Biochemical properties of indoleamine 2,3-dioxygenase: from structure to optimized design of inhibitors

Raimondo De Cristofaro, Linda Novarese, Sara Quinn Lancellotti

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)2205-2214
Number of pages10
JournalCURRENT MEDICINAL CHEMISTRY
Volume18
Publication statusPublished - 2011

Keywords

  • Animals
  • Crystallography, X-Ray
  • Enzyme Inhibitors
  • Gene Expression
  • Heme
  • Humans
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Kynurenine
  • Models, Molecular
  • Protein Conformation
  • Tryptophan

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