Publications

• Redox reactions related to indoleamine 2,3-dioxygenase and tryptophan metabolism along the kynurenine pathway.

  Thomas S.R., Stocker R.

  The heme enzyme indoleamine 2,3-dioxygenase (IDO) oxidizes the pyrrole moiety of L-tryptophan (Trp) and other indoleamines and represents the initial and rate-limiting enzyme of the kynurenine (Kyn) pathway. IDO is a unique enzyme in that it can utilize superoxide anion radical (O2*-) as both a su ... >> More

  The heme enzyme indoleamine 2,3-dioxygenase (IDO) oxidizes the pyrrole moiety of L-tryptophan (Trp) and other indoleamines and represents the initial and rate-limiting enzyme of the kynurenine (Kyn) pathway. IDO is a unique enzyme in that it can utilize superoxide anion radical (O2*-) as both a substrate and a co-factor. The latter role is due to the ability of O2*-to reduce inactive ferric-IDO to the active ferrous form. Nitrogen monoxide (*NO) and H2O2 inhibit the dioxygenase and various inter-relationships between the nitric oxide synthase- and IDO-initiated amino acid degradative pathways exist. Induction of IDO and metabolism of Trp along the Kyn pathway is implicated in a variety of physiological and pathophysiological processes, including anti-microbial and anti-tumor defense, neuropathology, immunoregulation and antioxidant activity. Antioxidant activity may arise from O2*-scavenging by IDO and formation of the potent radical scavengers and Kyn pathway metabolites, 3-hydroxyanthranilic acid and 3-hydroxykynurenine. Under certain conditions, these aminophenols and other Kyn pathway metabolites may exhibit pro-oxidant activities. This article reviews findings indicating that redox reactions are involved in the regulation of IDO and Trp metabolism along the Kyn pathway and also participate in the biological activities exhibited by Kyn pathway metabolites. << Less

  Redox Rep 4:199-220(1999) [PubMed] [EuropePMC]

  This publication is cited by 1 other entry.

• Asp274 and his346 are essential for heme binding and catalytic function of human indoleamine 2,3-dioxygenase.

  Littlejohn T.K., Takikawa O., Truscott R.J., Walker M.J.

  L-Tryptophan is the least abundant essential amino acid in humans. Indoleamine 2,3-dioxgyenase (IDO) is a cytosolic heme protein which, together with the hepatic enzyme tryptophan 2,3-dioxygenase, catalyzes the first and rate-limiting step in the major pathway of tryptophan metabolism, the kynuren ... >> More

  L-Tryptophan is the least abundant essential amino acid in humans. Indoleamine 2,3-dioxgyenase (IDO) is a cytosolic heme protein which, together with the hepatic enzyme tryptophan 2,3-dioxygenase, catalyzes the first and rate-limiting step in the major pathway of tryptophan metabolism, the kynurenine pathway. The physiological role of IDO is not fully understood but is of great interest, because IDO is widely distributed in human tissues, can be up-regulated via cytokines such as interferon-gamma, and can thereby modulate the levels of tryptophan, which is vital for cell growth. To identify which amino acid residues are important in substrate or heme binding in IDO, site-directed mutagenesis of conserved residues in the IDO gene was undertaken. Because it had been proposed that a histidine residue might be the proximal heme ligand in IDO, mutation to alanine of the three highly conserved histidines His16, His303, and His346 was conducted. Of these, only His346 was shown to be essential for heme binding, indicating that this histidine residue may be the proximal ligand and suggesting that neither His303 nor His16 act as the proximal ligand. Site-directed mutagenesis of Asp274 also compromised the ability of IDO to bind heme. This observation indicates that Asp274 may coordinate to heme directly as the distal ligand or is essential in maintaining the conformation of the heme pocket. << Less

  J Biol Chem 278:29525-29531(2003) [PubMed] [EuropePMC]

• Indoleamine 2,3-dioxygenase-2; a new enzyme in the kynurenine pathway.

  Ball H.J., Yuasa H.J., Austin C.J., Weiser S., Hunt N.H.

  The kynurenine pathway of tryptophan metabolism converts the amino acid tryptophan into a number of biologically active metabolites. The first and rate-limiting step in this pathway is the conversion of tryptophan to N-formylkynurenine and until recently this reaction was thought to be performed b ... >> More

  The kynurenine pathway of tryptophan metabolism converts the amino acid tryptophan into a number of biologically active metabolites. The first and rate-limiting step in this pathway is the conversion of tryptophan to N-formylkynurenine and until recently this reaction was thought to be performed by either of two enzymes, tryptophan 2,3-dioxygenase and indoleamine 2,3-dioxygenase. A third enzyme, indoleamine 2,3-dioxygenase-2, indoleamine 2,3-dioxygenase-like protein or proto-indoleamine 2,3-dioxygenase (IDO2, IDO-2, INDOL1 or proto-IDO), with this activity recently has been described. The gene encoding IDO2 is adjacent and structurally similar to the indoleamine 2,3-dioxygenase gene and both mouse genes use multiple promoters to express transcripts with alternate 5' exons. The IDO2 protein is expressed in the murine kidney, liver, male and female reproductive system. The two IDO enzymes can utilise a similar range of substrates, however they differ in their selectivity for some inhibitors. The selective inhibition of IDO2 by 1-methyl-D-tryptophan suggests that IDO2 activity may have a role in the inhibition of immune responses to tumours. << Less

  Int J Biochem Cell Biol 41:467-471(2009) [PubMed] [EuropePMC]