title: Biochemical properties of indoleamine 2,3-dioxygenase: from structure to optimized design of inhibitors.
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 Fe(3+) 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 b(5)), requiring the single electron reduction of ferric-to-ferrous iron (Fe(3+)→Fe(2+)), which facilitates binding of L-Trp and O(2) 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.
authors.affiliation: Department of Internal Medicine & Geriatrics, Haemostasis Research Center, Catholic University School of Medicine, Largo Francesco Vito, Rome, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Lancellotti
authors.forename: L
authors.initials: L
authors.lastname: Novarese
authors.forename: R
authors.initials: R
authors.lastname: De Cristofaro
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D015870:Gene Expression; D006418:Heme / Q000737:chemistry; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D007737:Kynurenine / Q000378:metabolism; D008958:Models, Molecular; D011487:Protein Conformation; D014364:Tryptophan / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007737:Kynurenine; D006418:Heme; D014364:Tryptophan