Tryptophan-catabolizing enzymes - party of three

Abstract

Indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) are tryptophan-degrading enzymes that have independently evolved to catalyze the first step in tryptophan catabolism via the kynurenine pathway (KP). The depletion of tryptophan and formation of KP metabolites modulates the activity of the mammalian immune, reproductive, and central nervous systems. IDO and TDO enzymes can have overlapping or distinct functions depending on their expression patterns. The expression of TDO and IDO enzymes in mammals differs not only by tissue/cellular localization but also by their induction by distinct stimuli. To add to the complexity, these genes also have undergone duplications in some organisms leading to multiple isoforms of IDO or TDO. For example, many vertebrates, including all mammals, have acquired two IDO genes via gene duplication, although the IDO1-like gene has been lost in some lower vertebrate lineages. Gene duplications can allow the homologs to diverge and acquire different properties to the original gene. There is evidence for IDO enzymes having differing enzymatic characteristics, signaling properties, and biological functions. This review analyzes the evolutionary convergence of IDO and TDO enzymes as tryptophan-catabolizing enzymes and the divergent evolution of IDO homologs to generate an enzyme family with diverse characteristics not possessed by TDO enzymes, with an emphasis on the immune system.

Keywords: convergent evolution; divergent evolution; gene duplication; immunoregulation; indoleamine 2,3-dioxygenase; tryptophan 2,3-dioxygenase.

Figure 1

A conceptual diagram depicting the overlapping activities of IDO and TDO enzymes and the distinct characteristics of some IDO homologs.

Figure 2

Phylogenetic relationships of known TDOs constructed with the maximum-likelihood method (unrooted tree). Multiple sequence alignment at the amino acid level was generated using the MUSCLE program (3) and the ML tree was constructed using MEGA 6 (4). The internal branch labels are bootstrap values with 100 replications. D. rerio (D. rer) and S. purpuratus (S. pur) have two TDOs. A few bacteria, Myxococcus xanthus (M. xan), Ralstonia solanacearum GMI1000 (R. sal), R. eutropha JMP134 (R. eut), and Xanthomonas campestris 33913 (X. cam), also have two TDOs. A complete tree, with names of all species, is shown in Figure S1 in Supplementary Material.

Figure 3

Phylogenetic relationships of known IDOs and IDO-related proteins constructed with the maximum-likelihood method (unrooted tree). Multiple sequence alignment at the amino acid level was generated using the MUSCLE program (3) and the ML tree was constructed using MEGA 6 (4). The internal branch labels are bootstrap values with 100 replications. The Medaka-fish, Oryzias latipes (O. lat) and a soft-shelled turtle, Pelodiscus sinensis (P. sin) have a putative IDO1. A complete tree, with names of all species, is shown in Figure S2 in Supplementary Material.

Figure 4

Schematic representation of amino acid alignments for selected IDO and TDO proteins. Amino acid contigs are shown as red (IDO) or blue (TDO) boxes, and positions of introns indicated by thick vertical bars. Gaps less than two amino acids in the alignments were omitted. Selected sequences are from human beings, frog (Xenopus tropicalis), chicken (Gallus gallus), zebrafish (Danio rerio), and abalone (Haliotis diversicolor).