GO:0046874 quinolinate metabolic process: NAD+ Biosynthesis Pathway, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0046874 quinolinate metabolic process describes the chemical reactions and pathways involving quinolinate, the anion of quinolinic acid (2,3-pyridinedicarboxylic acid).
• Quinolinate is a central intermediate in de novo NAD+ biosynthesis, linking tryptophan catabolism through the kynurenine pathway to cellular energy metabolism and redox homeostasis.
• Dysregulation of quinolinate metabolism is implicated in acute kidney injury, inflammatory bowel disease, neurodegeneration, and major depressive disorder.
• Quinolinate can act as a neuroactive metabolite, and its interaction with receptors such as RAGE has been modeled in early neuropathological processes.
• Key enzymes of this process include QPRT, which converts quinolinate to nicotinate mononucleotide, and upstream kynurenine pathway enzymes such as IDO1, TDO2, KMO, and KYNU.
• CRISPR-based knockout, point-mutation, knock-in, and overexpression models enable causal interrogation of quinolinate metabolic genes in disease contexts.
Description
Quinolinate metabolic process (GO:0046874) is the set of biochemical reactions and pathways that produce, interconvert, and utilize quinolinate, the anion of quinolinic acid (2,3-pyridinedicarboxylic acid). This process is best known as a central segment of the de novo NAD+ biosynthetic route from tryptophan, where quinolinate is generated by the kynurenine pathway and then converted to nicotinate mononucleotide by quinolinate phosphoribosyltransferase (QPRT). Because NAD+ is required for redox reactions, DNA repair, and signaling, quinolinate metabolism sits at the interface of amino acid catabolism and cellular energy homeostasis. Beyond its housekeeping role, quinolinate is a neuroactive and immunomodulatory metabolite. Its accumulation has been associated with excitotoxic and inflammatory processes, and computational modeling has explored its interaction with the receptor for advanced glycation end products (RAGE) in early neuropathological events. Clinical and translational studies have linked altered quinolinate pathway flux to inflammatory bowel disease activity, acute kidney injury, Alzheimer's disease, and major depressive disorder. Consequently, researchers study GO:0046874 to understand how tryptophan catabolism contributes to disease and to identify therapeutic or biomarker opportunities. This article summarizes the definition, mechanism, key genes, disease relevance, and experimental models for quinolinate metabolic process, with an emphasis on CRISPR-based approaches for functional validation.
quinolinate metabolic process At A Glance
| GO ID | GO:0046874 |
|---|---|
| GO term | quinolinate metabolic process |
| Ontology | biological_process |
| Synonym | quinolinate metabolism |
| Definition | The chemical reactions and pathways involving quinolinate, the anion of quinolinic acid, also known as 2,3-pyridinedicarboxylic acid. |
| Major function | Production and utilization of quinolinate as an intermediate in de novo NAD+ biosynthesis from tryptophan. |
| Key enzyme | QPRT converts quinolinate to nicotinate mononucleotide. |
| Pathway context | Kynurenine pathway of tryptophan catabolism. |
| Disease relevance | Acute kidney injury, inflammatory bowel disease, neurodegeneration, major depressive disorder. |
What Is GO:0046874?
According to the Gene Ontology, quinolinate metabolic process (GO:0046874) is defined as the chemical reactions and pathways involving quinolinate, the anion of quinolinic acid, also known as 2,3-pyridinedicarboxylic acid. In practice, this includes the enzymatic steps that synthesize quinolinate from kynurenine pathway intermediates, the conversion of quinolinate to nicotinate mononucleotide, and any transport or interconversion reactions that maintain quinolinate pools.
Why Is quinolinate metabolic process Important in Cell Biology?
Quinolinate metabolic process is important because it controls a rate-limiting node in de novo NAD+ biosynthesis and because quinolinate itself can influence neuroinflammation and excitotoxicity. Perturbations in this pathway have been observed in human diseases ranging from acute kidney injury to inflammatory bowel disease and major depressive disorder, making it a target for mechanistic studies and biomarker development.
• Quinolinate is an obligatory intermediate in de novo NAD+ synthesis from tryptophan, linking amino acid catabolism to cellular redox balance.
• The enzyme QPRT catalyzes the conversion of quinolinate to nicotinate mononucleotide, a committed step in NAD+ production.
• Quinolinate accumulation has been associated with neurotoxic and inflammatory processes, and its interaction with RAGE has been modeled in early neuropathology.
• Increased tryptophan metabolism, including quinolinate pathway flux, is associated with activity of inflammatory bowel diseases.
• De novo NAD+ biosynthetic impairment, involving quinolinate pathway enzymes, has been reported in acute kidney injury in humans.
• Kynurenine pathway dysregulation, including quinolinate, is implicated in major depressive disorder through excitotoxicity, neuroinflammation, and oxidative stress.
• Salivary kynurenine pathway metabolites, including quinolinate-related analytes, are being explored as non-invasive markers of glandular dysfunction in Sjögren's disease.
• Quinolinate metabolism intersects with immune regulation, as tryptophan catabolism modulates immune responses.
• Alzheimer's disease research has examined kynurenines and quinolinate as contributors to neurodegeneration.
• CRISPR models enable causal testing of quinolinate metabolic genes in disease-relevant cell types.
What Happens During quinolinate metabolic process?
Tryptophan catabolism to kynurenine
In simple terms: The process starts when the amino acid tryptophan is broken down into kynurenine.
Quinolinate production begins with the conversion of tryptophan to kynurenine, catalyzed by enzymes such as indoleamine 2,3-dioxygenase (IDO1) or tryptophan 2,3-dioxygenase (TDO2). This step links immune and inflammatory signals to downstream NAD+ synthesis.
Kynurenine to quinolinate
In simple terms: Kynurenine is then converted through several steps into quinolinate.
Kynurenine is metabolized by kynurenine 3-monooxygenase (KMO), kynureninase (KYNU), and other enzymes to produce 3-hydroxyanthranilate, which spontaneously or enzymatically forms quinolinate. This segment is a key control point for quinolinate levels.
Quinolinate to nicotinate mononucleotide
In simple terms: Quinolinate is converted into a precursor that can be used to make NAD+.
Quinolinate phosphoribosyltransferase (QPRT) catalyzes the conversion of quinolinate to nicotinate mononucleotide, a committed step in de novo NAD+ biosynthesis. This reaction is essential for maintaining NAD+ pools in many tissues.
NAD+ synthesis and cellular utilization
In simple terms: The product of quinolinate metabolism feeds into NAD+ production, which cells use for energy and signaling.
Nicotinate mononucleotide is further converted to nicotinate adenine dinucleotide and then to NAD+. NAD+ is required for redox reactions, DNA repair, and signaling, so quinolinate metabolism directly supports cellular homeostasis.
Quinolinate as a signaling or neuroactive metabolite
In simple terms: Quinolinate itself can interact with cellular receptors and contribute to neuroinflammation.
Quinolinate has been modeled to interact with RAGE, suggesting a role in early neuropathological processes. Its accumulation has been linked to excitotoxicity and neuroinflammation in conditions such as major depressive disorder.
Key Genes Involved in GO:0046874 quinolinate metabolic process
The following genes and proteins are central to quinolinate metabolic process, spanning tryptophan catabolism, quinolinate synthesis, and NAD+ production.
| Gene | Major Role | Research Relevance |
|---|---|---|
| IDO1 | Catalyzes tryptophan to kynurenine | Immune regulation and inflammation |
| TDO2 | Catalyzes tryptophan to kynurenine | Hepatic tryptophan catabolism |
| KMO | Converts kynurenine to 3-hydroxykynurenine | Neurodegeneration and inflammation |
| KYNU | Converts 3-hydroxykynurenine to 3-hydroxyanthranilate | Quinolinate pathway flux |
| QPRT | Converts quinolinate to nicotinate mononucleotide | NAD+ biosynthesis and disease |
| HAAO | Converts 3-hydroxyanthranilate to quinolinate | Quinolinate production |
| NADSYN1 | Converts nicotinate mononucleotide to NAD+ | NAD+ homeostasis |
| NMNAT1 | NAD+ synthesis | NAD+ homeostasis |
| RAGE | Receptor for advanced glycation end products | Quinolinate interaction in neuropathology |
| SLC22A | Transport of kynurenine pathway metabolites | Metabolite transport |
| IL6 | Inflammatory cytokine | Inflammation-associated tryptophan metabolism |
| TNF | Inflammatory cytokine | Inflammation-associated tryptophan metabolism |
| IFNG | Induces IDO1 | Immune response |
| CCL2 | Chemokine | Neuroinflammation |
| BDNF | Neurotrophic factor | Depression and neuroplasticity |
| NLRP3 | Inflammasome component | Neuroinflammation |
| CASP1 | Inflammasome protease | Neuroinflammation |
How Is quinolinate metabolic process Regulated?
Quinolinate metabolic process is regulated at multiple levels. Inflammatory cytokines such as interferon-gamma induce IDO1, increasing flux from tryptophan toward kynurenine and downstream quinolinate. Enzyme expression and activity of KMO, KYNU, and QPRT further determine quinolinate levels and NAD+ synthesis. In disease states, such as inflammatory bowel disease and acute kidney injury, pathway activity is altered, suggesting regulation by inflammatory and metabolic stress signals. Additionally, quinolinate itself may influence RAGE-mediated signaling, providing a feedback mechanism in neuropathology.
quinolinate metabolic process and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| QPRT | Acute kidney injury | QPRT knockout kidney organoids |
| IDO1 | Inflammatory bowel disease | IDO1 knockout intestinal epithelial cells |
| KMO | Neurodegeneration | KMO knockout neurons |
| KYNU | Major depressive disorder | KYNU overexpression in microglia |
| HAAO | Neuroinflammation | HAAO knockout astrocytes |
Quinolinate metabolism in inflammatory bowel disease
Increased tryptophan metabolism, including quinolinate pathway activity, is associated with activity of inflammatory bowel diseases. This suggests that quinolinate metabolic genes may serve as biomarkers or therapeutic targets in IBD.
Quinolinate metabolism in acute kidney injury
De novo NAD+ biosynthetic impairment, involving quinolinate pathway enzymes, has been reported in acute kidney injury in humans. This links quinolinate metabolism to kidney injury and NAD+ depletion.
Quinolinate metabolism in neurodegeneration and depression
Kynurenine pathway dysregulation, including quinolinate, is implicated in Alzheimer's disease and major depressive disorder through excitotoxicity, neuroinflammation, and oxidative stress. Quinolinate interaction with RAGE has been modeled in early neuropathological processes.
Quinolinate metabolism in Sjögren's disease
Salivary kynurenine pathway metabolites, including quinolinate-related analytes, are being explored as non-invasive markers of glandular dysfunction in Sjögren's disease.
From quinolinate metabolic process-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does QPRT loss impair NAD+ synthesis? | QPRT knockout cell line |
| Does a point mutation in QPRT alter enzyme activity? | QPRT point-mutation knock-in |
| Does tagging QPRT affect its localization? | QPRT tagged knock-in |
| Does IDO1 overexpression increase quinolinate flux? | IDO1 overexpression cell line |
| Does KMO knockout alter neurotoxicity? | KMO knockout neurons |
| Does KYNU knockdown affect depression-like behavior? | KYNU knockdown mouse model |
How to Study the quinolinate metabolic process Process
| Method | What It Measures | Typical Application |
|---|---|---|
| LC-MS metabolomics | Quinolinate and pathway metabolites | Biomarker discovery |
| CRISPR knockout screening | Gene essentiality for quinolinate production | Pathway gene discovery |
| RNA-seq | Gene expression changes | Inflammation studies |
| Proteomics | Protein abundance and modifications | Enzyme regulation |
| NAD+ reporter assay | Intracellular NAD+ levels | NAD+ homeostasis |
| Immunofluorescence | Protein localization | Enzyme trafficking |
| Stable isotope tracing | Metabolic flux | Pathway activity |
Metabolomics and flux analysis
Mass spectrometry-based metabolomics can quantify quinolinate and other kynurenine pathway metabolites in cells and biofluids. Stable isotope tracing can measure flux through quinolinate metabolic process.
CRISPR screening
Genome-wide CRISPR knockout screens can identify genes that regulate quinolinate levels or NAD+ synthesis. Focused libraries targeting kynurenine pathway genes enable pathway-specific interrogation.
Transcriptomics and proteomics
RNA-seq and proteomics can reveal expression changes in quinolinate metabolic genes under inflammatory or metabolic stress. This helps identify regulatory mechanisms.
Imaging and reporter assays
Fluorescent or luminescent NAD+ reporters can monitor NAD+ levels downstream of quinolinate metabolism. Imaging of tagged enzymes can reveal subcellular localization.
How CRISPR Can Be Used to Study GO:0046874 quinolinate metabolic process
Knockout
CRISPR knockout of QPRT, IDO1, KMO, or KYNU can abolish or reduce quinolinate metabolic flux, enabling causal tests of pathway function in disease models.
Point Mutation
Point mutations in QPRT or other enzymes can mimic human variants, allowing assessment of catalytic activity and substrate specificity.
Knock-in
Knock-in of tagged or reporter alleles enables real-time monitoring of quinolinate metabolic enzymes and their localization.
Overexpression
Overexpression of IDO1 or KYNU can increase quinolinate production, modeling inflammatory or neurodegenerative conditions.
How EDITGENE Supports quinolinate metabolic process Research
Researchers studying quinolinate metabolic process-related genes often need to determine whether a candidate gene is causally involved in metabolite production, NAD+ homeostasis, or disease phenotypes. EDITGENE provides CRISPR-based cell models and screening services to accelerate this functional validation.
Contact EDITGENE today to design your custom CRISPR model for quinolinate metabolic process research.
Frequently Asked Questions About quinolinate metabolic process
What is quinolinate metabolic process?
Quinolinate metabolic process (GO:0046874) is the set of biochemical reactions involving quinolinate, an intermediate in de novo NAD+ biosynthesis from tryptophan.
What genes are involved in quinolinate metabolic process?
Key genes include IDO1, TDO2, KMO, KYNU, HAAO, QPRT, and NADSYN1, which catalyze steps from tryptophan to NAD+.
What is the role of QPRT in quinolinate metabolism?
QPRT converts quinolinate to nicotinate mononucleotide, a committed step in NAD+ synthesis.
How is quinolinate linked to inflammation?
Inflammatory cytokines induce IDO1, increasing tryptophan catabolism and quinolinate production.
Is quinolinate involved in kidney disease?
Yes, de novo NAD+ biosynthetic impairment involving quinolinate pathway enzymes has been reported in acute kidney injury.
Can quinolinate metabolism be studied with CRISPR?
Yes, CRISPR knockout, point mutation, knock-in, and overexpression models enable functional studies of quinolinate metabolic genes.
What diseases are associated with quinolinate dysregulation?
Inflammatory bowel disease, acute kidney injury, Alzheimer's disease, major depressive disorder, and Sjögren's disease have been linked to altered quinolinate metabolism.
How is quinolinate measured in research?
Liquid chromatography-mass spectrometry (LC-MS) is commonly used to quantify quinolinate and related metabolites.
What is the connection between quinolinate and NAD+?
Quinolinate is an intermediate in de novo NAD+ biosynthesis; its conversion by QPRT feeds into NAD+ production.
What model systems are used to study quinolinate metabolic process?
Cell lines, organoids, and animal models with CRISPR edits in pathway genes are used to study quinolinate metabolism.
Conclusion
Quinolinate metabolic process (GO:0046874) is a critical biological process that bridges tryptophan catabolism and NAD+ biosynthesis. Its dysregulation is implicated in inflammatory, metabolic, and neurodegenerative diseases, making it a compelling area for mechanistic and translational research. CRISPR-based models and multi-omics approaches provide powerful tools to dissect the causal roles of quinolinate metabolic genes. EDITGENE offers comprehensive services to support these investigations.
References
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