Low efficiency IDO2 enzymes are conserved in lower vertebrates, whereas higher efficiency IDO1 enzymes are dispensable

FEBS J. 2015 Jul;282(14):2735-45. doi: 10.1111/febs.13316. Epub 2015 May 20.


Indoleamine 2,3-dioxygenase (IDO) is a Trp-degrading enzyme that catalyzes the first step in the kynurenine pathway. Two IDO genes, IDO1 and IDO2, are found in vertebrates and the timing of the gene duplication giving rise to the genes has been controversial. In the present study, we report that several fishes and two turtles also have both IDO1 and IDO2. This represents definitive evidence for the gene duplication occurring before the divergence of vertebrates, with IDO1 having been lost in a number of lower vertebrate lineages. IDO2 enzymes have a relatively low affinity for l-Trp; however, Anolis carolinensis (lizard) IDO2 has an affinity for l-Trp comparable to mammalian IDO1 enzymes. We identified a Ser residue located in the distal heme pocket of IDO1 (distal-Ser) (corresponding to Ser167 of human IDO1) that is conserved in all IDO1 enzymes and the lizard IDO2. This residue is conserved as Thr (distal-Thr) in other IDO2 enzymes. Biochemical analyses, using IDO variants with either Ser or Thr substitutions, suggest that the distal-Ser change was crucial for the improvement in affinity for l-Trp in ancient IDO1. The ancestral IDO1 likely had a 'moderate' enzymatic efficiency for l-Trp, clearly higher than IDO2 but lower than mammalian IDO1. The distal-Ser of lizard IDO2 bestows a high affinity for l-Trp, however, this unique IDO2 has a low enzymatic efficiency because of its very low catalytic velocity. Thus, low efficiency IDO2 enzymes have been conserved throughout vertebrate evolution, whereas higher efficiency IDO1 enzymes are dispensable in many lower vertebrate lineages.

Keywords: Trp metabolism; comparative biochemistry; gene duplication; indoleamine 2,3-dioxygenase; molecular evolution.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Conserved Sequence
  • Evolution, Molecular*
  • Fishes / genetics
  • Fishes / metabolism
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / chemistry*
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / genetics
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism*
  • Lizards / genetics
  • Lizards / metabolism
  • Molecular Sequence Data
  • Phylogeny
  • Serine / metabolism
  • Tryptophan / metabolism
  • Turtles / genetics
  • Turtles / metabolism
  • Vertebrates / metabolism*
  • Xenopus Proteins / genetics
  • Xenopus Proteins / metabolism


  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Xenopus Proteins
  • Serine
  • Tryptophan