Evolution of Vertebrate Indoleamine 2,3-Dioxygenases

Abstract

Indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) are tryptophan-degrading enzymes that catalyze the same reaction, the first step in tryptophan catabolism via the kynurenine pathway. TDO is widely distributed among life-forms, being found not only in eukaryotes but also in bacteria. In contrast, IDO has been found only in mammals and yeast to date. However, recent genome and EST projects have identified IDO homologues in non-mammals and found an IDO paralogue that is expressed in mice. In this study, we cloned the frog and fish IDO homologues and the mouse IDO paralogue, and characterized their enzymatic properties using recombinants. The IDOs of lower vertebrates and the mouse IDO paralogue had IDO activity but had 500-1000 times higher K(m) values and very low enzyme efficiency compared with mammalian IDOs. It appears that L-Trp is not a true substrate for these enzymes in vivo, although their actual function is unknown. On the phylogenetic tree, these low-activity IDOs, which we have named "proto-IDOs," formed a cluster that was distinct from the mammalian IDO cluster. The IDO and proto-IDO genes are present tandemly on the chromosomes of mammals, including the marsupial opossum, whereas only the proto-IDO gene is observed in chicken and fish genomes. These results suggest that (mammalian) IDOs arose from proto-IDOs by gene duplication that occurred before the divergence of marsupial and eutherian (placental) mammals in mammalian evolutionary history.

The Kynurenine Pathway in Brain Tumor Pathogenesis

“…Structurally similar to IDO-1, IDO-2 is encoded by a gene downstream of the IDO-1 gene (14). TDO-2, which is primarily expressed within the liver (17)(18)(19), but also expressed in a variety of other tissues including the brain (18,(20)(21)(22)(23), catabolises the majority of dietary tryptophan for the maintenance of basal serum levels (24) and is induced by the availability of dietary tryptophan as well as tyrosine, histidine, glucocorticoids, and kynurenine (25,26).…”

Expression von Indolamin 2,3-dioxygenase in der Plazenta

“…In contrast to IDO, it is not blocked by 1-methyltryptophan and thus may not exclusively assume the role originally attributed to IDO in pregnancy. Recently, indoleamine 2,3-dioxygenase 2 (IDO2), an enzyme with high homology to IDO (henceforth named IDO1) has been described [32][33][34][35]. Its tryptophan-degrading activity is probably much lower as compared to IDO1.…”

Indoleamine 2,3-dioxygenase: First evidence of expression in rainbow trout (Oncorhynchus mykiss)

“…84 Some years ago, it was thought that this enzyme was present only in higher 85 vertebrates. However, Yuasa et al (2007) described IDO2 in the genome of zebra fish 86 (Danio rerio). Functional analysis showed that the molecule presented a K m for L-TRP 87 approximately 500 to 1000 times higher than the mammal isoform and it was assumed 88 that IDO1 probably evolved from IDO2, improving its specificity for tryptophan (Yuasa 89 et al, 2007).…”