OVERVIEW OF THE ROLE OF VITAMINS AND MINERALS
ON THE KYNURENINE PATHWAY IN HEALTH AND DISEASE
The kynurenine pathway (KP) of L-tryptophan metabolism is increasingly recognised as a critical source of neuroactive metabolites with relevance for health and disease. There is mounting evidence that L-tryptophan metabolism depends on the adequate availability of both vitamins (1-10) and minerals (11-19) which work as cofactors and coenzymes in metabolic reactions. L-tryptophan is an "essential" amino acid for mammals, as they cannot make it themselves. Therefore, they must obtain it in the form of food. This aromatic substance can be utilized not only for protein synthesis, but also for the biosynthesis of nicotinamide adenine dinucleotide (NAD+) through the KP, as well as the biosynthesis of serotonin and melatonin through the serotonin pathway (20).
L-tryptophan has been proven to modulate gene expression and nutrient metabolism with an impact on whole-body homeostasis. It has been demonstrated that a temporary L-tryptophan deficiency can cause memory failure in healthy humans; as well as dermatitis, depression, and anxiety (20, 21). A low dietary tryptophan intake during rat development produced lower rates of serotonin synthesis in the brain, affecting GABAergic cortical interneurons and contributing to an increased susceptibility to convulsions (22).
ENS, enteric nervous system.
In a preclinical study of pregnant rats, an excess of L-tryptophan in the diet caused hyperserotonaemia in the rat foetus, which had an adverse effect on the development of serotonergic neurons, thus affecting the growth of new-born rats (23). On the other hand, Strasser et al. (24) point out that L-tryptophan supplementation while dieting could be highly useful in preventing neuropsychiatric symptoms or in treating uncontrolled weight gain in mammals.
Serotonin is an important neurotransmitter in the enteric nervous system (ENS) (25-28), in the central nervous system (CNS) (29), as well as in the autonomic nervous system (ANS). In the ENS, serotonin regulates secretion, motility and sensation (Table 2), while in the CNS it modulates mood, cognition and sleep (20, 29). Serotonin also regulates the secretion of pituitary growth hormone, which in turn stimulates the liver to produce insulin-like growth factor-I, which is necessary for the development and growth of rat pups as well as other mammals (23). Neuropsychiatric problems have been attributed to too much or too little serotonin (27, 29, 30). Recent studies have proven, that changes in serotonin concentration play a crucial role in human gastrointestinal (GI) physiology, being a therapeutic target in irritable bowel syndrome (IBS) etiology (26, 27, 31).
The other product of L-tryptophan metabolism is melatonin. It has been shown in several studies to have free radical scavenging activity (55), antioxidant properties (56), anti-apoptotic activity (57), and enhancement of mitochondrial function (58).
In recent years, attention has increasingly focused on the medical significance of the enzymatic oxidation of L-tryptophan which is dependent on some B group vitamins and minerals to form compounds collectively known as "kynurenines". Segregated into at least two distinct branches, often termed as the "neurotoxic" and "neuroprotective" arms of the KP, they are regulated by the two key enzymes, flavin dependant (FAD) kynurenine 3-monooxygenase (KMO) and pyridoxal-5'-phosphate (PLP, vitamin B6) dependent kynurenine aminotransferase (KAT), respectively (59). These enzymes are mainly located in the brain (being segregated into specific cell types) (60), in the liver and kidney (59) as well as throughout the body. Several of these enzymes are under the tight control of inflammatory mediators (59, 61) (Table 3).
The KP produces several neuroactive metabolites. The neurotoxic ones are: amino acid 3-hydroxy-L-kynurenine (3-OH-L-KYN), 3-hydroxy-anthranilic acid (3-OH-AA), and quinolinic acid (QUIN). The neuroprotective metabolite is kynurenic acid (KYNA) (60, 62). Moreover, the KP is the major route of L-tryptophan metabolism (95% of all ingested L-tryptophan) that leads to the formation of the active form of niacin (NAD+) in the main chain (63). Meanwhile, the side-chains of this pathway generate KYNA and xanthurenic acid (XA) (64) (Fig. 1).
QUIN is considered to be an endogenous agonist of the N-methyl-D-aspartate (NMDA) receptor with strong excitotoxic properties (65). By contrast, KYNA possesses a neuroprotective action (in the CNS), and is an NMDA receptor antagonist as well as a non-competitive antagonist of the nicotinic receptor a-A7 subtype (66). What's more, QUIN, 3-OH-L-KYN and 3-OH-AA are responsible for the production of the extremely reactive free radical species, O2●- and H2O2 (62).
Some health related states may influence the proper functioning of the KP (Table 4). Excessive L-kynurenine (L-KYN) production and an accompanying deficiency of the substrate L-tryptophan, may be the cause of a number of pathological conditions. According to Sasaki et al. (104), insulin-dependent diabetes mellitus in rats may alter the activity of enzymes engaged in L-tryptophan metabolism, which may lead to changes in the production of different kynurenines. Matsuda et al. (105) recently found in rats that another KP enzyme - α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) - is also associated with proper cholesterol metabolism. This enzyme is dependent on proper concentrations of Fe2+, Co2+ and Zn2+ (13).
Abbreviations: 3-OH-AA, 3-hydroxy-antranilic acid; 3-OH-L-KYN, 3-hydroxy-L-kynurenine; 5-HT, serotonin; AA, anthranilic acid; IBS, irritable bowel syndrome; KYNA, kynurenic acid; L-KYN, L-kynurenine; L-TRP, L-tryptophan; PA, picolinic acid; QUIN, quinolinic acid; XA, xanthurenic acid.
L-tryptophan utilization as a fuel for energy production is dependent upon the adequate availability of both vitamins and minerals such as: pyridoxal 5'-phosphate (PLP, B6), riboflavin (B2), niacin (B3), thiamine (B1), pantothenic acid, lipoate, ubiquinone, Mg2+, Fe2+, Zn2+ and Co2+ (106). Consequently, a lack of certain vitamins and minerals may lead to the dysfunction of enzymes engaged in L-tryptophan metabolism and many health-related disorders (107) (Table 4).
ENZYMES ENGAGED IN TRYPTOPHAN METABOLISM
ALONG THE KYNURENINE PATHWAY
L-kynurenine to L-tryptophan ratio as a tryptophan and indoleamine 2,3-dioxygenase indicator
The first and rate-limiting step of the KP is the oxidative cleavage of the 2,3-double bond of the indole ring of L-tryptophan to form an unstable product (N-formyl-L-kynurenine, NFK) which is further converted to L-KYN. This reaction is catalysed by two iron dependent dioxygenases (122, 123). They are tryptophan 2,3-dioxygenase (TDO), which is constitutively expressed in liver; and the inflammatory cytokine-induced indoleamine 2,3-dioxygenase-1 (IDO-1) which is located in the brain and in the intestine (124). The enzyme catalyses the oxidation of L-tryptophan to L-KYN in a reaction that produces peroxides and gives rise to highly reactive and potentially harmful oxygen and hydroxyl radicals (62). The heme prosthetic group of TDO-heme-Fe3+ must be reduced to the heme-Fe2+ form prior to mediating L-tryptophan oxidation (122, 125). Like other hemeproteins, IDO binds O2 to the deoxy protein where it is involved in the oxidation of substrates (Table 4). It was proven that IDO activity is dependent on the proper concentration of Fe2+ and many inflammatory stimuli (Table 2).
The plasma (serum) ratio of L-KYN to L-tryptophan (K-TR ratio) is a generally accepted clinical marker of IDO activity (126). It is highly correlated to neopterin levels, which is a macrophage-derived metabolite that increases after interferon-gamma stimulation, and is a good reflection of inflammatory status (90). Considering that both IDO and TDO regulate the rate of L-tryptophan conversion into L-KYN, plasma concentrations of L-tryptophan and L-KYN might also be affected by the activity of TDO (21). However, the K-TR ratio most accurately reflects IDO activity in conditions associated with inflammation (91).
More recently, it has been found that mammals possess a third dioxygenase enzyme, in addition to TDO and IDO-1. IDO-2's active site contains a heme moiety for L-tryptophan binding and catabolism (127). This enzyme is capable of catalysing the oxidative cleavage of L-tryptophan, and is subsequently named indoleamine-2,3-dioxygenase type 2 (IDO-2) with a role in immunity (128). The discovery of a third initiating protein of the KP has attracted considerable research interest due to the established roles of IDO-2 in L-tryptophan metabolism (129) and TDO/IDO-1 dysfunction in numerous pathological conditions, including malaria (123, 130) and cancer (131).
An overexpression of IDO activity is connected with human cancer development (109, 110), IFN-α-induced depression (132) and IBS development (111, 112). Cytokines up-regulate IDO expression (132), causing a decrease in extracellular serotonin (Table 3). This can induce an increase in sleep, reduce locomotor activity, and decrease social exploration with co-existing anhedonia in animal models. These symptoms resemble the vegetative symptoms of depression in humans (133). Furthermore, dysregulation of L-tryptophan metabolism together with vitamin B6 insufficiency influences serotonin and melatonin formation, with an impact on motility and perception in the ENS (124).
In IBS patients, plasma kynurenine levels are significantly elevated as is the K-TR ratio, an index of IDO activity, in comparison to control levels (134).
The inhibition of IDO activity with L-tryptophan loading, exerts protective effects by suppressing the formation of neurotoxic QUIN, 3-OH-L-KYN, 3-OH-AA, and nitric oxide synthase (135), and increases melatonin formation. Therefore this could be a new therapeutic approach in the treatment of many CNS and ENS disorders. Moreover, down-regulation of IDO, leads to a reduction of proinflammatory cytokine activity (59).
Kynurenine-3-monooxygenase (kynurenine 3-hydroxylase)
KMO catalyses the specific hydroxylation of L-KYN at the third position of its phenol ring to generate 3-OH-L-KYN, an endogenous oxidative stress generator, which causes neuronal cell death with apoptotic features and regional selectivity (136). The mechanism of toxicity to the cells is through the generation of reactive oxygen species in the respiratory chain (137).
KMO is up-regulated by FAD coenzyme (a form of vitamin B2) and its monomeric protein is non-covalently and very tightly bound to FAD with the ability to slow chemical dissociation (1). NADPH, NADH, FAD and inflammatory stimuli up-regulate enzyme activity, whereas AA, XA and most likely vitamin B6 are the negative regulators of the enzyme activity (62) (Table 3 and Table 5). In vitamin B6 deficiency, KMO activity is decreased, which may further lead to the development of other neurological disorders (10, 108).
Physiologically, high KMO levels are found in the liver and kidney, as well as within macrophage and microglial cells, whereas low KMO levels are distributed throughout all regions of the brain (136). More thorough studies further indicate that the enzyme is localized upon the outer mitochondrial membrane (138-140).
Recently, KMO has been proven to be involved in the pathogenesis of Huntington's disease (113), post-traumatic sepsis (138), Alzheimer's disease (141), and is considered to be an important pharmaceutical target for the development of drugs against neurodegenerative diseases (142, 143). Increased concentrations of 3-OH-L-KYN have been found in the disorders described above. Thus, KMO inhibition can be a potential therapeutic target for the treatment of neurodegenerative diseases (1, 114).
Kynureninase (L-kynurenine hydrolase)
KYNU is a vitamin B6 dependent enzyme which lies on the main pathway towards acetyl-CoA or NAD+ synthesis. Both L-KYN and 3-OH-L-KYN can be oxidized to AA or 3-OH-AA, respectively (144). L-KYN to AA and 3-OH-L-KYN to 3-OH-AA ratios are considered to be the KYNU indicators (Table 4). The role of 3-OH-L-KYN in health and disease is controversial as there have been reports regarding its pro-oxidant and antioxidant properties (62).
In parallel with KYNU, another vitamin B6 dependent enzyme, KAT, utilizes the same reactants but obtains XA and KYNA as products instead (116).
In vitamin B6 deficiency states and in pregnancy, L-KYN and 3-OH-L-KYN predominate, suggesting a block in the pathway at the level of KYNU (76, 77). What is more, the KAT metabolites also exist, suggesting that although both enzymes require vitamin B6, KYNU has been shown to be more sensitive to vitamin B6 depletion than KAT (Table 7). Thus, depletion in vitamin B6 concentration shifts the pathway towards the formation of KYNA and XA (84). Pregnancy exerts a more pronounced effect on KYNU activity than vitamin B6 restrictions, and the effects of pregnancy and diet are additive (76, 77). In another study of vitamin B6 deficiency, KYNU activity in the kidneys was significantly reduced, while KAT was increased (145). Moderate deficiency of vitamin B6 causes an increase in the concentration of 3-OH-L-KYN whereas KYNA and AA concentration are decreased (146). According to Takeuchi et al. (145), the quantity of KYNA was highly increased. More serious deficiencies lead to an increase in the concentration of L-KYN and XA in blood and urine (146-149). The increase in the concentration of 3-OH-L-KYN is an important indicator of abnormalities occurring in the metabolism of vitamin B6. Vitamin B6 deficient animals excrete more XA and 3-OH-L-KYN, and less of the niacin metabolites (N-1-methyl nicotinamide and methyl-2-pyridone-4-carboxamide), when compared to the control group after L-tryptophan loading (84, 150). The 3-OH-L-KYN : 3-OH-AA ratio, which is a substrate-product ratio of KYNU, was proposed as the most sensitive and specific indicator of increased vitamin B6 dependency (151).
A recent study shows that minerals can also exert an influence on KYNU activity. According to studies conducted by El-Sewedy et al. (2), Mn2+ can activate the enzymes, whereas Zn2+, Co2+ and Cu2+ inhibit enzymatic activity. This inhibition is attributed to the blocking and inactivation of the sulfhydryl groups of the enzyme. The decreasing order by which these metal ions inhibit KYNU is Cu2+ > Co2+ > Zn2+.
Additionally, KYNU is inactivated by incubation with a reaction product, L-alanine, and its function is restored by the addition of vitamin B6 (153). The inhibition of KYNU is associated with sedative and anticonvulsant actions (154) (Table 4). On the other hand, interferon-gamma stimulation significantly potentiates the expression of KYNU in cultured human glioma cells (61) (Table 3).
Kynurenine aminotransferases, as implied by their names, are the primary enzymes involved in the irreversible transamination of KYNA from L-KYN in human brain tissue, and are referred to as KATs. KATs are homodimeric pyridoxal proteins that mediate this catalytic conversion (4). Although four isoforms (KAT-I to -IV) of this enzyme have been hitherto identified, KAT-II is the enzymatic isoform that mainly accounts for the synthesis of cerebral KYNA (155). KAT is also involved in the biosynthesis of glutamic (156, 157) and aspartic acid (4), which function as neurotransmitters for the NMDA receptors in mammals (158) (Table 5). Moreover, KAT is responsible for the transamination of 3-OH-L-KYN to XA in the competing, major branch of the metabolic cascade. However, this function of KAT has been rarely highlighted in the published literature as of yet (159). KATs are not sensitive to changes in minerals; however, there are some reports suggesting its sensitivity to vitamin B6 fluctuations (Table 7). The data as of present have shown little effect of dietary vitamin B6 on KATs' activity (76, 77).
KAT-I is potently inhibited by glutamine, whereas KAT-II is not sensitive to glutamine. KAT-I that is located in the brain is inhibited by competing substrates, like L-tryptophan, L-phenylalanine and L-glutamine, which are present in the human body under physiological conditions (160). On the other hand, KAT-I that is located in the heart is not inhibited by the afore-mentioned compounds (161).
It was reported that selective inhibitors of KAT-II restore nicotine-evoked glutamatergic activity in the cortex, being a possible treatment target for such cognitive impairments (162), as KAT-II is responsible for most of the KYNA synthesis in the brain. Notably, compounds targeting KAT-II selectively may provide clinical benefits in a host of psychiatric and neurological disorders by normalizing the function of brain KYNA and its receptors (116, 163).
The product of KAT activity - KYNA is known to be a highly neuroactive metabolite whose impairment is associated with a number of severe brain disorders such as Alzheimer's disease (164), schizophrenia (165) ischemic stroke (166), and with type 2 diabetes (88) (Table 6). High levels of KYNA have been identified in human urine during marked vitamin B6 deficiency. Kocki et al. (167) has proven that the amino acid L-cysteine can down-regulate KYNA formation in the brain. A study among acute ischemic stroke patients revealed decreased activity of KAT, KYNA, L-tryptophan, and apolipoprotein A1 (166). Pregnancy results in an overall reduction of enzyme activity; however, the degree of reduction is minimal, and pregnancy does not enhance the effect of vitamin B6 restriction.
The role of a second product, XA, and the influence of vitamins and minerals on its production is not well known. XA accumulates in pre-synaptic terminals and is intensively produced and excreted in urine after the ingestion of L-tryptophan during vitamin B6 deficiency (145). Copeland (168) suggests that XA may be the first potential endogenous allosteric agonist (termed "endocoid") for the metabotropic glutamate receptors. Additionally, XA may participate in apoptotic events in vascular smooth muscle and retinal pigment epithelium cells with modifications in mitochondrial Ca2+ transport and oxygen consumption (169).
3-hydroxy-anthranilic acid 3,4-dioxygenase
3-HAO is an iron dependent enzyme requiring O2, Fe2+ and sulfhydryl groups for its activation (3, 170, 171). This enzyme is mainly localized to hepatic tissue in the mitochondrial membrane, but is also expressed in the brain, mainly in astrocytes (172), in the liver, and in the inflammatory cells (65). There are no structural differences between the enzyme from the brain and the liver, except that higher amounts of 3-HAO have been observed in the liver (173).
3-HAO activity may normally be restrained by certain factors such as the availability of Fe2+ ions and O2. The addition of Fe2+ stimulates the enzyme's activity 4- to 6-fold in striatal homogenates of mouse, rat, and human; and can be inhibited by ferritin (176). Iron released during neuronal damage stimulates 3-HAO and inhibits QPRT, thus significantly elevating the production of QUIN, which thereby causes more damage to the CNS. On the other hand, Zn2+ was described as having a negative impact on enzyme activity (7). Moreover iron ions are responsible for 3-OH-L-KYN induced neuronal cell death either by catalysing the oxidation of 3-OH-L-KYN or in promoting the production of highly reactive hydroxyl radicals (136, 152).
The role of 3-HAO in proper CNS functioning is still unclear and controversial. The activity of 3-HAO is significantly reduced in schizophrenia (73, 74), Huntington's disease (85), chronic brain injury (118), stroke (119), depression (120), and osteoporosis (121) (Table 6). In pathology, the normal ratio between 3-OH-AA and AA is also changed, with lower levels of 3-OH-AA and higher levels of AA than normal (175). There are also reports suggesting that 3-HAO plays anti-inflammatory and neuroprotective roles during inflammation, and thus may have implications for future therapeutic approaches for neuroinflammatory disorders (174). Thus, it is justifiable that reducing levels of toxic QUIN by administering such inhibitors of the enzymes of the KP, particularly 3-HAO, may be a reasonable approach for the treatment of such cognitive impairments (7).
2-amino 3-carboxymuconate 6-semialdehyde decarboxylase
ACMSD diverts 2-amino-3-carboxymuconate semialdehyde from QUIN production, towards picolinic acid (PA) formation, and thus is responsible for the proper homeostasis between PA, QUIN and NAD+ (Fig. 1). ACMSD is a Zn-dependent amidohydrolase (14) and is activated slightly by Fe2+ and Co2+ (13) (Table 7). On the other hand, QUIN, PA and KYNA inhibit ACMSD activity (13). Furthermore, interferon-gamma significantly down-regulates the expression of both ACMSD and KAT-I in cultured human glioma cells (61); however, it significantly potentiates the expression of IDO-1, IDO-2, KYNU, and KMO (Table 3). ACMSD is present in kidney and liver, with its highest expression occurring in kidney (13). As the relative concentrations of PA and QUIN must be tightly controlled, modulation of ACMSD may be another key to the treatment of neurological disorders (Table 4). Therefore, ACMSD is an attractive therapeutic target for treating disorders associated with increased levels of neurotoxic QUIN, and factors which directly influence enzyme activity may be an interesting approach to modulate L-tryptophan metabolism.
An increased concentration of bivalent metals such as Fe2+, Co2+ and Zn2+ may increase the concentration of PA, thereby decreasing QUIN formation.
"+" up-regulation; "-" down-regulation
Interestingly, PA may inhibit QPRT activity through Zn2+ chelation, thus reducing QUIN induced neurotoxicity (177).
Quinolinate phosphoribosyl transferase
QPRT has been identified in the CNS of both rats and humans (178, 179). The role of QPRT is to catabolize QUIN to NAD+ with carbon dioxide as a by-product. QUIN is often implicated in the pathogenesis of a variety of human neurological diseases, as it is an agonist of the NMDA receptor (158), and has a high in vivo potency as an excitotoxin (177). NAD+ is an important enzymatic cofactor that is vital to ongoing cell viability and maintenance of mechanisms such as the DNA repair protein poly(ADP-ribose) polymerases (180). Under physiological conditions, Mg2+ is required for QPRT activation with further evidence that a cysteine residue at the active site is required for reaction catalysis (178) (Table 7). The proper functioning of QPRT, which is dependent on Mg2+ intake, prevents the accumulation of toxic QUIN (Table 5). Mg2+ insufficiency may lead to the inhibition of enzyme, thus promoting accumulation of neurotoxic reactants. Grimaldi et al. (103) point out that Mg2+ deficiency may be the central precipitating event resulting in the symptomatology of Tourette's syndrome and several reported comorbid conditions. As of now, it is not known if Mg2+ supplementation influences enzymatic activity during the development of QUIN-induced toxicity of neurological processes, as free radical generation and oxidative stress are involved in this process.
On the other side of the coin, Cu2+ Fe2+, Fe3+, Zn2+ deficiencies are considered to up-regulate QPRT activity, and thus may inhibit QUIN accumulation (17, 62). Moreover, the complex formation between QUIN and excess Fe2+ can produce oxidative cell damage through lipid peroxidation and can inhibit the auto-oxidation of the Fe2+ complex which is responsible for in vitro DNA chain breakage (181). Thus, an excess of Fe2+ plays an etiologically significant role in neurodegenerative disorders (176). Pathologic accumulation of QUIN has been found in neurodegenerative disorders including Alzheimer's (99) and Huntington's disease (100) and has also been connected with the aging process (101, 102) (Table 4). Moreover, Sahm et al. (172) identifies QPRT as a potential therapeutic target in malignant gliomas. Sasaki et al. (104) suggest that the immune and neuronal systems of insulin dependent diabetes mellitus would be influenced by the increased amounts of QUIN and L-KYN, but not by those of PA and NAD+ as diabetes mellitus does not augment the latter species. Treatment with metal chelates such as PA demonstrate significant neuroprotection against QUIN-formation, responsible for excitotoxic damage to the brain, towards NAD+ formation (177).
Under pathological conditions, the concentrations of L-tryptophan, vasoactive L-kynurenine, neuroactive KYNA, QUIN, 3-OH-L-KYN, 3-OH-AA, and enzymes responsible for their formation (IDO, KMO, KAT, KYNU, 3-HAO) are significantly changed in blood, in urine and in the brain (182) (Table 4). Several of these enzymes are under the tight control of inflammatory mediators (59, 61). Also, the concentration of the essential amino acid L-tryptophan was reported to be decreased by the pro-inflammatory cytokines (59, 61). In septic shock patients, the concentration of L-tryptophan is decreased, as opposed to L-KYN which is intensively produced (75). Studies performed by Celinski et al. (183) demonstrate the protective effect of melatonin and L-tryptophan by reducing concentrations of pro-inflammatory Il-1, Il-6 and TNF-α. Also the concentrations of B group vitamins (76, 77, 86, 89, 107, 126, 146, 150, 151) and minerals are significantly altered (Table 5).
The evidence presented in this paper suggests that the KP is highly sensitive to changes in the concentration of B group vitamins (B2, B6) as well as micro- (Fe3+, Mn2+, Zn2+, Cu2+, Co2+) and macro-elements (Mg2+). Both vitamins and minerals can work as coenzymes and cofactors in de novo synthesis of another B-vitamin niacin. Another pathway of L-tryptophan metabolism, the serotonin pathway, is also dependent on proper diet and vitamin B6 status (184-186), which suggests that any alterations to L-tryptophan metabolism might also influence the production and activity of both serotonin and melatonin (187).
Minerals and B group vitamins at physiological concentrations can either directly up-regulate and/or down-regulate the activity of enzymes engaged in L-tryptophan metabolism (Table 7). Vitamin B6 was found to be the most crucial vitamin engaged in L-tryptophan metabolism, since it is involved in the proper functioning of the serotonin pathway enzyme tryptophan hydroxylase, and the kynurenine pathway enzymes KYNU and KAT.
However, surplus administration of B-group vitamins did not elicit beneficial effects on L-tryptophan metabolism, since deficiencies rather than surpluses seem to influence the KP (107). The administration of minerals in a normally balanced diet is not known to influence the KP.
Nutrient deficiencies plus coexisting physiological processes may have hyper-additive effects on biological systems, therefore causing increased harmful effects (76, 77). In other words, in alcoholics, people experiencing decreased food intake, and during high physical activity when the needs are increased (188), the concentration of L-tryptophan in the diet is not sufficient. Any diseases to the GI-tract influence both proper food absorption and GI synthesis of many organic compounds such as melatonin, serotonin or kynurenines in the gut (185). Thus, it is crucial to maintain proper functioning of the GI-tract, which will also accelerate the healing processes (189).
Pharmacological down-regulation of the L-tryptophan - L-KYN - NAD+ pathway together with a tryptophan-rich diet and maintenance of adequate B vitamins and minerals is important for patients susceptible to depression, diabetes, post-traumatic stress disorder, chronic pain, cancer, and drug addiction (186). It is likely that this regulation can also influence the progression of epilepsy, Parkinson's disease, Alzheimer's disease or schizophrenia (141). Other conditions associated with inflammation and stress-induced excess of L-KYN production that coincide with vitamin B6 deficiency are obesity, cardiovascular diseases, aging, pre-and postmenstrual phase in certain females, pregnancy, and hepatitis C virus infection (91).
It is therefore reasonable to assume that nutrients that affect the enzymes involved in the formation or metabolism of the "kynurenines" are useful tools that may improve our understanding of the role of those enzymes in physiology and pathology. However, much more diversified research is still needed to fully understand the complex interaction between enzymes and B group vitamins and minerals, how they react with each other, how they react within the nervous systems, as well as how they react on the periphery.
Abbreviations: 3-HAO, 3-hydroxy-anthranilic acid dioxygenase; 3-OH-AA, 3-hydroxy-antranilic acid; 3-OH-L-KYN, 3-hydroxy-L-kynurenine; 5-HT, serotonin; AA, anthranilic acid; CNS, central nervous system; ENS, enteric nervous system; FAD, flavin adenine dinucleotide; IBS, irritable bowel syndrome; IDO, indoleamine 2,3-dioxygenase; KAT, kynurenine aminotransferase; KF, kynurenine formamidase; KMO, kynurenine 3-monooxygenase; KP, kynurenine pathway; KYNA, kynurenic acid; KYNU, kynureninase or L-kynurenine hydrolase; L-KYN, L-kynurenine; L-TRP, L-tryptophan; NAD+, nicotinamide adenine dinucleotide; NMDA, N-methyl-D-aspartate; PA, picolinic acid; QPRT, quinolinate phosphoribosyl transferase; QUIN, quinolinic acid; TDO, tryptophan 2,3-dioxygenase; XA, xanthurenic acid.
Conflict of interests: None declared.
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A c c e p t e d : December 9, 2015