbed by many factors, including TRP intake and changes in the gut microbiota [ 14 , 15 ].…”

The MTORC1-AHR pathway sustains translation and autophagy in tumours under tryptophan stress

“…Cancers contain poorly vascularized areas and tumor blood vessels are dilated and leaky, collectively compromising nutrient delivery to tumor cells. As the least abundant essential amino acid (Barik, 2020;Klaessens et al, 2022), tryptophan (Trp) will be the first amino acid to become limiting upon nutrient restriction in tumors.…”

“…Cancers contain poorly vascularized areas and tumor blood vessels are dilated and leaky, collectively compromising nutrient delivery to tumor cells. As the least abundant essential amino acid (Barik, 2020; Klaessens et al, 2022), tryptophan (Trp) will be the first amino acid to become limiting upon nutrient restriction in tumors. In addition, Trp catabolism is often upregulated in tumors and activation of the aryl hydrocarbon receptor (AHR) by Trp catabolites promotes tumor progression (Gargaro et al, 2021).…”

Developmental and Nutritional Dynamics of Malpighian Tubule Autofluorescence in the Asian Tiger Mosquito Aedes albopictus

“…In this context, the metabolism of the amino acid tryptophan has attracted attention because, beyond its role in protein synthesis, it serves as a precursor to a variety of bioactive molecules, including serotonin, melatonin and kynurenine (KYN) pathway metabolites, acting as hormones and neuronal and immune regulators [ 26 ]. The oxidation of tryptophan to KYN is the first step of a catabolic pathway that produces kynurenic acid through transamination or 3-hydroxy kynurenine (3-HK) through hydroxylation, while xanthurenic acid (XA) is derived from 3-HK transamination, each molecule possessing different chemical and signaling reactivities [ 27 , 28 , 29 ]. While in mammals the accumulation of excess 3-HK is mitigated through its hydrolysis, many insects, including D. melanogaster and mosquitoes, lack the hydrolytic enzyme kynureninase and 3-HK can only be removed through its transamination to XA or be used in the biosynthesis of ommochrome eye pigments [ 30 , 31 , 32 ].…”