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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Metabolic oxidation of the pyrrole ring: structure and origin of some urinary metabolites of the anti-hypertensive pyrrolylpyridazinamine, mopidralazine. III: Studies with the 13C-labelled drug.
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Investigation of the Impact of Tryptophan‐Metabolizing Enzymes and Kynurenic Acid on Antibody‐Mediated Glomerulonephritis
Umeda, R., Ito, Y., Minatoguchi, S., Koide, S., Takahashi, K., Hayashi, H., Hasegawa, M., Yuzawa, Y., Yamamoto, Y., Saito, K., et al. (2025) · The FASEB Journal · doi:10.1096/fj.202501800r · Cited by 5
“Indoleamine 2,3-dioxygenase (IDO), which has two isoforms—IDO1 and IDO2—serves as the rate-limiting enzyme in the kynurenine pathway [2, 3].”
Structural Basis of Selective Human Indoleamine‐2,3‐dioxygenase 1 (hIDO1) Inhibition
Kassab, S. E., & Mowafy, S. (2021) · ChemMedChem · doi:10.1002/cmdc.202100253 · Cited by 5
Shifts in the balance of brain tryptophan metabolism due to age and systemic administration of lipopolysaccharide
Miura, H., Shirokawa, T., Ozaki, N., & Isobe, K. (2010) · Health · doi:10.4236/health.2010.23032 · Cited by 4
“Because IDO can directly metabolize 5-HT [12], activated IDO may also decrease 5-HT levels [13].”
Background
Indoleamine 2,3‐Dioxygenase: Properties and Functions of a Superoxide Utilizing Enzyme
Hayaishi, O., Takikawa, O., & Yoshida, R. (2007) · doi:10.1002/9780470166390.ch2 · Cited by 4
Self-citation
Cloricromene effect on the enzyme activities of the tryptophan-nicotinic acid pathway in diabetic/hyperlipidemic rabbits.
Ragazzi, E., Costa, C., Comai, S., Bertazzo, A., Caparrotta, L., & Allegri, G. (2006) · Life Science · doi:10.1016/j.lfs.2005.05.077 · Cited by 4
VEEV TC-83 Triggers Dysregulation of the Tryptophan–Kynurenine Pathway in the Central Nervous System That Correlates with Cognitive Impairment in Tg2576 Mice
Fongsaran, C., Dineley, K. T., Paessler, S., & Cisneros, I. E. (2024) · Pathogens · doi:10.3390/pathogens13050397 · Cited by 3
RETRACTED: Physical activity and glioblastoma: a paradigm shift in neuro-oncology therapy
Xie, L., & Wang, F. (2025) · Frontiers in Oncology · doi:10.3389/fonc.2025.1638060 · Cited by 5
Retracted
Preliminary analyses of tryptophan, kynurenine, and the kynurenine: Tryptophan ratio in plasma, as potential biomarkers for systemic chlamydial infections in koalas
Chen, C.-J., Kimble, B., Aggelen, A. V., Fischer, S., Flanagan, C., Gillett, A. K., Reed, J., Wakeman, J., & Govendir, M. (2024) · PLoS ONE · doi:10.1371/journal.pone.0314945 · Cited by 2
Indoleamine-2,3-dioxygenase in murine and human systemic lupus erythematosus: Down-regulation by the tolerogeneic peptide hCDR1
Sthoeger, Z. M., Sharabi, A., Zinger, H., Asher, I., & Mozes, E. (2018) · Clinical Immunology · doi:10.1016/j.clim.2018.08.012 · Cited by 3
Possible occurrence of a β-carboline pathway in the oxidative catabolism of 5-hydroxytryptamine: Chemical approach and structure determination of a yellow substance and related β-carboline derivatives
Yamano, T., Miura, R., Kanashiro, M., & Uemura, T. (1988) · doi:10.1016/0045-2068(88)90008-9 · Cited by 3
Metabolic pathways of the anti-hypertensive agent, N-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(4-morpholinyl)-3-pyridazinamine hydrochloride. II: Studies in the dog.
Assandri, A., Perazzi, A., Bellasio, E., Ciabatti, R., Tarzia, G., Ferrari, P., Ripamonti, A., Tuan, G., & Zerilli, L. (1985) · Xenobiotica; the fate of foreign compounds in biological systems · doi:10.3109/00498258509049102 · Cited by 3
Kynurenine pathway enzymes in guinea pigs.
Allegri, G., Costa, C., Ragazzi, E., Bertazzo, A., & Biasiolo, M. (2003) · Advances in Experimental Medicine and Biology · doi:10.1007/978-1-4615-0135-0_54 · Cited by 3
EPR Detection of Nitrosylated Compounds : Introduction with some Historical Background
Henry, Y. A., & Guissani, A. (1998) · Springer eBooks · doi:10.1007/978-1-4615-5081-5_1 · Cited by 2
Occurrence of indoleamine 2,3-dioxygenase in human cutaneous malignant melanoma.
Bertazzo, A., Costa, C., Lise, M., Nitti, D., & Allegri, G. (1996) · Advances in Experimental Medicine and Biology · doi:10.1007/978-1-4613-0381-7_80 · Cited by 3
Hydroquinone simultaneously induces indole amine 2,3 dioxygenase (IOD) and inhibits tyrosinase in Bufo melanostictus
Chakraborty, A. K., CHAKRABORTY, D. P., & Chakraborty, D. P. (1993) · Life Sciences · doi:10.1016/0024-3205(93)90477-k · Cited by 4
The high-affinity tryptophan uptake transport system in human cells
Wakasugi, K., & Yokosawa, T. (2024) · Biochemical Society Transactions · doi:10.1042/bst20230742 · Cited by 4
Down-regulation of the indoleamine 2,3-dioxygenase (IDO) transcription by tryptophan analogues
Okamoto, T., Toné, S., Kanouchi, H., Ohyama, F., & Minatogawa, Y. (2007) · International Congress Series · doi:10.1016/j.ics.2007.07.015
Differential targeting of tryptophan catabolism in tumors and in tumor-draining lymph nodes by stereoisomers of the IDO inhibitor 1-methyl-tryptophan
Muller, A. J., Metz, R. A., & Prendergast, G. C. (2007) · International Congress Series · doi:10.1016/j.ics.2007.07.042 · Cited by 3
Reproductive Immunology – an Update
Poehlmann, T., Fitzgerald, J., Busch, S., Schleussner, E., Gutiérrez, G., Blois, S., Arck, P., Engert, S., Kämmerer, U., Szekeres-Bartho, J., et al. (2006) · Transfusion Medicine and Hemotherapy · doi:10.1159/000096044 · Cited by 2
Molecular Imaging of Tryptophan Metabolism in Tumors
Juhász, C., & Mittal, S. (2015) · doi:10.1007/978-3-319-11870-3_28 · Cited by 2
IDO in Immune Escape
Muller, A. J., Smith, C., Metz, R. A., & Prendergast, G. C. (2013) · Elsevier eBooks · doi:10.1016/b978-0-12-394296-8.00032-4 · Cited by 1
General Discussion: Crossregulations of Metalloenzymes Triggered by Nitric Oxide
Henry, Y. (1997) · Springer eBooks · doi:10.1007/978-1-4613-1185-0_15 · Cited by 2
Engineered indoleamine 2,3-dioxygenase variant: Oxidative activation of prodrug indole-3-acetic acid against cancer cells for targeted therapy
Liu, L., Li, W., & Ye, S. (2026) · Molecular Therapy Oncology · doi:10.1016/j.omton.2026.201310 · Cited by 1
“30,31 This finding is particularly relevant because the prodrug IAA is a structural derivative of indole.”
The neurotoxic branch of the kynurenine pathway is highly activated in the central nervous system of patients with pneumococcal meningitis
Cassiano, L. M. G., de Oliveira, D. B., Candiani, T. M. S., Campi‐Azevedo, A. C., Martins‐Filho, O. A., Kroon, E. G., Kohlhoff, M., & Coimbra, R. S. (2023) · Cytokine · doi:10.1016/j.cyto.2023.156237 · Cited by 1
In Memoriam: Osamu Hayaishi (1920–2015)
Narumiya, S., Shimizu, T., & Yamamoto, S. (2016) · Journal of Lipid Research · doi:10.1194/jlr.e067579 · Cited by 1
Self-citation
X-ray structure and reaction mechanism of human indoleamine 2,3-dioxygenase
Sugimoto, H., Oda, S., Otsuki, T., Yotsuya, K., Hino, T., Yoshida, T., & Shiro, Y. (2007) · International Congress Series · doi:10.1016/j.ics.2007.07.049 · Cited by 1
Editorial comment
Humphrey, M. (2003) · Australian and New Zealand Journal of Obstetrics and Gynaecology · doi:10.1034/j.1600-0897.2003.00093.x · Cited by 7
No evidence for a physiological role of 5-hydroxykynuramine in chicken hemostasis
Laekeman, G., Claeys, M., Vrints, M., & Herman, A. (1985) · Agents and Actions · doi:10.1007/bf01982886 · Cited by 1
Pyrroles and Their Benzo Derivatives: Structure
Dutta, I., Rachuri, Y., Gonçalves, T. P., Huang, M., & Huang, K. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-818655-8.00003-2
Regulação cruzada entre peroxidases e indolamina 2.3 dioxigenase no controle da metabolização do triptofano
Okada, S. S. (2011) · Universidade de São Paulo · doi:10.11606/t.9.2010.tde-21012011-151605 · Cited by 1
“Apesar de MLT ter sido considerada um substrato de IDO a partir dos primeiros trabalhos de Hayaishi e colaboradores (67, 87), esta ideia foi revista recentemente a partir do trabalho de Boutin e colaboradores (68) que Acido ascórbico Acido dihidro ascórbico”
A tryptophan pyrrole-ring cleavage enzyme in the most primitive eukaryote.
Iwamoto, Y., Lee, I. S. M., Tsubaki, M., & Kido, R. (1996) · Advances in Experimental Medicine and Biology · doi:10.1007/978-1-4613-0381-7_69 · Cited by 1
Tryptophan 2,3-dioxygenase
Schomburg, D., & Stephan, D. (1994) · doi:10.1007/978-3-642-57942-4_10 · Cited by 1
Janus Reactivity of a Mononuclear Non‐Heme Iron(III)‐Peroxo Complex Toward Indole Oxidation
Zhu, W., Wu, P., Wang, B.-J., Ray, K., & Nam, W. (2026) · Angewandte Chemie · doi:10.1002/anie.1874384
“In contrast, IDO features a less restrictive active site, allowing broader tolerance toward structurally diverse indole-containing substrates and related analogues, such as L-Trp, D-Trp, serotonin, melatonin, and tryptamine [16–19].”
Recombinant indoleamine 2,3-dioxygenase as a reliable alternative to HRP with enhanced cumulative output in immunoassays.
Liu, L.-R., & Ye, S. (2026) · Protein Expression and Purification · doi:10.1016/j.pep.2026.106952
Métabolisme du tryptophane : voie de la kynurénine
Launay, J., & Vodovar, N. (2026) · EMC - Biologie Médicale · doi:10.1016/s2211-9698(25)48374-5
Action mechanism and molecular design of indolepyrrodione inhibitors targeting IDO1
Wang, X.-M., Zhang, Z., Hu, K., Yu, W., Cheng, Y., Song, Y.-T., Sun, X., Li, S., Yang, T., Hu, J., et al. (2025) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2025.1661700
“Type I, exemplified by 1-methyl-L-tryptophan (1-MT), weakly competes with L-Trp in the distal heme (A) pocket and typically does not form a direct Fe coordination bond (Nakashima et al., 2008; Shimizu et al., 1978).”
Examination of Kynurenine Toxicity on Corneal and Conjunctival Epithelium: In vitro and in vivo Studies
Matysik-Woźniak, A., Turski, W., Turska, M., Paduch, R., Łańcut, M., Piwowarczyk, P., Czuczwar, M., Jünemann, A., & Rejdak, R. (2019) · Ophthalmic Research · doi:10.1159/000499021
Cholera Toxin Disrupts Oral Tolerance via NF-κB-mediated Downregulation of Indoleamine 2,3-dioxygenase Expression
Kim, K., & Im, S. (2017) · doi:10.15616/bsl.2017.23.3.175
“It has broad substrate specificity for various indoleamines including L-Trp, D-5OH-Kyn, L-5OH-Kyn, tryptamine and serotonin (Hayaishi 1996; Yamamoto and Hayaishi 1967; Shimizu et al., 1978).”
Background
Caracterização da fase inicial da artrite induzida pelo pristane em camundongos selecionados para alta ou baixa produção de anticorpos: envolvimento celular e molecular.
Rossato, C. (2012) · Digital Library of Theses and Dissertations (Universidade de São Paulo) · doi:10.11606/d.42.2012.tde-01082012-090046
Tryptophan Metabolite 3-Hydroxyanthranilic Acid Augments TRAIL-Induced Apoptosis in Activated T Cells
Seo, S. (2011) · Journal of Life Science · doi:10.5352/jls.2011.21.2.316 · Cited by 1
“IDO의 초기연구는 필수아미노산인 트립토판을 고갈시켜 세포내 기생균과 암세포의 증식을 억제하는 기능이 in vitro에서 보고되었다[21,22].”
The use of an amino acid as a precursor of a bioactive metabolite in combatting an infectious disease: The efficacy of a tryptophan-enriched diet in the treatment of leprosy
Mauron, J., Ganapati, R., Mahadevan, P., & Anantharaman, K. (1992) · Amino Acids · doi:10.1007/bf00805947

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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