7.4.2 Biological Functions of Indoleamine 2,3-diox...
IDO is a cytosolic monomeric hemoprotein of 403 aa long (MW45,324 kDa) that catalyses the first step in tryptophan catabolism by the kynurenine pathway.In humans, the kynurenine pathway catabolizes over 90% of tryptophan.The reaction is initiated by the oxidative cleavage of the tryptophan 2-3 double bond resulting in the production of N-formylkynurenine.This leads to further catabolic events mediated by other enzymes that result in many downstream metabolites with 3-hydroxyanthranilic acid, kynurenate and quinolinate being the most important due to their toxicity on cellular function.The conversion of tryptophan to N-formylkynurenine is catalyzed by IDO, whereby firstly IDO is bound by the substrate and secondly the IDO-tryptophan complex is then bound by oxygen to form an IDO-O2-complex (ternary complex).This complex is then converted to N-formylkynurenine.Only His346 is essential for heme binding, indicating that this histidine residue may be the proximal ligand.Moreover, sitedirected mutagenesis of Asp274 compromised the ability of IDO to bind heme.Thus, both His346 and Asp274 appear essential for the binding of heme and thus for IDO enzymatic activity [19].(https://www.daowen.com)
Human IDO gene spans 15 kb with 10 exons.The 5 terminus of the IDO mRNA is 33 nucleotides upstream of the translation initiation codon ATG .Southern blot analysis indicated that IDO is present as a single copy.By examining a series of human/Chinese hamster cell hybrids for the presence of the human IDO gene by PCR and Southern blot, the gene is located in the pericentromeric region of human chromosome 8, probably 8p11-q11.This was subsequently narrowed to 8p12-p11 by fluorescence in situ hybridization.The promoter region of human and murine IDO contains regulatory motifs conferring responsiveness to inflammatory cytokines.These motifs include in both promoters two interferon-stimulated response elements (ISRE), a single interferon-activating site (GAS) and the interferon gamma (IFN-) response region of MHC-II promoters X and Y box-like motif.These findings suggest that IDO was primarily used as an inflammatory agent, limiting microbial infections, and only later during evolution it acquired an immunoregulatory role [19].