Indoleamine 2,3-dioxgyenase (IDO, ) [, ]is a cytosolic heme protein which, together with the hepatic enzyme tryptophan 2,3-dioxygenase, catalyses the conversion of tryptophan and other indole derivatives to kynurenines. It is widely distributed in human tissues, involved in the peripheral immune tolerance, contributing to maintain homeostasis by preventing autoimmunity or immunopathology that would result from uncontrolled and overreacting immune responses [, ]. The degradative action of IDO on tryptophan leads to cell death by starvation of this essential and relatively scarce amino acid. Tryptophan shortage inhibits T lymphocytes division and accumulation of tryptophan catabolites induces T-cell apoptosis and differentiation of regulatory T-cells. IDO also acts as a suppressor of anti-tumor immunity and limits the growth of intracellular pathogens by depriving tryptophan. Elevated IDO1 expression is a hallmark of major viral infections including HIV, HBV, HCV or influenza and also of major bacteria infections []. This enzyme has also been associated to protection of the fetus from maternal immune rejection []. Indoleamine 2,3-dioxygenase from yeast (BNA2) plays a role in the cellular response to telomere uncapping []. IDO is a heme-containing enzyme of about 400 amino acids. Site-directed mutagenesis showed His346 () to be essential for haem binding, indicating that this histidine residue may be the proximal ligand. Mutation of Asp274 also compromised the ability of IDO to bind haem, suggesting that Asp274 may coordinate to heme directly as the distal ligand or is essential in maintaining the conformation of the haem pocket []. There are two IDO enzyme catalysing the same reaction, IDO1 and IDO2 which differ in their affinity for tryptophan being IDO2 affinity for tryptophan much lower than that of IDO1. 50% of Caucasians harbor polymorphisms which abolish IDO2 enzymatic activity. IDO2 is expressed in human tumors in an inactive form, thus, tryptophan degradation is entirely provided by IDO1 in these cells []. IDO2 may play a role as a negative regulator of IDO1 by competing for heme-binding with IDO1[]. ALthough low efficiency IDO2 enzymes have been conserved throughout vertebrate evolution, higher efficiency IDO1 enzymes are dispensable in many lower vertebrate lineages []. It is suggested that IDO1 may have arisen by gene duplication of a more ancient proto-IDO gene before the divergence of marsupial and eutherian (placental) mammals.Other proteins that are evolutionarily related to IDO include myoglobin from the red muscle of the archaeogastropodic molluscs, Nordotis madaka (Giant abalone) and Sulculus diversicolor [, ]. These unusual globins lack enzymatic activity but have kept the heme group.
This superfamily represents the tryptophan and indoleamine 2,3-dioxygenase.Tryptophan 2,3-dioxygenase () enzymes are involved in tryptophan metabolism, which catalyses the oxidative cleavage of the L-tryptophan (L-Trp) pyrrole ring [].Indoleamine 2,3-dioxgyenase (IDO, ) [, ]is a cytosolic heme protein which, together with the hepatic enzyme tryptophan 2,3-dioxygenase, catalyses the conversion of tryptophan and other indole derivatives to kynurenines. It is widely distributed in human tissues, involved in the peripheral immune tolerance, contributing to maintain homeostasis by preventing autoimmunity or immunopathology that would result from uncontrolled and overreacting immune responses [, ]. The degradative action of IDO on tryptophan leads to cell death by starvation of this essential and relatively scarce amino acid. Tryptophan shortage inhibits T lymphocytes division and accumulation of tryptophan catabolites induces T-cell apoptosis and differentiation of regulatory T-cells. IDO also acts as a suppressor of anti-tumor immunity and limits the growth of intracellular pathogens by depriving tryptophan. Elevated IDO1 expression is a hallmark of major viral infections including HIV, HBV, HCV or influenza and also of major bacteria infections []. This enzyme has also been associated to protection of the fetus from maternal immune rejection []. Indoleamine 2,3-dioxygenase from yeast (BNA2) plays a role in the cellular response to telomere uncapping []. IDO is a heme-containing enzyme of about 400 amino acids. Site-directed mutagenesis showed His346 () to be essential for haem binding, indicating that this histidine residue may be the proximal ligand. Mutation of Asp274 also compromised the ability of IDO to bind haem, suggesting that Asp274 may coordinate to heme directly as the distal ligand or is essential in maintaining the conformation of the haem pocket []. There are two IDO enzyme catalysing the same reaction, IDO1 and IDO2 which differ in their affinity for tryptophan being IDO2 affinity for tryptophan much lower than that of IDO1. 50% of Caucasians harbor polymorphisms which abolish IDO2 enzymatic activity. IDO2 is expressed in human tumors in an inactive form, thus, tryptophan degradation is entirely provided by IDO1 in these cells []. IDO2 may play a role as a negative regulator of IDO1 by competing for heme-binding with IDO1[]. ALthough low efficiency IDO2 enzymes have been conserved throughout vertebrate evolution, higher efficiency IDO1 enzymes are dispensable in many lower vertebrate lineages []. It is suggested that IDO1 may have arisen by gene duplication of a more ancient proto-IDO gene before the divergence of marsupial and eutherian (placental) mammals.Other proteins that are evolutionarily related to IDO include myoglobin from the red muscle of the archaeogastropodic molluscs, Nordotis madaka (Giant abalone) and Sulculus diversicolor [, ]. These unusual globins lack enzymatic activity but have kept the heme group.
