Review
Biochemical and medical aspects of the indoleamine 2,3-dioxygenase-initiated l-tryptophan metabolism☆

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Abstract

Indoleamine 2,3-dioxygenase (EC 1.13.11.42) is a heme-containing dioxygenase which catalyzes the first and rate-limiting step in the major pathway of l-tryptophan catabolism in mammals. Much attention has recently been focused on the dioxygenase because this metabolic pathway is involved not only in a variety of physiological functions but also in many diseases. In this review, the discovery and unique catalytic properties of dioxygenase are described first, and then the recent findings regarding the dioxygenase-initiated tryptophan metabolism are summarized, with special emphasis on the detrimental role of dioxygenase in side effects of interferon-γ and interleukin-12 (by systemic tryptophan depletion), the escape of malignant tumors from immune surveillance (by immunosuppression caused by tryptophan depletion), several neurodegenerative disorders including Alzheimer’s disease (by an aberrant production of neurotoxin, quinolinic acid), and age-related cataract (due to “Kynurenilation,” a novel post-translational modification of lens proteins with tryptophan-derived UV filters).

Section snippets

Discovery of IDO

l-Tryptophan (Trp) is the least abundant of the essential amino acids for mammals. It is utilized not only for protein synthesis but also for the synthesis of a neurotransmitter, serotonin. A small part of serotonin is further converted into melatonin in the pineal body in the brain. It is well known that only a tiny amount (about 1%) of Trp from food is converted to serotonin and most (more than 95%) dietary Trp is metabolized along the kynurenine (Kyn) pathway, thus leading to the

Properties of human IDO

In 1985, the existence of human IDO was examined in various human tissues obtained from 9 corpses within 10 h after death and from the fresh term placenta after delivery [15]. As seen in the rabbit, IDO was expressed in many human tissues and relatively high activities were detected in the lungs and intestines. In addition, the highest expression of IDO was found in the term placenta [15]. In 1988, human IDO was purified from the placenta and it was demonstrated to have a similar broad substrate

Structure of IDO

A cDNA encoding human [17], [18], mouse [19], or rat IDO [20] has been cloned and the deduced primary structure of each IDO was obtained. Human IDO cDNA encodes a protein of 403 amino acids with a molecular weight of about 45 kDa [17], [18]. Mouse and rat IDO cDNA encodes a 407 amino acid protein [19]. The primary sequence of human IDO shows either 57% or 58% identity to that of mouse IDO or rat IDO, respectively, but there is no sequence homology between human IDO and rat TDO [21], even though

The catalytic properties of IDO

Purified IDO is a ferric form (Fe3+) of hemoprotein which is completely inactive for oxygenation reaction in vitro, and it therefore requires an artificial reducing system to maintain its active reduced (Fe2+) form [22]. The reducing system routinely used in vitro is a combination of methylene blue (a redox dye) with ascorbic acid [12], and ascorbic acid is replaced with xanthine oxidase [12] or glutathione reductase [23]. In these systems, superoxide anion (O2−), which is generated as a result

Is IDO a scavenger of superoxide anion?

It has been suggested [26] that IDO functions as an anti-oxidant because it utilizes a superoxide anion which reduces the inactive ferric form to an active ferrous form in vitro [22]. However, the ferrous form is easily oxidized to the ferric form again, thus resulting in the release of superoxide anion [22]. As a result, IDO never decomposes superoxide anion like superoxide dismutase and therefore it does not work as an anti-oxidant enzyme.

Endogenous reducing system for IDO

The active ferrous IDO is rapidly autooxidized to the inactive ferric form (Fe3+) in the absence of a reducing system [22]. Dihydroflavin mononucleotide [27] and tetrahydropteridine [28] have been proposed as endogenous cofactors for the reduction of IDO based on an in vitro study. However, their role in the IDO reduction in vivo has not yet been assessed. Based on the fact that in erythrocytes a reducing enzyme system is present which maintains the ferrous active form of hemoglobin [29], a

Implication of IDO in the defense mechanism against various infectious pathogens

The physiological function(s) of IDO expressed in many tissues remained unknown for more than 10 years after its discovery in the rabbit intestine in 1967. However, in the late 1970s, Yoshida and Hayaishi [31] discovered that IDO in the mouse lung is markedly induced (up to 100-fold) during either bacterial endotoxin shock or during an influenza virus infection [32]. Such IDO induction caused an enhancement of Trp degradation along the Kyn pathway in the mouse body, which was indicated by a

Detrimental effects of the systemic IDO induction

In most cases of infection with viruses (e.g., influenza virus) and parasites (e.g., Chlamydia), the induction of IDO is limited to the tissues infected with the pathogens. For example, during a pulmonary infection with an influenza virus, the IDO induction occurred in the lung [32] and such a local induction of IDO seems to effectively suppress the growth of pathogens through IDO-mediated tryptophan deprivation from the infected area, as suggested from the in vitro studies with cultured cells

Immunosuppressive role of IDO in immune system

The fundamental function of the immune system is to discriminate between self and non-self. The question remains as to why the maternal immune system cannot recognize the genetically different (allogeneic) fetus as non-self in the placenta. The molecular mechanisms underlying this maternal-tolerance toward the allogeneic fetus are still unknown. In 1998, Munn et al. proposed the hypothesis that the placental IDO prevents the rejection of the fetus. This was based on the finding that a

Escape of tumor cells from the immune surveillance by IDO expression

Immune escape is a crucial property of cancer progression. In 2003, Uyttenhove et al. [54] discovered that most of human malignant tumor cells express IDO, and using a mouse model system, they showed that tumors expressing IDO at a high level effectively escape the immune surveillance of the host by degrading local Trp, which thus inhibits T-cell responses as described above. In the model system, the same tumor, but expressing little or no IDO, was easily recognized by the immune system and

Production of neurotoxin, quinolinic acid in neurodegenerative disorders

Some of intermediate metabolites of the Kyn pathway of Trp metabolism (Fig. 1) are neuroactive [56]. Of these metabolites, much attention has been focused on quinolinic acid (QA) because it causes neural death by direct intracerebral injection [57] or when applied to neurons in culture in vitro [58]. This toxicity is due to the activation of the subpopulation of neural glutamate receptors sensitive to N-methyl-d-aspartate (NMDA) [59]. The accumulation of QA within the brain occurs in a broad

IDO induction and QA accumulation in Alzheimer’s disease

Alzheimer’s disease (AD) is the most common form of dementia that affects millions of people around the world. As AD increases with the increasing age of the population, it is estimated that the number of AD patients will reach as many as 16 million in United States alone [64]. Although the precise etiology of AD is still unknown, quite recently, in 2005, using immunostaining techniques Guillemin et al. [65] demonstrated the Kyn pathway to be up-regulated in the AD brain, thus leading to

Synthesis of UV filters in human lens

The function of the primate lens is not only to transmit and focus light, but also to filter a UV light between 300 and 400 nm to protect the retina from the UV light. The UV filter compounds in the human lens are Kyn, 3-hydroxy-l-kynurenine (3HKyn), 3-hydroxy-l-kynurenine glucoside (3HKG), and 4-(2-amino-3-hydroxypheny)-4-oxobutanoic acid glucoside (AHBG) (Fig. 3). These UV filters are synthesized locally from tryptophan in the lens epithelial cells [69] and they are also present at a high

Is Kynurenilation of lens proteins with UV filters involved in age-related cataract?

With age, the human lens becomes progressively more yellow and fluorescent, and such yellowing is much more prominent in age-related nuclear cataract, resulting in an irreversible loss of vision [73]. The underlying cause for this age-related disease has been poorly understood for a long time. However, the pivotal role of the tryptophan-derived UV filter pathway in the age-related lenticular change has been elucidated over the past 5 years by Truscott’s group in Australia. Their new finding is

Conclusions

IDO plays an important physiological role in the defense mechanism against a variety of infectious pathogens, in the regulation of T-cell function by macrophages and a subset of DC, and in the synthesis of UV filters in human lenses. However, serious problems arise from the unregulated over-expression of IDO, which often results in a deleterious systemic Trp depletion and/or the accumulation of neurotoxin, QA in the brain. The IDO expression in malignant tumors helps them to avoid the immune

Acknowledgments

I thank Profs. Hayaishi, Que, and Yamamoto for giving me this opportunity to contribute to this memorial volume celebrating the discovery of “Oxygenases” 50 years ago [1], [2].

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    ☆

    Abbreviations: IDO, indoleamine 2,3-dioxygenase; TDO, l-tryptophan 2,3-dioxygenase; IFN, interferon; Kyn, l-kynurenine; 3HKyn, 3-hydroxy-l-kynurenine; 3HKG, 3-hydroxy-l-kynurenine glucoside, AHBG, 4-(2-amino-3-hydroxypheny)-4-oxobutanoic acid glucoside; XA, xanthurenic acid; QA, quinolinic acid; DC, dendritic cells.

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