Journal article : Review
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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 3.5MB, Terms of use)
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- Publisher copy:
- 10.3389/fmolb.2022.897929
Authors
- Publisher:
- Frontiers Media
- Journal:
- Frontiers in Molecular Biosciences More from this journal
- Volume:
- 9
- Article number:
- 897929
- Place of publication:
- Switzerland
- Publication date:
- 2022-09-14
- Acceptance date:
- 2022-08-01
- DOI:
- EISSN:
-
2296-889X
- Pmid:
-
36188218
- Language:
-
English
- Keywords:
- Subtype:
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Review
- Pubs id:
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1282673
- Local pid:
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pubs:1282673
- Deposit date:
-
2023-07-10
Terms of use
- Copyright holder:
- Klaessens et al
- Copyright date:
- 2022
- Rights statement:
- © 2022 Klaessens, Stroobant, De Plaen and Van den Eynde. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
- Licence:
- CC Attribution (CC BY)
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