Tryptophan 2,3-dioxygenase

Source: Wikipedia, the free encyclopedia.
TDO2
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
Ensembl

ENSG00000262635
ENSG00000151790

ENSMUSG00000028011

UniProt

P48775

P48776

RefSeq (mRNA)

NM_005651

NM_019911

RefSeq (protein)

NP_005642

NP_064295

Location (UCSC)Chr 4: 155.85 – 155.92 MbChr 3: 81.86 – 81.88 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

In

enzymology, tryptophan 2,3-dioxygenase (EC 1.13.11.11) is a heme enzyme that catalyzes the oxidation of L-tryptophan (L-Trp) to N-formyl-L-kynurenine, as the first and rate-limiting step of the kynurenine pathway
.

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, as part of the overall biological process of tryptophan metabolism. TDO catalyses the first and rate-limiting step of tryptophan degradation along the kynurenine pathway and thereby regulates systemic tryptophan levels.[5] In humans, tryptophan 2,3-dioxygenase is encoded by the TDO2 gene.[6]

Function

Tryptophan 2,3-dioxygenase
ExPASy
NiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Search
PMCarticles
PubMedarticles
NCBIproteins

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). This family includes tryptophan 2,3-dioxygenase (TDO, also sometimes referred to as tryptophan oxygenase and L-tryptophan pyrrolase) and the closely related indoleamine 2,3-dioxygenase enzyme (IDO).[7][8] Both TDO and IDO contain one noncovalently bound heme per monomer; TDO is usually tetrameric, whereas IDO is monomeric.

Tryptophan 2,3-dioxygenase was initially discovered in the 1930s

E. coli).[10] Human TDO has also been expressed.[11][12]

The same family of enzymes also includes an indole 2,3-dioxygenase from

IDO2, was identified.[15]

Structure

Tryptophan 2,3-dioxygenase is a

homotetrameric enzymes.[17] 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. This loop appears to be substrate-binding induced, as it is observed only in crystals grown in the presence of L-tryptophan.[17]

There are two TDO structures available with substrate (tryptophan) bound.[17],[18]

Mechanism

Early proposals for the mechanism of tryptophan oxidation were presented by Sono and Dawson.[19] This suggested a base-catalysed abstraction mechanism, involving only the ferrous (FeII) heme. It is assumed that TDO and IDO react by the same mechanism, although there is no concrete evidence for that. In IDO, a ferryl heme (FeIV) has been identified during turnover.[20][21] Mechanistic proposals have therefore been adjusted to include the formation of ferryl heme during the mechanism.[22] TDO is assumed to react in the same way, but a ferryl heme has not been observed in TDO. See also discussion of mechanism for indoleamine 2,3-dioxygenase.

Proposed mechanism of action

Clinical significance

It has been shown that tryptophan 2,3-dioxygenase is expressed in a significant proportion of human

tumors.[5]
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

knock-out
mice, the findings demonstrating a direct link between tryptophan 2,3-dioxygenase and tryptophan metabolism and anxiety-related behavior under physiological conditions.

See also

References

  1. ^ a b c ENSG00000151790 GRCh38: Ensembl release 89: ENSG00000262635, ENSG00000151790 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000028011 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^
    PMID 22308364
    .
  6. ^ "Entrez Gene: TDO2 tryptophan 2,3-dioxygenase".
  7. PMID 21361337
    .
  8. ^
    doi:10.1002/0470028637.met223
    .
  9. doi:10.1515/bchm2.1936.243.6.237
    .
  10. PMID 8806758
    .
  11. PMID 18027945
    .
  12. PMID 18370401
    .
  13. ^
    PMID 17197414
    .
  14. PMID 17924666
    .
  15. PMID 17499941
    .
  16. PMID 17198384
    .
  17. ^
    PMID 19021508
    .
  18. PMID 27762317
    .
  19. PMID 11848843
    .
  20. PMID 19805032
    .
  21. doi:10.1246/cl.2010.36
    .
  22. PMID 21892828
    .
  23. PMID 19323847
    .

Further reading
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