GO:1904985 negative regulation of quinolinate biosynthetic process: Metabolic Control, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:1904985 describes any process that stops, prevents, or reduces the frequency, rate, or extent of quinolinate biosynthetic process, a key branch of tryptophan catabolism.
• Quinolinate is an intermediate in the kynurenine pathway, and its biosynthesis is tightly linked to mitochondrial oxidative stress and neuroprotection.
• The kynurenine pathway, including quinolinate production, is implicated in chronic pain, schizophrenia, and psoriasis.
• Key enzymes such as QPRT, KYNU, and TDO2 regulate quinolinate levels, and their expression is altered in cancers such as triple-negative breast cancer.
• Cytochrome P450 enzymes engage in tryptophan metabolism, indirectly influencing quinolinate biosynthetic flux.
• CRISPR knockout, point mutation, knock-in, and overexpression models are essential to dissect the negative regulation of quinolinate biosynthesis in disease contexts.
Description
The Gene Ontology term GO:1904985, negative regulation of quinolinate biosynthetic process, defines any process that stops, prevents, or reduces the frequency, rate, or extent of quinolinate biosynthesis. Quinolinate is a neuroactive intermediate of the kynurenine pathway, which is the major route of tryptophan catabolism. The kynurenine pathway is involved in immune regulation, neurotoxicity, and mitochondrial function, and its dysregulation has been linked to chronic pain, schizophrenia, and psoriasis. Understanding how quinolinate biosynthesis is negatively regulated is therefore critical for developing therapeutic strategies that target this pathway. Recent studies have highlighted the role of enzymes such as QPRT, KYNU, and TDO2 in controlling quinolinate levels, and their expression patterns have been associated with cancer progression and survival. Additionally, cytochrome P450 enzymes contribute to tryptophan metabolism, further influencing quinolinate production. This article synthesizes current knowledge on the negative regulation of quinolinate biosynthesis, focusing on the molecular players, regulatory mechanisms, and experimental models used to study this process.
negative regulation of quinolinate biosynthetic process At A Glance
| GO ID | GO:1904985 |
|---|---|
| GO term | negative regulation of quinolinate biosynthetic process |
| Ontology | biological_process |
| Synonym | down regulation of quinolinate anabolism; inhibition of quinolinate biosynthesis; negative regulation of quinolinate formation |
| Major function | Reduces the rate of quinolinate production, impacting kynurenine pathway flux and downstream neuroactive metabolites |
| Related pathway | Kynurenine pathway of tryptophan catabolism |
| Key enzymes | QPRT, KYNU, TDO2, and cytochrome P450 enzymes |
| Disease relevance | Chronic pain, schizophrenia, psoriasis, and triple-negative breast cancer |
What Is GO:1904985?
GO:1904985 refers to any biological process that negatively regulates the biosynthesis of quinolinate, a key intermediate in the kynurenine pathway. This regulation can occur at transcriptional, post-transcriptional, or enzymatic levels, ultimately reducing the production of quinolinate.
Why Is negative regulation of quinolinate biosynthetic process Important in Cell Biology?
Negative regulation of quinolinate biosynthesis is crucial because quinolinate is a potent neurotoxin and an NMDA receptor agonist; its overproduction is associated with neurodegenerative and inflammatory conditions. Tight control of this pathway prevents excitotoxicity and maintains mitochondrial homeostasis. Moreover, the kynurenine pathway is a source of NAD+ and immune modulators, so its dysregulation can affect cancer progression and immune responses.
• Prevents neurotoxicity by limiting quinolinate accumulation.
• Modulates chronic pain conditions through kynurenine pathway metabolites.
• Influences schizophrenia treatment outcomes via inflammation-linked kynurenine metabolites.
• Regulates skin inflammation in psoriasis through AhR signaling.
• Affects cancer cell survival and pharmacotherapy strategies in triple-negative breast cancer.
• Impacts mitochondrial function and oxidative stress responses.
• Interacts with cytochrome P450-mediated tryptophan metabolism.
• Provides targets for therapeutic intervention in inflammatory and neurological disorders.
What Happens During negative regulation of quinolinate biosynthetic process?
Initiation of negative regulation
In simple terms: The cell senses excess quinolinate or upstream signals and triggers a brake on its production.
Negative regulation can be initiated by transcriptional repression of genes encoding quinolinate biosynthetic enzymes such as QPRT or KYNU, or by post-translational modifications that inhibit their activity. Inflammatory signals and oxidative stress can also modulate this process.
Enzymatic control points
In simple terms: Specific enzymes act as gatekeepers that slow down quinolinate synthesis.
QPRT catalyzes the conversion of quinolinate to NAD+, effectively reducing quinolinate levels. KYNU and TDO2 are upstream enzymes whose inhibition can decrease quinolinate flux. Cytochrome P450 enzymes can divert tryptophan away from the kynurenine pathway, indirectly reducing quinolinate production.
Feedback and signaling
In simple terms: The pathway can shut itself down when products accumulate.
NAD+ levels can feedback to inhibit upstream enzymes, while AhR signaling activated by quinolinate can induce negative regulators. In chronic pain, kynurenine metabolites may modulate neuroinflammation, affecting quinolinate production.
Integration with mitochondrial function
In simple terms: Mitochondria are the site of quinolinate synthesis, so their health affects regulation.
Mitochondrial dysfunction and oxidative stress can impair quinolinate biosynthesis, and negative regulation may involve mitochondrial sirtuins or antioxidant responses.
Key Genes Involved in GO:1904985 negative regulation of quinolinate biosynthetic process
The following genes and proteins are key players in the negative regulation of quinolinate biosynthesis, based on their roles in the kynurenine pathway and associated regulatory mechanisms.
| Gene | Major Role | Research Relevance |
|---|---|---|
| QPRT | Converts quinolinate to NAD+, reducing quinolinate levels | Biomarker in triple-negative breast cancer |
| KYNU | Catalyzes upstream step in kynurenine pathway | Target for modulating quinolinate production |
| TDO2 | Rate-limiting enzyme in tryptophan catabolism | Influences quinolinate flux |
| IDO1 | Alternative tryptophan catabolism enzyme | Immune regulation and cancer |
| IDO2 | Tryptophan catabolism | Less characterized, potential regulator |
| KMO | Kynurenine 3-monooxygenase | Neuroprotection |
| AHR | Aryl hydrocarbon receptor, mediates quinolinate signaling | Psoriasis and inflammation |
| CYP1A1 | Cytochrome P450, tryptophan metabolism | Indirect regulation |
| CYP1B1 | Cytochrome P450, tryptophan metabolism | Indirect regulation |
| NLRP3 | Inflammasome, negatively regulated by quinolinate | Psoriasis |
| SIRT3 | Mitochondrial sirtuin, oxidative stress response | Mitochondrial regulation |
| NFE2L2 | Oxidative stress response transcription factor | Neuroprotection |
| IL6 | Inflammatory cytokine, modulates kynurenine pathway | Schizophrenia |
| TNF | Inflammatory cytokine | Chronic pain |
| FMO2 | Intestinal enzyme, metabolic regulation | Behavior and metabolism |
| RAB26 | Vesicle trafficking, potential biomarker | Triple-negative breast cancer |
| SRPRB | Signal recognition particle receptor | Triple-negative breast cancer |
How Is negative regulation of quinolinate biosynthetic process Regulated?
The negative regulation of quinolinate biosynthesis is controlled by multiple mechanisms, including transcriptional repression of biosynthetic enzymes, feedback inhibition by NAD+, and inflammatory signaling. Cytochrome P450 enzymes can divert tryptophan from the kynurenine pathway, reducing quinolinate production. AhR signaling activated by quinolinate can induce negative feedback loops. Mitochondrial oxidative stress and sirtuin activity also modulate this process.
negative regulation of quinolinate biosynthetic process and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| QPRT | Triple-negative breast cancer | Knockout in MDA-MB-231 cells |
| AHR | Psoriasis | Knockout in keratinocytes |
| KYNU | Chronic pain | Knockdown in dorsal root ganglia neurons |
| IL6 | Schizophrenia | Overexpression in patient-derived cells |
| SIRT3 | Neurodegeneration | Knockout in neurons |
Quinolinate dysregulation in chronic pain
The kynurenine pathway, including quinolinate, is implicated in chronic pain conditions. Negative regulation of quinolinate biosynthesis may reduce neuroinflammation and pain sensitization.
Schizophrenia and inflammation
In schizophrenia, electroconvulsive therapy alters kynurenine metabolites, and inflammation is associated with clinical efficacy. Negative regulation of quinolinate may influence treatment response.
Psoriasis and skin inflammation
Quinolinic acid from skin microbiota negatively regulates NLRP3 inflammasome through AhR, suggesting that negative regulation of quinolinate biosynthesis could modulate psoriasis inflammation.
Triple-negative breast cancer
Expression of QPRT, RAB26, and SRPRB is altered in triple-negative breast cancer, and QPRT-mediated reduction of quinolinate may affect cancer metabolism and survival.
From negative regulation of quinolinate biosynthetic process-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does QPRT knockout increase quinolinate levels? | CRISPR knockout in cancer cell lines |
| Does point mutation in KYNU affect enzyme activity? | CRISPR point mutation in HEK293 cells |
| Can knock-in of a tagged QPRT track localization? | Knock-in of fluorescent tag in iPSCs |
| Does overexpression of AHR reduce quinolinate? | Overexpression in keratinocytes |
| Does SIRT3 knockout alter mitochondrial quinolinate? | Knockout in neuronal cells |
| Does IL6 overexpression affect kynurenine pathway? | Overexpression in immune cells |
How to Study the negative regulation of quinolinate biosynthetic process Process
| Method | What It Measures | Typical Application |
|---|---|---|
| RNA-seq | Gene expression changes | Identify transcriptional repression of biosynthetic genes |
| LC-MS/MS | Metabolite levels | Quantify quinolinate and kynurenine |
| CRISPR knockout | Gene function loss | Test candidate negative regulators |
| CRISPR activation | Gene overexpression | Screen for suppressors of quinolinate |
| Proteomics | Protein modifications | Detect inhibitory phosphorylation |
| Immunofluorescence | Protein localization | Track enzyme localization |
| Seahorse assay | Mitochondrial function | Assess oxidative stress |
| Flow cytometry | Immune cell phenotypes | Measure inflammasome activity |
Transcriptomic analysis
RNA-seq can quantify expression of quinolinate biosynthetic genes such as QPRT, KYNU, and TDO2 under conditions that induce negative regulation.
Metabolomics
LC-MS/MS can measure quinolinate and other kynurenine pathway metabolites to assess pathway flux.
Proteomics
Mass spectrometry-based proteomics can identify post-translational modifications on enzymes involved in quinolinate biosynthesis.
CRISPR screening
Genome-wide CRISPR knockout screens can identify negative regulators of quinolinate production by selecting for cells with altered metabolite levels.
How CRISPR Can Be Used to Study GO:1904985 negative regulation of quinolinate biosynthetic process
Knockout
CRISPR knockout of QPRT or KYNU can abolish negative regulation, leading to quinolinate accumulation, which can be measured by metabolomics.
Point Mutation
Introducing point mutations in catalytic residues of QPRT can dissect its role in quinolinate turnover without affecting protein stability.
Knock-in
Knock-in of a fluorescent tag on QPRT allows real-time tracking of its localization and interaction with other pathway components.
Overexpression
Overexpression of AHR or SIRT3 can enhance negative regulation of quinolinate biosynthesis, providing a gain-of-function model.
How EDITGENE Supports negative regulation of quinolinate biosynthetic process Research
Researchers studying negative regulation of quinolinate biosynthetic process-related genes often need to determine whether a candidate gene is causally involved in controlling quinolinate levels or is merely a bystander. EDITGENE provides comprehensive CRISPR gene editing services to enable precise functional studies.
Contact EDITGENE today to design your custom CRISPR model for negative regulation of quinolinate biosynthetic process research.
Frequently Asked Questions About negative regulation of quinolinate biosynthetic process
What is GO:1904985?
GO:1904985 is the Gene Ontology term for negative regulation of quinolinate biosynthetic process, describing any process that reduces the rate of quinolinate production.
What genes are involved in negative regulation of quinolinate biosynthetic process?
Key genes include QPRT, KYNU, TDO2, AHR, and SIRT3, which modulate quinolinate levels through enzymatic or signaling mechanisms.
How is quinolinate biosynthesis regulated?
It is regulated by transcriptional repression, feedback inhibition by NAD+, and inflammatory signals that affect enzyme activity.
What diseases are associated with quinolinate dysregulation?
Chronic pain, schizophrenia, psoriasis, and triple-negative breast cancer have been linked to altered quinolinate levels.
What is the role of QPRT in quinolinate regulation?
QPRT converts quinolinate to NAD+, thereby reducing quinolinate levels and acting as a negative regulator.
How can CRISPR be used to study quinolinate biosynthesis?
CRISPR knockout, point mutation, knock-in, and overexpression can manipulate genes like QPRT and KYNU to assess their impact on quinolinate production.
What experimental models are used for quinolinate research?
Common models include cancer cell lines, neuronal cells, and keratinocytes, often with CRISPR editing.
What is the kynurenine pathway?
The kynurenine pathway is the major route of tryptophan catabolism, producing quinolinate and other neuroactive metabolites.
How does oxidative stress affect quinolinate biosynthesis?
Mitochondrial oxidative stress can impair quinolinate biosynthesis and induce negative regulatory mechanisms.
What methods measure quinolinate levels?
LC-MS/MS and other metabolomic approaches are used to quantify quinolinate and related metabolites.
Conclusion
Negative regulation of quinolinate biosynthetic process (GO:1904985) is a critical control point in the kynurenine pathway, with implications for neurotoxicity, inflammation, and cancer. Understanding its molecular players and regulatory mechanisms can guide therapeutic development. EDITGENE offers advanced CRISPR services to facilitate this research.
References
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- 8. Wang Y et al.. 2023. The association between inflammation and kynurenine pathway metabolites in electroconvulsive therapy for schizophrenia: Implications for clinical efficacy.. Brain Behav Immun 113:1-11 PMID: 37353059
