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The kynurenine pathway of tryptophan degradation as a drug target
The kynurenine pathway of tryptophan degradation as a drug target Robert Schwarcz In mammalian cells, the essential amino acid tryptophan is degraded primarily by the kynurenine pathway, a cascade of enzymatic steps containing several biologically active compounds. Metabolites of this pathway, collectively termed ‘kynurenines’, have been shown to be involved in many diverse physiological and pathological processes. In particular, fluctuations in the levels of kynurenines have discrete effects on the nervous and immune systems. A considerable number of pharmacological tools have recently become available to probe the kynurenine pathway experimentally. Some of these ‘kynurenergic’ agents can be envisioned to be of therapeutic value, especially in the treatment of diseases that are associated with impaired kynurenine pathway metabolism. Addresses Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, Maryland 21228, USA e-mail: [email protected]
Current Opinion in Pharmacology 2004, 4:12–17 This review comes from a themed issue on Neurosciences Edited by Joseph Coyle 1471-4892/$ – see front matter ß 2003 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coph.2003.10.006
Abbreviations 3-HANA 3-hydroxyanthranilic acid 3-HK 3-hydroxykynurenine CSF cerebrospinal fluid IDO indoleamine-2,3-dioxygenase KAT kynurenine aminotransferase KYNA kynurenic acid NMDA N-methyl-D-aspartate QUIN quinolinic acid
Introduction The kynurenine pathway accounts for the oxidative ring opening and subsequent degradation of the essential amino acid tryptophan in mammals. Named after a pivotal metabolite, kynurenine, this sequence of enzymatic steps produces two free radical generators (3-hydroxykynurenine [3-HK] and 3-hydroxyanthranilic acid [3HANA]) and two neuroactive compounds that act at ionotropic glutamate receptors (quinolinic acid [QUIN] and kynurenic acid [KYNA]) (Figure 1) [1–3]. Alone or jointly, these kynurenine pathway metabolites (‘kynurenines’) are believed to play substantive roles in physiology and pathology [3,4]. Facilitated by the availability of Current Opinion in Pharmacology 2004, 4:12–17
novel pharmacological agents, several surprising features of kynurenine biology have been uncovered recently. These studies, in turn, have stimulated the search for second generation kynurenergic drugs [5].
Physiological roles of kynurenines Although a century has passed since kynurenines were first recognized as major catabolic products of tryptophan, very little attention was paid to their possible involvement in biological processes until the 1980s. The neuroactive properties of QUIN, a selective but rather weak N-methyl-D-aspartate (NMDA) receptor agonist, and KYNA, a non-selective antagonist of excitatory amino acid receptors with high affinity for the glycine co-agonist site of the NMDA receptor (the glycineB receptor), first suggested that endogenous kynurenines may participate in normal brain function — possibly as modulators of glutamatergic neurotransmission. The presence of kynurenines and kynurenine pathway enzymes in the mammalian brain and the discovery of intricate, in some cases brain-specific, mechanisms that regulate the formation and disposition of pathway metabolites further supported a possible role of kynurenines in brain physiology [1–5]. Recent studies indicate much broader biological functions of kynurenines. Most intriguingly, tryptophan and its degradation products have been found to possess remarkable immunomodulatory properties. Several metabolites of the QUIN branch of the kynurenine pathway, including 3-HK, 3-HANA and QUIN itself, when applied exogenously in micromolar concentrations, suppress the proliferation of activated T cells and thus affect or facilitate tolerance to non-harmful antigens [6–8]. B cells and natural killer cells also succumb after exposure to these metabolites [8]. This phenomenon is significant because the endogenous formation of kynurenine and its downstream metabolites is greatly enhanced in immunocompromised situations due to the activation of indoleamine2,3-dioxygenase (IDO) by g-interferon and other cytokines [9–11]. These findings therefore suggest that cells containing both IDO and the entire enzymatic machinery responsible for QUIN synthesis, but which are themselves resistant to metabolite-induced apoptosis, may play a critical role in suppressing T cell proliferation and in mediating immune tolerance. This function is most likely performed by activated, immature dendritic cells, which are increasingly recognized as essential control elements in the prevention of autoimmunity [12]. This active participation of kynurenines in the immune response is in apparent contrast with influential earlier www.sciencedirect.com
The kynurenine pathway of tryptophan degradation as a drug target Schwarcz 13
Figure 1
monocytic origin [18,19], effective compartmentalization must exist to segregate the intracellular sequestration of kynurenine along the two pathway branches (Figure 1). In the brain, separation of KYNA and QUIN formation appears to be accomplished differently, namely by the absence of kynurenine 3-hydroxylase from astrocytes [19]. This allows astrocytes to convert kynurenine preferentially to KYNA [20]. In contrast, resident and — especially in situations of local injury or inflammation — reactive microglial cells, together with infiltrating macrophages, are primarily responsible for the formation of QUIN in the brain [10,21,22].
L-Tryptophan Indoleamine 2,3-dioxygenase
N-Formylkynurenine
Formamidase Kynurenine aminotransferases Kynurenine
Kynurenic acid
Kynurenine 3-hydroxylase 3-Hydroxykynurenine Kynureninase 3-Hydroxyanthranilic acid 3-Hydroxyanthranilic acid oxygenase Quinolinic acid Quinolinic acid phosphoribosyltransferase
NAD+ Current Opinion in Pharmacology
The kynurenine pathway of tryptophan degradation in mammalian cells. Enzymes are shown in red.
reports by Mellor, Munn and colleagues [13,14], who demonstrated that apoptosis of T cells occurs when tryptophan concentrations are experimentally reduced. These studies had suggested that IDO activation following immune stimulation, together with the resulting tryptophan depletion, interferes with the cell cycle of T cells and thus causes their hypervulnerability and death. However, as pointed out in two recent reviews, the ‘tryptophan utilization theory’ and the ‘tryptophan depletion theory’ of immune tolerance are not necessarily incompatible and might in fact complement each other [15,16]. Dendritic cells are not the only immunologically active cells that synthesize and release kynurenines. Several cells of monocyte lineage, including macrophages and microglia, have long been known to contain all elements of the QUIN branch of the pathway and increase pathway flux after exposure to cytokines. Interestingly, immune stimulation accelerates the entire enzymatic cascade, resulting in enhanced intracellular NADþ production in these cells [17]; however, the synthesis of KYNA is affected to a far lesser degree [18]. As kynurenine aminotransferases (KATs) are clearly present in cells of www.sciencedirect.com
Recent studies demonstrated that the role of kynurenines in the central nervous system is not limited to direct interactions with glutamate receptors. Thus, KYNA is a potent, non-competitive antagonist of the a7 nicotinic acetylcholine receptor [23], which might account for its interference with sensory gating mechanisms when brain concentrations are increased [24]. QUIN, like 3-HK and 3-HANA, is a generator of free radicals; this property might, in part, be responsible for the compound’s neurotoxic properties [25,26] and for its surprising ability to stimulate chemokine formation and induce chemokine receptor expression in astrocytes at low concentrations [27]. It remains to be seen if, and to what extent, these properties of KYNA and QUIN, as well as the production of highly reactive free radicals by 3-HK and 3-HANA, play a role in newly discovered effects of endogenous kynurenines within and outside the brain [28–34].
Involvement of kynurenines in pathology There can be little doubt that research into the biology of the kynurenine pathway has been greatly stimulated by the realization that kynurenines might be causally involved in the pathophysiology of human diseases. Speculations about this link were first formed from studies in which exogenously applied kynurenines were used to produce disease models in animals [1–3], but it has since become increasingly clear that fluctuations in the endogenous levels of kynurenines can also have pathological consequences. Originally, most hypotheses focused on a role of kynurenines in neurodegenerative, seizure and immunological diseases [4,5]. However, recent animal studies demonstrated that kynurenine pathway metabolism is also impaired during fetal development when placental function is compromised [35], during chronic renal insufficiency [36] and in association with a portosystemic shunt [37]; all of these changes could be pathophysiologically significant. The list of human diseases showing abnormal kynurenine pathway metabolism has grown and now includes cerebral malaria (cerebrospinal fluid [CSF] QUIN increased) [38], severe cases of amyotrophic lateral sclerosis (CSF KYNA increased; serum KYNA decreased) [39], multiple sclerosis (CSF KYNA decreased) [40], neonatal asphyxia (brain KYNA decreased) [41], chronic inflammatory bowel disease Current Opinion in Pharmacology 2004, 4:12–17
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(serum KYNA increased) [42], Huntington’s disease (striatum and cerebral cortex QUIN increased during early stages) [43] and schizophrenia (cerebral cortex KYNA increased) [44]. Notably, the latter abnormality, which constitutes the first documented kynurenergic impairment in a psychiatric disease, could contribute to the suspected hypoglutamatergic tone in schizophrenia [44]. Importantly, all of these changes suggest new treatment strategies based on the pharmacological modulation of endogenous kynurenines.
Kynurenergic enzymes The newly identified roles of kynurenines in physiology and pathology have triggered renewed interest in the characteristics of individual kynurenine pathway enzymes. Recent biochemical, immunocytochemical and molecular biological studies suggest previously unsuspected functions of these enzymes, resulting in conceptual advances with potentially far-reaching implications. In addition to extensive immunology-related work on IDO (see above), several recent discoveries have involved KATs (i.e. the enzymes responsible for the biosynthesis of KYNA). Several such enzymes exist, and at least two of these are present in the brain; their relative importance in vivo appears to vary with species, tissue and developmental stage. KAT I occurs in a cytosolic and a mitochondrial form, and its activity is controlled at the level of both transcription and translation [45]. In the rat brain, this enzyme could have a major function in cortical maturation, as it is exclusively contained in subplate neurons during the perinatal period [46]. The same enzyme shows a missense mutation in spontaneously hypertensive rats and might therefore, by reducing the availability of KYNA, contribute to heightened sensitivity to ischemic insults [47]. In contrast to the rat, KYNA formation in the mouse is mainly catalyzed by KAT II, and very recent evidence from mice nullizygous for KAT II indicates the existence of a third KAT (‘KAT III’), preferentially in the adult brain [48]. Both KAT I and KAT II have been identified in retinal glial cells, and have been suggested to participate in local glutamatergic neurotransmission [49]. A role for abnormal kynurenine pathway metabolism in hypertension is supported by the finding of a polymorphism in the kynureninase gene in spontaneously hypertensive rats [50]. Expression of kynureninase mRNA in the brainstem of these animals is increased by approximately threefold compared with controls. Less wellcharacterized enzyme changes have been reported in diabetic rabbits [51] and in rats with experimental chronic renal failure [52].
Kynurenergic drugs The pharmacological exploitation of the kynurenine pathway is still in its early stages but has gained momentum in recent years. Development of new compounds has Current Opinion in Pharmacology 2004, 4:12–17
accelerated since it was recognized that appropriately designed drugs are likely to have clinical benefits in a variety of human disorders. These new compounds can also be used as experimental tools for hypothesis testing, and are therefore critical for progress in the field. Synthetic analogs of biologically active kynurenines, especially KYNA, have revealed important information regarding the nature and characteristics of excitatory amino acid receptors and other endogenous targets in the brain. Many of these compounds exhibit high affinity for NMDA receptors and other excitatory receptors in vitro. They are less useful for studying kynurenine neurobiology in vivo because they penetrate the blood-brain barrier very poorly. An interesting case is 4-Cl-kynurenine, which readily enters the brain from the circulation and is then transaminated by KATs to produce the highly specific, potent glycineB receptor antagonist 7-Cl-KYNA. 7-Cl-KYNA produced in situ has the expected anticonvulsant and neuroprotective effects [53]. More generally, work with structural analogs of KYNA in animals has confirmed their potential therapeutic usefulness, particularly in neurological diseases associated with abnormal glutamatergic neurotransmission [2–4]. Recent developments have focused on the possibility of modulating the endogenous concentration and function of kynurenines by manipulating individual pathway enzymes. Increasingly specific and potent enzyme inhibitors have been synthesized and characterized both in vitro and in vivo. In most cases, these compounds are too polar to readily penetrate the blood-brain barrier; effects in the brain are therefore often secondary to fluctuations in the blood concentration of kynurenine or 3-HK (both of which are actively transported from the circulation to the brain [5]). Most importantly, pharmacologically induced changes in the brain levels of neuroactive kynurenines have the predicted functional consequences: exacerbating NMDA receptor-mediated processes when 3-HK and QUIN levels are increased, and inhibiting excitatory transmission when KYNA levels are elevated. Several of the currently available enzyme inhibitors have been successfully used for proof-of-concept studies in experimental animals, and have been critical for elucidating the role of the kynurenine pathway in biological systems [3–5]. A review of the armamentarium of kynurenergic compounds has been published recently [5]. Effective inhibitors of mammalian IDO, kynurenine 3-hydroxylase and 3-HANA oxygenase have been available for years, although the targeting of other pathway enzymes has lagged behind. Most of the original enzyme inhibitors were simple derivatives or structural analogs of the naturally occurring substrates, such as 1-methyl-tryptophan (for IDO) and 4-Cl-3-hydroxyanthranilic acid (for 3-HANA www.sciencedirect.com
The kynurenine pathway of tryptophan degradation as a drug target Schwarcz 15
oxygenase). Novel chemical structures were later identified by further rational design or by screening chemical libraries (e.g. the discovery of N-(4-phenylthiazol-2-yl)benzenesulfonamides as potent kynurenine 3-hydroxylase inhibitors) [54]. More recently, potent and highly specific kynureninase inhibitors, which preferentially block the mammalian enzyme, were synthesized by Botting and collaborators [55,56]. These compounds have so far not been tested in vivo, but can be expected to reveal important information on the dynamics of kynurenine pathway metabolism.
References and recommended reading
Because of the low substrate specificity of aminotransferases, efforts to synthesize specific KAT inhibitors have not been successful. The challenge is aggravated by the existence and diverse functional significance of several KYNA-producing enzymes. New discoveries, such as the demonstration of KAT II-specific inhibition by both the endogenous amino acid cysteine sulfinic acid [57] and the dopaminergic neurotoxin 1-methyl-4phenylpyridinium [58], or the surprising attenuation of the 1-methyl-4-phenylpyridinium-induced reduction of KYNA synthesis by the immunophilin ligand FK506 [59], provide structural hints for future rational drug design. This bodes well for the development of compounds that selectively influence enzymatic KYNA formation.
Conclusions Recent studies have revealed that the physiological properties of kynurenines, and the involvement of these tryptophan metabolites in pathological conditions, are more extensive and diverse than previously assumed. These new findings have triggered the development of pharmacological agents designed to augment or attenuate the effects of specific kynurenines, such as QUIN and KYNA. Prototypical inhibitors of most kynurenine pathway enzymes are now available, and several have been successfully used for proof-of-concept testing in experimental animals. However, agents with greater efficacy and specificity, and improved blood-brain barrier permeability, are clearly needed. New knowledge regarding the three-dimensional composition of individual pathway enzymes, the screening of chemical libraries, and leads from serendipitous findings now make it possible to generate novel, structurally distinct compounds. Such compounds will not only constitute valuable research tools but will be instrumental for exploring the clinical benefits of normalizing impaired kynurenine pathway metabolism in humans.
Acknowledgements Work in the author’s laboratory is supported by grants from the United States Public Health Service (NIH) and the National Alliance for Research on Schizophrenia and Depression (NARSAD). I thank Sharon Stilling for help with manuscript preparation. www.sciencedirect.com
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Current Opinion in Pharmacology 2004, 4:12–17
Current Opinion in Pharmacology 2004, 4:12–17 This review comes from a themed issue on Neurosciences Edited by Joseph Coyle 1471-4892/$ – see front matter ß 2003 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coph.2003.10.006
Abbreviations 3-HANA 3-hydroxyanthranilic acid 3-HK 3-hydroxykynurenine CSF cerebrospinal fluid IDO indoleamine-2,3-dioxygenase KAT kynurenine aminotransferase KYNA kynurenic acid NMDA N-methyl-D-aspartate QUIN quinolinic acid
Introduction The kynurenine pathway accounts for the oxidative ring opening and subsequent degradation of the essential amino acid tryptophan in mammals. Named after a pivotal metabolite, kynurenine, this sequence of enzymatic steps produces two free radical generators (3-hydroxykynurenine [3-HK] and 3-hydroxyanthranilic acid [3HANA]) and two neuroactive compounds that act at ionotropic glutamate receptors (quinolinic acid [QUIN] and kynurenic acid [KYNA]) (Figure 1) [1–3]. Alone or jointly, these kynurenine pathway metabolites (‘kynurenines’) are believed to play substantive roles in physiology and pathology [3,4]. Facilitated by the availability of Current Opinion in Pharmacology 2004, 4:12–17
novel pharmacological agents, several surprising features of kynurenine biology have been uncovered recently. These studies, in turn, have stimulated the search for second generation kynurenergic drugs [5].
Physiological roles of kynurenines Although a century has passed since kynurenines were first recognized as major catabolic products of tryptophan, very little attention was paid to their possible involvement in biological processes until the 1980s. The neuroactive properties of QUIN, a selective but rather weak N-methyl-D-aspartate (NMDA) receptor agonist, and KYNA, a non-selective antagonist of excitatory amino acid receptors with high affinity for the glycine co-agonist site of the NMDA receptor (the glycineB receptor), first suggested that endogenous kynurenines may participate in normal brain function — possibly as modulators of glutamatergic neurotransmission. The presence of kynurenines and kynurenine pathway enzymes in the mammalian brain and the discovery of intricate, in some cases brain-specific, mechanisms that regulate the formation and disposition of pathway metabolites further supported a possible role of kynurenines in brain physiology [1–5]. Recent studies indicate much broader biological functions of kynurenines. Most intriguingly, tryptophan and its degradation products have been found to possess remarkable immunomodulatory properties. Several metabolites of the QUIN branch of the kynurenine pathway, including 3-HK, 3-HANA and QUIN itself, when applied exogenously in micromolar concentrations, suppress the proliferation of activated T cells and thus affect or facilitate tolerance to non-harmful antigens [6–8]. B cells and natural killer cells also succumb after exposure to these metabolites [8]. This phenomenon is significant because the endogenous formation of kynurenine and its downstream metabolites is greatly enhanced in immunocompromised situations due to the activation of indoleamine2,3-dioxygenase (IDO) by g-interferon and other cytokines [9–11]. These findings therefore suggest that cells containing both IDO and the entire enzymatic machinery responsible for QUIN synthesis, but which are themselves resistant to metabolite-induced apoptosis, may play a critical role in suppressing T cell proliferation and in mediating immune tolerance. This function is most likely performed by activated, immature dendritic cells, which are increasingly recognized as essential control elements in the prevention of autoimmunity [12]. This active participation of kynurenines in the immune response is in apparent contrast with influential earlier www.sciencedirect.com
The kynurenine pathway of tryptophan degradation as a drug target Schwarcz 13
Figure 1
monocytic origin [18,19], effective compartmentalization must exist to segregate the intracellular sequestration of kynurenine along the two pathway branches (Figure 1). In the brain, separation of KYNA and QUIN formation appears to be accomplished differently, namely by the absence of kynurenine 3-hydroxylase from astrocytes [19]. This allows astrocytes to convert kynurenine preferentially to KYNA [20]. In contrast, resident and — especially in situations of local injury or inflammation — reactive microglial cells, together with infiltrating macrophages, are primarily responsible for the formation of QUIN in the brain [10,21,22].
L-Tryptophan Indoleamine 2,3-dioxygenase
N-Formylkynurenine
Formamidase Kynurenine aminotransferases Kynurenine
Kynurenic acid
Kynurenine 3-hydroxylase 3-Hydroxykynurenine Kynureninase 3-Hydroxyanthranilic acid 3-Hydroxyanthranilic acid oxygenase Quinolinic acid Quinolinic acid phosphoribosyltransferase
NAD+ Current Opinion in Pharmacology
The kynurenine pathway of tryptophan degradation in mammalian cells. Enzymes are shown in red.
reports by Mellor, Munn and colleagues [13,14], who demonstrated that apoptosis of T cells occurs when tryptophan concentrations are experimentally reduced. These studies had suggested that IDO activation following immune stimulation, together with the resulting tryptophan depletion, interferes with the cell cycle of T cells and thus causes their hypervulnerability and death. However, as pointed out in two recent reviews, the ‘tryptophan utilization theory’ and the ‘tryptophan depletion theory’ of immune tolerance are not necessarily incompatible and might in fact complement each other [15,16]. Dendritic cells are not the only immunologically active cells that synthesize and release kynurenines. Several cells of monocyte lineage, including macrophages and microglia, have long been known to contain all elements of the QUIN branch of the pathway and increase pathway flux after exposure to cytokines. Interestingly, immune stimulation accelerates the entire enzymatic cascade, resulting in enhanced intracellular NADþ production in these cells [17]; however, the synthesis of KYNA is affected to a far lesser degree [18]. As kynurenine aminotransferases (KATs) are clearly present in cells of www.sciencedirect.com
Recent studies demonstrated that the role of kynurenines in the central nervous system is not limited to direct interactions with glutamate receptors. Thus, KYNA is a potent, non-competitive antagonist of the a7 nicotinic acetylcholine receptor [23], which might account for its interference with sensory gating mechanisms when brain concentrations are increased [24]. QUIN, like 3-HK and 3-HANA, is a generator of free radicals; this property might, in part, be responsible for the compound’s neurotoxic properties [25,26] and for its surprising ability to stimulate chemokine formation and induce chemokine receptor expression in astrocytes at low concentrations [27]. It remains to be seen if, and to what extent, these properties of KYNA and QUIN, as well as the production of highly reactive free radicals by 3-HK and 3-HANA, play a role in newly discovered effects of endogenous kynurenines within and outside the brain [28–34].
Involvement of kynurenines in pathology There can be little doubt that research into the biology of the kynurenine pathway has been greatly stimulated by the realization that kynurenines might be causally involved in the pathophysiology of human diseases. Speculations about this link were first formed from studies in which exogenously applied kynurenines were used to produce disease models in animals [1–3], but it has since become increasingly clear that fluctuations in the endogenous levels of kynurenines can also have pathological consequences. Originally, most hypotheses focused on a role of kynurenines in neurodegenerative, seizure and immunological diseases [4,5]. However, recent animal studies demonstrated that kynurenine pathway metabolism is also impaired during fetal development when placental function is compromised [35], during chronic renal insufficiency [36] and in association with a portosystemic shunt [37]; all of these changes could be pathophysiologically significant. The list of human diseases showing abnormal kynurenine pathway metabolism has grown and now includes cerebral malaria (cerebrospinal fluid [CSF] QUIN increased) [38], severe cases of amyotrophic lateral sclerosis (CSF KYNA increased; serum KYNA decreased) [39], multiple sclerosis (CSF KYNA decreased) [40], neonatal asphyxia (brain KYNA decreased) [41], chronic inflammatory bowel disease Current Opinion in Pharmacology 2004, 4:12–17
14 Neurosciences
(serum KYNA increased) [42], Huntington’s disease (striatum and cerebral cortex QUIN increased during early stages) [43] and schizophrenia (cerebral cortex KYNA increased) [44]. Notably, the latter abnormality, which constitutes the first documented kynurenergic impairment in a psychiatric disease, could contribute to the suspected hypoglutamatergic tone in schizophrenia [44]. Importantly, all of these changes suggest new treatment strategies based on the pharmacological modulation of endogenous kynurenines.
Kynurenergic enzymes The newly identified roles of kynurenines in physiology and pathology have triggered renewed interest in the characteristics of individual kynurenine pathway enzymes. Recent biochemical, immunocytochemical and molecular biological studies suggest previously unsuspected functions of these enzymes, resulting in conceptual advances with potentially far-reaching implications. In addition to extensive immunology-related work on IDO (see above), several recent discoveries have involved KATs (i.e. the enzymes responsible for the biosynthesis of KYNA). Several such enzymes exist, and at least two of these are present in the brain; their relative importance in vivo appears to vary with species, tissue and developmental stage. KAT I occurs in a cytosolic and a mitochondrial form, and its activity is controlled at the level of both transcription and translation [45]. In the rat brain, this enzyme could have a major function in cortical maturation, as it is exclusively contained in subplate neurons during the perinatal period [46]. The same enzyme shows a missense mutation in spontaneously hypertensive rats and might therefore, by reducing the availability of KYNA, contribute to heightened sensitivity to ischemic insults [47]. In contrast to the rat, KYNA formation in the mouse is mainly catalyzed by KAT II, and very recent evidence from mice nullizygous for KAT II indicates the existence of a third KAT (‘KAT III’), preferentially in the adult brain [48]. Both KAT I and KAT II have been identified in retinal glial cells, and have been suggested to participate in local glutamatergic neurotransmission [49]. A role for abnormal kynurenine pathway metabolism in hypertension is supported by the finding of a polymorphism in the kynureninase gene in spontaneously hypertensive rats [50]. Expression of kynureninase mRNA in the brainstem of these animals is increased by approximately threefold compared with controls. Less wellcharacterized enzyme changes have been reported in diabetic rabbits [51] and in rats with experimental chronic renal failure [52].
Kynurenergic drugs The pharmacological exploitation of the kynurenine pathway is still in its early stages but has gained momentum in recent years. Development of new compounds has Current Opinion in Pharmacology 2004, 4:12–17
accelerated since it was recognized that appropriately designed drugs are likely to have clinical benefits in a variety of human disorders. These new compounds can also be used as experimental tools for hypothesis testing, and are therefore critical for progress in the field. Synthetic analogs of biologically active kynurenines, especially KYNA, have revealed important information regarding the nature and characteristics of excitatory amino acid receptors and other endogenous targets in the brain. Many of these compounds exhibit high affinity for NMDA receptors and other excitatory receptors in vitro. They are less useful for studying kynurenine neurobiology in vivo because they penetrate the blood-brain barrier very poorly. An interesting case is 4-Cl-kynurenine, which readily enters the brain from the circulation and is then transaminated by KATs to produce the highly specific, potent glycineB receptor antagonist 7-Cl-KYNA. 7-Cl-KYNA produced in situ has the expected anticonvulsant and neuroprotective effects [53]. More generally, work with structural analogs of KYNA in animals has confirmed their potential therapeutic usefulness, particularly in neurological diseases associated with abnormal glutamatergic neurotransmission [2–4]. Recent developments have focused on the possibility of modulating the endogenous concentration and function of kynurenines by manipulating individual pathway enzymes. Increasingly specific and potent enzyme inhibitors have been synthesized and characterized both in vitro and in vivo. In most cases, these compounds are too polar to readily penetrate the blood-brain barrier; effects in the brain are therefore often secondary to fluctuations in the blood concentration of kynurenine or 3-HK (both of which are actively transported from the circulation to the brain [5]). Most importantly, pharmacologically induced changes in the brain levels of neuroactive kynurenines have the predicted functional consequences: exacerbating NMDA receptor-mediated processes when 3-HK and QUIN levels are increased, and inhibiting excitatory transmission when KYNA levels are elevated. Several of the currently available enzyme inhibitors have been successfully used for proof-of-concept studies in experimental animals, and have been critical for elucidating the role of the kynurenine pathway in biological systems [3–5]. A review of the armamentarium of kynurenergic compounds has been published recently [5]. Effective inhibitors of mammalian IDO, kynurenine 3-hydroxylase and 3-HANA oxygenase have been available for years, although the targeting of other pathway enzymes has lagged behind. Most of the original enzyme inhibitors were simple derivatives or structural analogs of the naturally occurring substrates, such as 1-methyl-tryptophan (for IDO) and 4-Cl-3-hydroxyanthranilic acid (for 3-HANA www.sciencedirect.com
The kynurenine pathway of tryptophan degradation as a drug target Schwarcz 15
oxygenase). Novel chemical structures were later identified by further rational design or by screening chemical libraries (e.g. the discovery of N-(4-phenylthiazol-2-yl)benzenesulfonamides as potent kynurenine 3-hydroxylase inhibitors) [54]. More recently, potent and highly specific kynureninase inhibitors, which preferentially block the mammalian enzyme, were synthesized by Botting and collaborators [55,56]. These compounds have so far not been tested in vivo, but can be expected to reveal important information on the dynamics of kynurenine pathway metabolism.
References and recommended reading
Because of the low substrate specificity of aminotransferases, efforts to synthesize specific KAT inhibitors have not been successful. The challenge is aggravated by the existence and diverse functional significance of several KYNA-producing enzymes. New discoveries, such as the demonstration of KAT II-specific inhibition by both the endogenous amino acid cysteine sulfinic acid [57] and the dopaminergic neurotoxin 1-methyl-4phenylpyridinium [58], or the surprising attenuation of the 1-methyl-4-phenylpyridinium-induced reduction of KYNA synthesis by the immunophilin ligand FK506 [59], provide structural hints for future rational drug design. This bodes well for the development of compounds that selectively influence enzymatic KYNA formation.
Conclusions Recent studies have revealed that the physiological properties of kynurenines, and the involvement of these tryptophan metabolites in pathological conditions, are more extensive and diverse than previously assumed. These new findings have triggered the development of pharmacological agents designed to augment or attenuate the effects of specific kynurenines, such as QUIN and KYNA. Prototypical inhibitors of most kynurenine pathway enzymes are now available, and several have been successfully used for proof-of-concept testing in experimental animals. However, agents with greater efficacy and specificity, and improved blood-brain barrier permeability, are clearly needed. New knowledge regarding the three-dimensional composition of individual pathway enzymes, the screening of chemical libraries, and leads from serendipitous findings now make it possible to generate novel, structurally distinct compounds. Such compounds will not only constitute valuable research tools but will be instrumental for exploring the clinical benefits of normalizing impaired kynurenine pathway metabolism in humans.
Acknowledgements Work in the author’s laboratory is supported by grants from the United States Public Health Service (NIH) and the National Alliance for Research on Schizophrenia and Depression (NARSAD). I thank Sharon Stilling for help with manuscript preparation. www.sciencedirect.com
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