Cited by 367Metal-Catalyzed Oxygenation MechanismsAmino Acid Enzymes and MetabolismHemoglobin structure and function

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Indoleamine 2,3-dioxygenase. Purification and some properties

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Shimizu, T., Nomiyama, S., Hirata, F., Hayaishi, O.·1978·Journal of Biological Chemistry

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Abstract

Indoleamine 2,3-dioxygenase was purified from rabbit small intestine to apparent homogeneity as judged by polyacrylamide gel electrophoresis and analytical ultracentrifugation. The native enzyme was a monomeric protein of a molecular weight of 41,000 +/- 1,000 with an s020,w value of 3.45 S. It had a relative abundance of hydrophobic amino acids such as valine, leucine, and isoleucine, and contained approximately 5% carbohydrate by weight. The estimated content of sugar residues per mol of enzyme was: galactose, 1.2; mannose, 2.6; N-acetylglucosamine, 5.2; and sialic acid, 0.8. One mole of enzyme had 0.8 mol of protoheme IX as a prosthetic group. However, copper was not detected in a significant amount and the ratio of copper to heme was less than 0.03. EPR spectra of the nitric oxide complex of the ferrous enzyme indicated that a nitrogen atom, possibly in an imidazole group, might be coordinated as the fifth ligand of the heme coenzyme. The anisotropic g values were gx = 2.08, gy = 1.98, and gz = 2.01. A single enzyme protein catalyzed the oxygenative ring cleavage of D- and L-tryptophan, D- and L-5-hydroxytryptophan, tryptamine, and serotonin. In addition, the purified enzyme had a peroxidase activity with guaiacol and potassium iodide as hydrogen donors, but not a catalase activity.

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Background
Tumor Cell IDO Enhances Immune Suppression and Decreases Survival Independent of Tryptophan Metabolism in Glioblastoma
Zhai, L., Bell, A., Ladomersky, E., Lauing, K. L., Bollu, L., Nguyen, B., Genet, M., Kim, M., Chen, P., Mi, X., et al. (2021) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-21-1392 · Cited by 129
“IDO is canonically characterized as a rate-limiting immunosuppressive enzyme that converts the essential amino acid, tryptophan (Trp), into downstream metabolites that are collectively referred to as kynurenines (Kyn) (9).”
Background
Singlet molecular oxygen regulates vascular tone and blood pressure in inflammation
Stanley, C. P., Maghzal, G., Ayer, A., Talib, J., Giltrap, A. M., Shengule, S., Wolhuter, K., Wang, Y.-T., Chadha, P., Suarna, C., et al. (2019) · Nature · doi:10.1038/s41586-019-0947-3 · Cited by 103
Antimicrobial and immunoregulatory properties of human tryptophan 2,3‐dioxygenase
Schmidt, S. K., Müller, A., Heseler, K., Woite, C., Spekker, K., MacKenzie, C. R., & Däubener, W. (2009) · European Journal of Immunology · doi:10.1002/eji.200939535 · Cited by 99
Molecular evidence that melatonin is enzymatically oxidized in a different manner than tryptophan: investigations with both indoleamine 2,3-dioxygenase and myeloperoxidase.
Ferry, G., Ubeaud, C., Lambert, P., Bertin, S., Cogé, F., Chomarat, P., Delagrange, P., Serkiz, B., Bouchet, J., Truscott, R., et al. (2005) · Biochemical Journal · doi:10.1042/bj20042075 · Cited by 95
Tumor Necrosis Factor-alpha and Lipopolysaccharide Enhance Interferon-Induced Antichlamydial Indoleamine Dioxygenase Activity Independently
Currier, A. R., Ziegler, M., Riley, M., Babcock, T., Telbis, V. P., & Carlin, J. (2000) · Journal of Interferon and Cytokine Research · doi:10.1089/107999000312306 · Cited by 92
Metabolomics and Metabolic Reprogramming in Kidney Cancer
Weiss, R. H. (2018) · Seminars in Nephrology · doi:10.1016/j.semnephrol.2018.01.006 · Cited by 110
1-Methyl-Tryptophan Can Interfere with TLR Signaling in Dendritic Cells Independently of IDO Activity
Agaugué, S., Perrin‐Cocon, L., Coutant, F., André, P., & Lotteau, V. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.4.2061 · Cited by 87
Modulation of cellular tryptophan metabolism in human fibroblasts by transforming growth factor-β: Selective inhibition of indoleamine 2,3-dioxygenase and tryptophanyl-tRNA synthetase gene expression
Yuan, W., Collado-Hidalgo, A., Yufit, T., Taylor, M. W., & Varga, J. (1998) · Journal of Cellular Physiology · doi:10.1002/(sici)1097-4652(199810)177:1 · Cited by 85
Interferons and indoleamine 2,3-dioxygenase: Role in antimicrobial and antitumor effects
Carlin, J. M., Ozaki, Y., Byrne, G. I., Brown, R. R., & Borden, E. C. (1989) · Experientia · doi:10.1007/bf01990503 · Cited by 87
Beta interferon inhibits Toxoplasma gondii growth in human monocyte-derived macrophages
Schmitz, J., Carlin, J. M., Borden, E. C., & Byrne, G. I. (1989) · Infection and Immunity · doi:10.1128/iai.57.10.3254-3256.1989 · Cited by 86
“IDO has been shown to mediate the inhibition by catalyzing the decyclization of tryptophan to N-formylkynurenine (12), thus depriving the infecting organism of the essential amino acid tryptophan (9).”
Background
Tryptophan metabolite 3-hydroxyanthranilic acid selectively induces activated T cell death via intracellular GSH depletion
Lee, S., Lee, Y.-S., Choi, J.-H., Park, S.-G., Choi, I., Joo, Y., Lee, W.-S., Lee, J.-N., Choi, I., & Seo, S. (2010) · Immunology Letters · doi:10.1016/j.imlet.2010.05.008 · Cited by 82
“Indoleamine 2,3-dioxygenase (IDO) is a cytoplasmic enzyme hat converts tryptophan to catabolic products, collectively known s kynurenines [1,2].”
Background
ONIOM Study on a Missing Piece in Our Understanding of Heme Chemistry: Bacterial Tryptophan 2,3-Dioxygenase with Dual Oxidants
Chung, L. W., Li, X., Sugimoto, H., Shiro, Y., & Morokuma, K. (2010) · Journal of the American Chemical Society · doi:10.1021/ja103530v · Cited by 100
Indoleamine 2,3-Dioxygenase, an Emerging Target for Anti-Cancer Therapy
Liu, X., Newton, R., Friedman, S., & Scherle, P. (2009) · Current Cancer Drug Targets · doi:10.2174/156800909790192374 · Cited by 83
Oxidation of L-tryptophan in biology: a comparison between tryptophan 2,3-dioxygenase and indoleamine 2,3-dioxygenase.
Rafice, S. A., Chauhan, N., Efimov, I., Basran, J., & Raven, E. (2009) · Biochemical Society Transactions · doi:10.1042/bst0370408 · Cited by 83
In Vivo Uptake and Metabolism of α-[11C]Methyl- l -Tryptophan in Human Brain Tumors
Juhász, C., Chugani, D. C., Muzik, O., Wu, D., Sloan, A. E., Barger, G. R., Watson, C. E., Shah, A. K., Sood, S., Ergün, E. L., et al. (2005) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/sj.jcbfm.9600199 · Cited by 93
Identification of Tryptophan 2,3‐Dioxygenase RNA in Rodent Brain
Haber, R., Bessette, D., Hulihan-Giblin, B. A., Durcan, M. J., & Goldman, D. A. (1993) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1993.tb03269.x · Cited by 81
Immunological Relevance of the Coevolution of IDO1 and AHR
Jaronen, M., & Quintana, F. J. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00521 · Cited by 85
“Indoleamine-2,3-dioxygenase (IDO1), tryptophan2,3-dioxygenase (TDO), and recently discovered IDO-related enzyme IDO2 (54) are the first and rate-limiting enzymes converting tryptophan to N -formylkynurenine (55, 56) which is then metabolized to l-kynurenine.”
Background
Possible roles of excess tryptophan metabolites in cancer
Chung, K., & Gadupudi, G. S. (2010) · Environmental and Molecular Mutagenesis · doi:10.1002/em.20588 · Cited by 81
“Although both TDO and IDO catalyze the same reaction [Shimizu et al., 1978; Yamazaki et al., 1985], TDO is highly substrate-specific, only dioxygenating L-tryptophan and some tryptophan derivatives substituted in the five- and six-positions.”
Background
Redox and spectroscopic properties of human indoleamine 2,3-dioxygenase and a His303Ala variant: implications for catalysis.
Papadopoulou, N. D., Mewies, M., McLean, K., Seward, H. E., Svistunenko, D., Munro, A., & Raven, E. (2005) · Biochemistry · doi:10.1021/bi0513958 · Cited by 78
Enzyme kinetic and spectroscopic studies of inhibitor and effector interactions with indoleamine 2,3-dioxygenase. 1. Norharman and 4-phenylimidazole binding to the enzyme as inhibitors and heme ligands.
Sono, M., & Cady, S. G. (1989) · Biochemistry · doi:10.1021/bi00439a012 · Cited by 78
The Role of the Kynurenine Signaling Pathway in Different Chronic Pain Conditions and Potential Use of Therapeutic Agents
Jovanović, F., Candido, K. D., & Knežević, N. N. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21176045 · Cited by 86
Interleukin-1 Enhances Indoleamine 2,3-Dioxygenase Activity by Increasing Specific mRNA Expression in Human Mononuclear Phagocytes
Hu, B., Hissong, B. D., & Carlin, J. M. (1995) · Journal of Interferon & Cytokine Research · doi:10.1089/jir.1995.15.617 · Cited by 80
Tryptophan Catabolism Restricts IFN-γ-expressing Neutrophils and Clostridium difficile Immunopathology
El-zaatari, M., Chang, Y.-M., Zhang, M. F., Franz, M., Shreiner, A., McDermott, A. J., van der Sluijs, K. F., Lutter, R., Grasberger, H., Kamada, N., et al. (2014) · Journal of Immunology · doi:10.4049/jimmunol.1302913 · Cited by 75
Upregulation of IFN-γ Receptor Expression by Proinflammatory Cytokines Influences IDO Activation in Epithelial Cells
Shirey, K. A., Jung, J., Maeder, G. S., & Carlin, J. M. (2006) · Journal of Interferon & Cytokine Research · doi:10.1089/jir.2006.26.53 · Cited by 80
“IDO catalyzes the decyclization of L -tryptophan into N -formylkynurenine, 5 thereby limiting the availability of this essential amino acid and, consequently, inhibiting the growth of tryptophan auxotrophs.”
A Perspective on the Safety of Supplemental Tryptophan Based on Its Metabolic Fates.
Fernstrom, J. (2016) · Journal of NutriLife · doi:10.3945/jn.115.228643 · Cited by 74
A high-affinity, tryptophan-selective amino acid transport system in human macrophages
Seymour, R. L., Ganapathy, V., Mellor, A. L., & Munn, D. H. (2006) · Journal of Leukocyte Biology · doi:10.1189/jlb.1205727 · Cited by 69
Inhibition of indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase by β-carboline and indole derivatives☆
Eguchi, N., Watanabe, Y., Kawanishi, K., Hashimoto, Y., & Hayaishi, O. (1984) · Archives of Biochemistry and Biophysics · doi:10.1016/0003-9861(84)90579-4 · Cited by 73
Self-citation
NF-κB activation contributes to indoleamine dioxygenase transcriptional synergy induced by IFN-γ and tumor necrosis factor-α
Robinson, C. M., Hale, P. T., & Carlin, J. M. (2006) · Cytokine · doi:10.1016/j.cyto.2006.07.007 · Cited by 73
Comparative effects of oxygen on indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase of the kynurenine pathway.
Dang, Y.-H., Dale, W. E., & Brown, O. R. (2000) · Free Radical Biology & Medicine · doi:10.1016/s0891-5849(99)00272-5 · Cited by 72
Indoleamine-2,3-dioxygenase, an immunosuppressive enzyme that inhibits natural killer cell function, as a useful target for ovarian cancer therapy
WANG, D., Saga, Y., Mizukami, H., Sato, N., NONAKA, H., Fujiwara, H., Takei, Y., 町田, 静., Takikawa, O., Ozawa, K., et al. (2011) · International Journal of Oncology · doi:10.3892/ijo.2011.1295 · Cited by 74
“IDO was originally discovered in 1967 (7,8) in the rabbit small intestine and was first purified in 1978 (9).”
Background
Biochemical characteristics and inhibitor selectivity of mouse indoleamine 2,3-dioxygenase-2
Austin, C. J. D., Mailu, B. M., Maghzal, G., Sánchez-Pérez, Á., Rahlfs, S., Zocher, K., Yuasa, H., Arthur, J. W., Becker, K., Stocker, R., et al. (2010) · Amino Acids · doi:10.1007/s00726-010-0475-9 · Cited by 71
Tryptophan metabolism in breast cancers: molecular imaging and immunohistochemistry studies
Juhász, C., Nahleh, Z. A., Zitron, I. M., Chugani, D. C., Janabi, M., Bandyopadhyay, S., Ali‐Fehmi, R., Mangner, T. J., Chakraborty, P. K., Mittal, S., et al. (2012) · Nuclear Medicine and Biology · doi:10.1016/j.nucmedbio.2012.01.010 · Cited by 78
“However, it is a substrate for TPH (leading to synthesis of alpha-methyl-serotonin) [19,20] and IDO (due to its low substrate specificity) [21,22].”
Background
Research Progress of Indoleamine 2,3-Dioxygenase Inhibitors
Jiang, T., Sun, Y., Yin, Z., Feng, S., Sun, L., & Li, Z. (2015) · Future Medicinal Chemistry · doi:10.4155/fmc.14.151 · Cited by 73
Asp274 and His346 Are Essential for Heme Binding and Catalytic Function of Human Indoleamine 2,3-Dioxygenase*
Littlejohn, T., Takikawa, O., Truscott, R., & Walker, M. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m301700200 · Cited by 69
Analysis of Transcription Factors Regulating Induction of Indoleamine 2,3-Dioxygenase by IFN- gamma
Du, M. X., Sotero-Esteva, W. D., & Taylor, M. W. (2000) · Journal of Interferon & Cytokine Research · doi:10.1089/107999000312531 · Cited by 67
“(25,38) Substantial increases in the tryptophan-kynurenine pathway metabolites, 1-kynurenine and the neuro-toxin quinolinic acid, occur in human brain, blood, and systemic tissues during immune activation.”
Type I Interferon-Mediated Skewing of the Serotonin Synthesis Is Associated with Severe Disease in Systemic Lupus Erythematosus
Lood, C., Tydén, H., Gullstrand, B., Klint, C., Wenglén, C., Nielsen, C., Heegaard, N., Jönsen, A., Kahn, R., & Bengtsson, A. (2015) · PLoS ONE · doi:10.1371/journal.pone.0125109 · Cited by 67
“Interestingly, even though IDO mainly catalyzes the conversion of tryptophan into kynurenine, several other IDO substrates have been described, including serotonin itself [44].”
Background
The Kynurenine Pathway in Stem Cell Biology
Jones, S. P., Guillemin, G. J., & Brew, B. J. (2013) · International Journal of Tryptophan Research · doi:10.4137/ijtr.s12626 · Cited by 76
Characterization and evolution of vertebrate indoleamine 2, 3-dioxygenases
Yuasa, H. J., Ball, H. J., Ho, Y. F., Austin, C., Whittington, C. M., Belov, K., Maghzal, G. J., Jermiin, L. S., & Hunt, N. H. (2009) · Comparative Biochemistry and Physiology Part B Biochemistry and Molecular Biology · doi:10.1016/j.cbpb.2009.02.002 · Cited by 72
The niacin required for optimum growth can be synthesized from L-tryptophan in growing mice lacking tryptophan-2,3-dioxygenase.
Terakata, M., Fukuwatari, T., Kadota, E., Sano, M., Kanai, M., Nakamura, T., Funakoshi, H., & Shibata, K. (2013) · Journal of NutriLife · doi:10.3945/jn.113.176875 · Cited by 65
The Mechanism of Substrate Inhibition in Human Indoleamine 2,3-Dioxygenase
Efimov, I., Basran, J., Sun, X., Chauhan, N., Chapman, S., Mowat, C., & Raven, E. (2012) · Journal of the American Chemical Society · doi:10.1021/ja208694g · Cited by 65
Indoleamine and tryptophan 2,3-dioxygenases as important future therapeutic targets
Dolšak, A., Gobec, S., & Sova, M. (2020) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2020.107746 · Cited by 73

Authors: Shimizu, T., Nomiyama, S., Hirata, F., & Hayaishi, O.
Affiliations: Kyoto University (JP)
ORCID: Shimizu, T.
Hirata, F.
Venue: Journal of Biological Chemistry
Publisher: Elsevier BV
Published: 1978-07
Volume: 253
Issue: 13
Pages: 4700-4706
ISSN: 0021-9258 (ISSN-L)
DOI: 10.1016/s0021-9258(17)30447-7
OpenAlex: W1607682771
Cited by: 367
References: 38
Citations by year: 2026: 4 · 2025: 6 · 2024: 6 · 2023: 5 · 2022: 3 · 2021: 14 · 2020: 9 · 2019: 10 · 2018: 9 · 2017: 13 · 2016: 15 · 2015: 12 · 2014: 13 · 2013: 12 · 2012: 20
FWCI: 5.77
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 15461 d)
Locations: Journal of Biological Chemistry (publishedVersion, cc-by)
PubMed (publishedVersion)
Topics: Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Hemoglobin structure and function
Keywords: indoleamine 2,3-dioxygenase, enzyme purification, rabbit small intestine, protoheme, sialic acid, carbohydrate content, protein secondary structure, electron spin resonance, tryptophan oxidation, serotonin oxidation, peroxidase activity, guaiacol
MeSH terms: Amino Acids, Animals, Electrophoresis, Disc, Hexoses, Hydrogen-Ion Concentration, Indoles, Intestine, Small, Molecular Weight, Oxygenases, Rabbits, Seasons, Substrate Specificity

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Indoleamine 2,3-dioxygenase. Purification and some properties

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