Inhibition of indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase by β-carboline and indole derivatives

https://doi.org/10.1016/0003-9861(84)90579-4Get rights and content

Abstract

β-Carboline derivatives inhibited both indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase activities from various sources. Among them, norharman is most potent for both enzymes from mammalian sources. Kinetic studies revealed that norharman is uncompetitive (Ki = 0.12 mm) with l-tryptophan for rabbit intestinal indoleamine 2,3-dioxygenase, and linearly competitive (Ki = 0.29 mm) with l-tryptophan for mouse liver tryptophan 2,3-dioxygenase. In addition, some β-carbolines selectively inhibited one enzyme or the other. Pseudomonad tryptophan 2,3-dioxygenase was inhibited by a different spectrum of β-carbolines. Such a selective inhibition by the structure of substrate analogs is more evident by the use of indole derivatives. Indole-3-acetamide, indole-3-acetonitrile and indole-3-acrylic acid exhibited a potent inhibition for mammalian tryptophan 2,3-dioxygenase, while they moderately inhibited the pseudomonad enzyme. However, they showed no inhibition for indoleamine 2,3-dioxygenase. These results suggest the difference of the structures of the active sites among these enzymes from various sources.

References (23)

  • T. Shimizu et al.

    J. Biol. Chem

    (1978)
  • E. Frieden et al.

    Arch. Biochem. Biophys

    (1961)
  • Y. Watanabe et al.

    Biochem. Biophys. Res. Commun

    (1978)
  • S. Udenfriend et al.

    Biochem. Pharmacol

    (1958)
  • Y. Hashimoto et al.

    Phytochemistry

    (1975)
  • Y. Hashimoto et al.

    Phytochemistry

    (1976)
  • Y. Ishimura
  • G. Ballin

    J. Chromatogr

    (1964)
  • O.H. Lowry et al.

    J. Biol. Chem

    (1951)
  • N.S. Buckholtz et al.

    Biochem. Pharmacol

    (1977)
  • W.E. Müller et al.

    Pharmac. Biochem. Behav

    (1981)
  • Cited by (0)

    This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science and Culture of Japan, and by grants from the Japanese Foundation on Metabolism and Diseases, Fujiwara Memorial Foundation, the Japan Heart Foundation and Shimadzu Science Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    View full text