Abstract
The enzyme indoleamine 2,3-dioxygenase (IDO, EC 1.13.11.42) belongs to the family of heme-containing oxidoreductases and catalyzes the first and rate-limiting step in the kynurenine pathway, the major pathway of tryptophan metabolism. IDO is folded into one large and one small distinct α-helical domains, with the heme prosthetic ring positioned between them. The enzyme, through the oxidative properties of the Fe3+ atom present at the centre of the heme ring, catalyses the oxidative cleavage of the pyrrole ring of L-Trp to generate N-formyl-kynurenine. The active IDO conformer exists only in the presence of reducing cofactors (such as cytochrome b5), requiring the single electron reduction of ferric-to-ferrous iron (Fe3+ Fe2+), which facilitates binding of L-Trp and O2 to the enzyme active site. IDO, through production of kynurenine and other downstream metabolites, can regulate immune responses, suppressing effector T-cell function and favouring the differentiation of regulatory T cells. Local expression of the enzyme during inflammation is another self-protection mechanism, which limits antigen-specific immune responses, especially in some organs, as the central nervous system. The detailed knowledge of the structural and functional properties of IDO, was a fundamental step to design and develop new molecules for the pharmacological inhibition of IDO activity in several clinical settings.
Keywords: Indoleamine 2,3-dioxygenase, Immune tolerance, X-ray structure of oxygenases, enzyme, heme-containing oxidoreductases, kynurenine, tryptophan metabolism, helical domains, N-formyl-kynurenine, IDO
Current Medicinal Chemistry
Title: Biochemical Properties of Indoleamine 2,3-dioxygenase: From Structure to Optimized Design of Inhibitors
Volume: 18 Issue: 15
Author(s): S. Lancellotti, L. Novarese and R. De Cristofaro
Affiliation:
Keywords: Indoleamine 2,3-dioxygenase, Immune tolerance, X-ray structure of oxygenases, enzyme, heme-containing oxidoreductases, kynurenine, tryptophan metabolism, helical domains, N-formyl-kynurenine, IDO
Abstract: The enzyme indoleamine 2,3-dioxygenase (IDO, EC 1.13.11.42) belongs to the family of heme-containing oxidoreductases and catalyzes the first and rate-limiting step in the kynurenine pathway, the major pathway of tryptophan metabolism. IDO is folded into one large and one small distinct α-helical domains, with the heme prosthetic ring positioned between them. The enzyme, through the oxidative properties of the Fe3+ atom present at the centre of the heme ring, catalyses the oxidative cleavage of the pyrrole ring of L-Trp to generate N-formyl-kynurenine. The active IDO conformer exists only in the presence of reducing cofactors (such as cytochrome b5), requiring the single electron reduction of ferric-to-ferrous iron (Fe3+ Fe2+), which facilitates binding of L-Trp and O2 to the enzyme active site. IDO, through production of kynurenine and other downstream metabolites, can regulate immune responses, suppressing effector T-cell function and favouring the differentiation of regulatory T cells. Local expression of the enzyme during inflammation is another self-protection mechanism, which limits antigen-specific immune responses, especially in some organs, as the central nervous system. The detailed knowledge of the structural and functional properties of IDO, was a fundamental step to design and develop new molecules for the pharmacological inhibition of IDO activity in several clinical settings.
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Lancellotti S., Novarese L. and De Cristofaro R., Biochemical Properties of Indoleamine 2,3-dioxygenase: From Structure to Optimized Design of Inhibitors, Current Medicinal Chemistry 2011; 18 (15) . https://dx.doi.org/10.2174/092986711795656108
DOI https://dx.doi.org/10.2174/092986711795656108 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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