1-methyl-dl-tryptophan, β-(3-benzofuranyl)-dl-alanine (the oxygen analog of tryptophan), and β-[3-benzo(b)thienyl]-dl-alanine (the sulfur analog of tryptophan) are competitive inhibitors for indoleamine 2,3-dioxygenase

doi:10.1016/0003-9861(91)90142-6

Archives of Biochemistry and Biophysics

Volume 291, Issue 2, December 1991, Pages 326-333

https://doi.org/10.1016/0003-9861(91)90142-6 Get rights and content

Abstract

1-methyl-dl-Trp, β-(3-benzofuranyl)-dl-alanine (the oxygen analog of Trp), and β-[3-benzo(b)thienyl]-dl-al-anine (the sulfur analog of Trp), each of which has a substitution at the indole nitrogen atom, were found to be the first examples of potent substrate analog competitive inhibitors (K_i 7–70 μM) with respect to the substrates d-Trp and l-Trp for rabbit small intestinal indoleamine 2,3-dioxygenase. Binding studies using optical absorption and CD spectroscopy demonstrated that these three inhibitors cause spectral changes upon binding to the native ferric, ferrous, ferrous-CO, and ferrous-NO enzymes. Such spectral effects of 1-methyl-dl-Trp on all of these enzyme derivatives were similar to those caused by l-Trp, while the sulfur and the oxygen analogs of Trp exhibit relatively small effects except for those observed for the sulfur analog with CD spectroscopy. Each of these three Trp analog inhibitors competes with l-Trp for the ferrous-CO enzyme, a model for the ferrous-O₂ enzyme. The present findings demonstrate that, although substitution of a methyl group for the hydrogen atom on the indole nitrogen or of a more electron-inductive sulfur or oxygen atom for the indole nitrogen atom does not prevent the binding of the resulting Trp analog to indoleamine 2,3-dioxygenase, the free form of the indole nitrogen base is an important physical and/or electronic structural requirement for Trp to be metabolized by the enzyme. The inability of 1-methyl-Trp to serve as a substrate for the dioxygenase supports a view that singlet oxygen is not the reactive oxygen species involved in the dioxygenation of Trp by the enzyme.

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^☆: Supported by United States Public Health Service Grant GM 37806 (M.S.)

²: Portions of this work have been presented by S.G.C. in partial fulfillment of the Ph.D. requirements at the University of South Carolina. Present address: Department of Chemistry, Arkansas State University, State University, AR 72467-0419.

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1-methyl-dl-tryptophan, β-(3-benzofuranyl)-dl-alanine (the oxygen analog of tryptophan), and β-[3-benzo(b)thienyl]-dl-alanine (the sulfur analog of tryptophan) are competitive inhibitors for indoleamine 2,3-dioxygenase☆

Abstract

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