Quinolinic Acid in Neurological Disease: Opportunities for Novel Drug Discovery

Reinhard, John F.; Erickson, Joel B.; Flanagan, Ellen

doi:10.1016/s1054-3589(08)60173-8

Cited by 46 publications

(28 citation statements)

References 145 publications

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“…Finally, the observation that the S. pyogenes ⌬nadC mutant no longer grows on Qa while sustaining normal growth on Nm or Na confirms the physiological role of sp.NadC in Qa salvage. Although Qa, an intermediate of human NAD de novo synthesis from Trp, may accumulate in the host under certain pathological conditions (20), it is not expected to be nearly as abundant as the dietary niacin. Therefore, the actual physiological role of this pathway and its potential association with virulence have yet to be clarified.…”

Section: Resultsmentioning

confidence: 99%

“…Here, we report the experimental verification of this hypothesis by biochemical and genetic methods. The accumulation of quinolinate, a product of tryptophan degradation and a NAD precursor in humans, is associated with certain pathological conditions (20,21). It is tempting to speculate that the revealed unique metabolic capabilities of the group A streptococci may play a (yet unknown) role in hostpathogen interactions.…”

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confidence: 99%

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Quinolinate Salvage and Insights for Targeting NAD Biosynthesis in Group A Streptococci

Sorci¹,

Blaby²,

Rodionova³

et al. 2012

Journal of Bacteriology

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eThe essential coenzyme NAD plays important roles in metabolic reactions and cell regulation in all organisms. As such, NAD synthesis has been investigated as a source for novel antibacterial targets. Cross-species genomics-based reconstructions of NAD metabolism in group A streptococci (GAS), combined with focused experimental testing in Streptococcus pyogenes, led to a better understanding of NAD metabolism in the pathogen. The predicted niacin auxotrophy was experimentally verified, as well as the essential role of the nicotinamidase PncA in the utilization of nicotinamide (Nm). PncA is dispensable in the presence of nicotinate (Na), ruling it out as a viable antibacterial target. The function of the "orphan" NadC enzyme, which is uniquely present in all GAS species despite the absence of other genes of NAD de novo synthesis, was elucidated. Indeed, the quinolinate (Qa) phosphoribosyltransferase activity of NadC from S. pyogenes allows the organism to sustain growth when Qa is present as a sole pyridine precursor. Finally, the redundancy of functional upstream salvage pathways in GAS species narrows the choice of potential drug targets to the two indispensable downstream enzymes of NAD synthesis, nicotinate adenylyltransferase (NadD family) and NAD synthetase (NadE family). Biochemical characterization of NadD confirmed its functional role in S. pyogenes, and its potential as an antibacterial target was supported by inhibition studies with previously identified class I inhibitors of the NadD enzyme family. One of these inhibitors efficiently inhibited S. pyogenes NadD (sp.NadD) in vitro (50% inhibitory concentration [IC 50 ], 15 M), exhibiting a noncompetitive mechanism with a K i of 8 M.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Quinolinate Salvage and Insights for Targeting NAD Biosynthesis in Group A Streptococci

Sorci¹,

Blaby²,

Rodionova³

et al. 2012

Journal of Bacteriology

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“…Some L-KYN is also actively transported into neurons, but this process is much slower and, unlike glial L-KYN uptake, critically dependent on the supply of Na ϩ (Speciale and Schwarcz, 1990). Of possible functional significance, 3-HK also penetrates into the brain and is then accumulated by brain cells, using the same uptake mechanisms as L-KYN (Eastman et al, 1992;Reinhard et al, 1994; cf. Fig.…”

Section: Dynamics Of Kynurenine Pathway Metabolism In the Periphery Amentioning

confidence: 99%

“…These enzyme inhibitors allow the judicious up-or down-regulation of the brain concentration of 3-HK, QUIN, and KYNA. Although the levels of brain kynurenines can be effectively manipulated by influencing the activity of peripheral KP enzymes (Reinhard et al, 1994), new agents with better brain access and pharmacodynamic properties should soon make it possible to target cerebral KP enzymes directly. Such compounds are currently under development and hold promise as investigative tools and therapeutically useful drugs.…”

Section: Outlook: the Road To Kynurenergic Therapiesmentioning

confidence: 99%

Manipulation of Brain Kynurenines: Glial Targets, Neuronal Effects, and Clinical Opportunities

Schwarcz

Pellicciari²

2002

J Pharmacol Exp Ther

501

418

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Degradation of the essential amino acid tryptophan along the kynurenine pathway (KP) yields several neuroactive intermediates, including the free radical generator 3-hydroxykynurenine, the excitotoxic N-methyl-D-aspartate (NMDA) receptor agonist quinolinic acid, and the NMDA and ␣7 nicotinic acetylcholine receptor antagonist kynurenic acid. The ambient levels of these compounds are determined by several KP enzymes, which in the brain are preferentially localized in astrocytes and microglial cells. Normal fluctuations in the brain levels of neuroactive KP intermediates might modulate several neurotransmitter systems. Impairment of KP metabolism is functionally significant and occurs in a variety of diseases that affect the brain. Pharmacological agents targeting specific KP enzymes are now available to manipulate the concentration of neuroactive KP intermediates in the brain. These compounds can be used to normalize KP defects, show remarkable efficacy in animal models of central nervous system disorders, and offer novel therapeutic opportunities. Neuroactive Tryptophan MetabolitesIn mammals, the vast majority of dietary tryptophan is metabolized via the kynurenine pathway (KP) (Scheme 1), which is initiated by the oxidative opening of the indole ring and eventually produces the ubiquitous enzyme cofactor NAD ϩ . This catabolic cascade is notable for the fact that it contains three neuroactive intermediates, all of which derive directly or indirectly from L-kynurenine (L-KYN), the primary major degradation product of tryptophan. One of the three compounds, kynurenic acid (KYNA), is formed in a "dead end" side-arm of the pathway, whereas the other two, 3-hydroxykynurenine (3-HK) and quinolinic acid (QUIN), are synthesized from L-KYN en route to NAD ϩ . Although all kynurenines-the collective term used for KP intermediates shown in Scheme 1-are found in high concentration in urine (hence the name), none of them has so far been assigned an important physiological function in peripheral organs.The first indication that kynurenines might play a role in the brain was provided by Lapin (1978), who noted convulsions after an intracerebroventricular QUIN injection in mice. Soon thereafter, ionophoretically applied QUIN was found to excite rat cortical neurons (Stone and Perkins, 1981), and intracerebrally injected QUIN was shown to cause excitotoxic lesions in rat brain (Schwarcz et al., 1983). Both QUIN-induced excitation and neurotoxicity are mediated by N-methyl-D-aspartate (NMDA) receptors, leading to the suggestion that endogenous QUIN might participate in physiological and pathological processes that are associated with NMDA receptor activation. Indeed, QUIN occurs naturally in the mammalian brain, although the low QUIN content of cerebral tissue (50 -1000 nM) is difficult to reconcile with its low receptor affinity (ED 50 Ͼ100 M). It appears that the remarkably high in vivo potency of QUIN, particularly as an excitotoxin, is caused by a combination of factors, including the absence of effective removal mech...

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“…27 Briefly, CSF and blood samples (50 pi) were mixed with 10 pmol of [13C7]quinolinic acid as the internal standard (Cambridge Isotope Laboratories, Andover, MA) and dried in 1.5-ml polypropylene tubes in a negative-pressure centrifuge (Savant, Hicksville, NY). Hexafluoro-2-propanol (50 pi) and trifluoroacetylimidazole (50 pi) were added to the dried residues.…”

Section: Quinolinic Acidmentioning

confidence: 99%

Quinolinic Acid and Lymphocyte Subsets in the Intrathecal Compartment as Biomarkers of SIV Infection and Simian AIDS

Coe¹,

Reyes²,

Pauza³

et al. 1997

AIDS Research and Human Retroviruses

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Cerebrospinal fluid (CSF) samples were collected from monkeys infected with SIVmac251 (SIV) or HIV-1/SIVmac chimeric viruses (SHIV(HXBc2) and SHIV(89.6P)) to investigate quinolinic acid (QUIN) levels in the intrathecal compartment. CSF levels of QUIN were elevated in the SIV-infected monkeys, especially in animals with end-stage disease, and in those infected with pathogenic SHIV(89.6P), but not after infection with the nonpathogenic construct SHIV(HXBc2). QUIN elevations occurred in association with reduced CD4+ and increased CD8+ lymphocytes, cellular alterations that were more pronounced in CSF than in the blood. These findings support the view that the intrathecal compartment provides a unique window on viral infection, and are in keeping with the a priori prediction that QUIN increases primarily in response to more pathogenic viral strains.

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Quinolinic Acid in Neurological Disease: Opportunities for Novel Drug Discovery

Cited by 46 publications

References 145 publications

Quinolinate Salvage and Insights for Targeting NAD Biosynthesis in Group A Streptococci

Quinolinate Salvage and Insights for Targeting NAD Biosynthesis in Group A Streptococci

Manipulation of Brain Kynurenines: Glial Targets, Neuronal Effects, and Clinical Opportunities

Quinolinic Acid and Lymphocyte Subsets in the Intrathecal Compartment as Biomarkers of SIV Infection and Simian AIDS

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