|Symbols||; TDO; TO; TPH2; TRPO|
|External IDs||ChEMBL: GeneCards:|
|RNA expression pattern|
- L-tryptophan + O2 N-formyl-L-kynurenine
Tryptophan 2,3-dioxygenase plays a central role in the physiological regulation of tryptophan flux in the human body. It catalyses the first and rate limiting step of tryptophan degradation along the kynurenine pathway and thereby regulates systemic tryptophan levels.
Crystal structure of the tryptophan 2,3-dioxygenase from xanthomonas campestris
|PDB structures||RCSB PDB PDBe PDBsum|
|Gene Ontology||AmiGO / EGO|
This enzyme belongs to the family of oxidoreductases, specifically those acting on single donors with O2 as oxidant and incorporation of two atoms of oxygen into the substrate (oxygenases). The oxygen incorporated need not be derived from O2. This family of enzymes includes tryptophan 2,3-dioxygenase (TDO, also known as tryptophan oxygenase and L-tryptophan pyrrolase) and indoleamine 2,3-dioxygenase (IDO, also known as tryptophan pyrrolase). These two enzymes are oxidoreductase enzymes that contain one noncovalently bound iron–protoporphyrin IX per monomer. These enzymes catalyze the dioxygenation of L-tryptophan (L-Trp) to N-formyl-L-kynurenine in the first and rate-limiting step of the kynurenine pathway.
The same family of enzymes also includes sIDO from Shewanella oneidensis and PrnB, the second enzyme in the pyrrolnitrin biosynthesis pathway from Pseudomonas fluorescens, although dioxygenase activity has not been demonstrated for either as yet. Recently, a new enzyme with the ability to catalyze L-tryptophan dioxygenation, INDOL1, was identified.
Tryptophan 2,3-dioxygenase was initially discovered in the 1930s and is found in both eukaryotes (human, rat, and rabbit) and prokaryotes (Xanthomonas campestris, and P. fluorescens) Expression of tryptophan 2,3-dioxygenase in mammals is normally restricted to the liver, but it has been identified in the brain and epididymis of some species, and, in some tissues, its production can be induced in response to stimuli.
Tryptophan 2,3-dioxygenase is a heme-containing cytosolic enzyme encoded by gene TDO2. Crystallographic studies of xcTDO (Xanthomonas campestris TDO) and rmTDO (Ralstonia metallidurans TDO) have revealed that the crystal structures of xcTDO and rmTDO are essentially identical and are intimately associated homotetrameric enzymes. They are best described as a dimer of dimers because the N terminal residues of each monomer form part of the substrate binding site in an adjacent monomer. The proteins are completely helical, and a flexible loop, involved in L-tryptophan binding, is observed just outside the active-site pocket. Interestingly, this loop appears to be substrate-binding induced, as it is observed only in crystals grown in the presence of L-tryptophan.
The only structure available with substrate bound at the active site in the catalytically active ferrous state is xcTDO. In the structure of xcTDO, the carboxy group of L-tryptophan interacts with Arg117, Tyr113 and Thr254. Amino acid residues equivalent to Arg117 and Tyr113 are found in nearly all TDO and IDO proteins. This carboxy-binding motif appears to be essential for substrate binding; arginine reorients in the presence of substrate, co-ordinating the carboxy group of L-tryptophan. The substrate ammonium group is hydrogen-bonded to the side-chain hydroxyl group of Thr254, the 7-propionate group of the heme, and a water molecule.
The initial formation of the ternary complex (1) occurs by substrate binding, followed by dioxygen binding to the ferrous protein. The ternary complex activates O2 and allows the otherwise spin-forbidden reaction to proceeed. The formation of the hydroperoxide intermediate (2) is catalyzed by the loss of the indole proton. Two mechanisms are possible: base-catalysed deprotonation or proton abstraction by bound dioxygen. However, catalysis by the ironbound dioxygen is generally proposed, as a result of experiments showing that catalytic activity is maintained upon substitution of alanine for His55 (the only basic residue in the active site of the enzyme).
The rearrangement of the hydroperoxide intermediate to form the product could occur via the dioxetane intermediate (see figure) or a Criegee intermediate. However, density functional theory calculations on the catalytic mechanism of tryptophan 2,3-dioxygenase have cast doubt on the relevance of the Criegee mechanism.
It has been shown that tryptophan 2,3-dioxygenase is expressed in a significant proportion of human tumors. In the same study, tryptophan 2,3-dioxygenase expression by tumors prevented their rejection by immunized mice. A tryptophan 2,3-dioxygenase inhibitor developed by the group restored the ability of these mice to reject tryptophan 2,3-dioxygenase-expressed tumors, demonstrating that tryptophan 2,3-dioxygenase inhibitors display potential in cancer therapy.
Another study showed that tryptophan 2,3-dioxygenase is potentially involved in the metabolic pathway responsible for anxiety-related behavior. Generating mice deficient for tryptophan 2,3-dioxygenase and comparing them to the wild type, the group found that the tryptophan 2,3-dioxygenase-deficient mice showed increased plasma levels not only of tryptophan, but also of serotonin and 5-HIAA in the hippocampus and midbrain. A variety of tests, such as elevated plus maze and open-field tests showed anxiolytic modulation in these knock-out mice, the findings demonstrating a direct link between tryptophan 2,3-dioxygenase and tryptophan metabolism and anxiety-related behavior under physiological conditions.
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