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Ludwig Institute for Cancer Research, Brussels, Belgium.
de Duve Institute, UCLouvain, Brussels, Belgium.
Front Mol Biosci. 2022 Sep 14;9:897929. doi: 10.3389/fmolb.2022.897929. eCollection 2022.
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.
色氨酸是一种必需氨基酸，它不仅是蛋白质合成的组成部分，也是辅酶和神经调节剂生物合成的前体，如NAD/NADP(H)、犬尿氨酸、褪黑素和血清素。它在免疫稳态中也发挥作用，因为局部色氨酸分解代谢会损害T淋巴细胞介导的免疫。因此，尽管饮食供应存在很大差异，血浆色氨酸浓度仍需保持稳定。在此，我们综述了色氨酸稳态的主要检查点，包括吸收、转运、代谢和消除，并讨论了与其功能障碍相关疾病的病理生理学。色氨酸通过犬尿氨酸途径被两种酶分解代谢，这两种酶介导该途径的第一步和限速步骤：吲哚胺2,3-双加氧酶1（IDO1）和色氨酸2,3-双加氧酶（TDO）。虽然IDO1的表达仅限于免疫调节的外周部位，但TDO在肝脏中大量表达，占色氨酸分解代谢的90%。最近的数据表明，TDO蛋白的稳定性受色氨酸调节，这种调节可严格控制色氨酸血症。当血浆中色氨酸丰富时，TDO会被稳定下来，导致饮食中的色氨酸迅速降解。相反，当色氨酸稀缺时，TDO会被蛋白酶体降解，以避免色氨酸过度分解代谢。这是由非催化性色氨酸结合位点中的一个降解子暴露引发的，导致E3连接酶SKP1-CUL1-F-box对TDO进行泛素化。TDO或肝脏芳香族转运蛋白SLC16A10缺乏会导致严重的色氨酸血症，这可能会扰乱免疫和神经稳态。
