GO:0080164 regulation of nitric oxide metabolic process: Signaling Pathway, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0080164 (regulation of nitric oxide metabolic process) describes any process that modulates the frequency, rate or extent of the chemical reactions and pathways involving nitric oxide (NO), a colorless gas only slightly soluble in water.
• Nitric oxide is a pleiotropic signaling molecule whose production and clearance are tightly controlled in plants, the immune system, the brain and the vasculature.
• Regulation occurs at multiple levels: transcriptional control of NOS enzymes, post-translational modification of NO targets, redox-dependent protein homeostasis and epigenetic modulation.
• NO regulates protein function through S-nitrosylation, metal-nitrosylation and tyrosine nitration, affecting channels, connexins, cytochromes and metabolic enzymes.
• Dysregulated NO metabolism is implicated in cancer immune evasion, neurodegeneration, cardiovascular dysfunction and metabolic disorders.
• CRISPR knockout, point-mutation, knock-in and overexpression models, combined with CRISPR library screening and bioinformatics, are powerful tools to dissect the causal roles of NO-regulatory genes.
Description
Regulation of nitric oxide metabolic process (GO:0080164) is a biological process ontology term that encompasses any process modulating the frequency, rate or extent of the chemical reactions and pathways involving nitric oxide (NO), a colorless gas only slightly soluble in water. NO is a short-lived free radical that acts as a signaling molecule in diverse organisms, from plants to mammals. Because NO is both a signaling agent and a reactive species, its production, diffusion, and degradation must be precisely regulated to avoid toxicity and to ensure appropriate physiological responses. The term GO:0080164 therefore captures a wide range of regulatory inputs, including transcriptional control of NO synthases, post-translational modifications of NO targets, redox-dependent protein stability, and epigenetic mechanisms. In plants, NO regulates metabolism, development and stress responses, and its levels are modulated by environmental cues and by interactions with reactive oxygen species. In the immune system, NO produced by dendritic cells and macrophages shapes T-cell responses and tumor immunity, and its metabolic regulation is critical for immune function. In the brain, NO participates in synaptic plasticity, neurovascular coupling and neurodegeneration, with dysregulation linked to Alzheimer's and Parkinson's diseases. The breadth of these functions explains why GO:0080164 is a hub for researchers in plant biology, immunology, neuroscience and cancer biology. Understanding how NO metabolism is regulated requires integrating molecular, cellular and physiological data. Recent studies have revealed that NO can directly modify cysteine residues, control protein degradation via N-degron pathways, and influence epigenetic marks. These findings highlight the need for precise experimental models to test causality, which is where CRISPR-based approaches become indispensable.
regulation of nitric oxide metabolic process At A Glance
| GO ID | GO:0080164 |
|---|---|
| GO term | regulation of nitric oxide metabolic process |
| Ontology | biological_process |
| Synonym | none |
| Definition | Any process that modulates the frequency, rate or extent of the chemical reactions and pathways involving nitric oxide, nitrogen monoxide (NO), a colorless gas only slightly soluble in water. |
| Major function | Controls NO levels and downstream signaling in plants, immune cells, neurons and vasculature. |
| Related processes | Nitric oxide biosynthetic process, nitric oxide mediated signal transduction, response to oxidative stress. |
| Key enzymes | Nitric oxide synthases (NOS1, NOS2, NOS3), nitrate reductases, nitrite reductases. |
| Disease relevance | Cancer, neurodegeneration, cardiovascular disease, metabolic disorders. |
What Is GO:0080164?
In our own words, GO:0080164 (regulation of nitric oxide metabolic process) refers to any biological process that controls the rate, timing or extent of the chemical reactions and pathways that produce, convert or remove nitric oxide (NO). This includes regulation of NO synthase activity, availability of substrates such as L-arginine, scavenging of NO by reactive oxygen species, and the downstream modifications that NO exerts on proteins and other molecules. The term is agnostic to the specific organism or pathway, covering plants, animals and microbes.
Why Is regulation of nitric oxide metabolic process Important in Cell Biology?
Regulation of nitric oxide metabolic process is important because NO is a double-edged molecule: at low concentrations it acts as a signaling agent controlling vasodilation, neurotransmission and immune defense, while at high concentrations it can cause nitrosative stress, protein dysfunction and tissue damage. The balance between NO production and clearance determines whether NO exerts protective or deleterious effects. Consequently, understanding GO:0080164 is essential for deciphering mechanisms of diseases such as cancer, where NO can promote tumor progression or enhance immune-mediated killing depending on context, and neurodegeneration, where NO contributes to synaptic dysfunction and neuronal death. Moreover, NO regulates plant metabolism and stress responses, with implications for crop resilience. The term also intersects with redox biology, epigenetics and protein homeostasis, making it a central node in cellular regulation.
• NO is a key vasodilator and neurotransmitter; its dysregulation contributes to hypertension and stroke.
• In cancer, NO produced by immune cells can either kill tumor cells or promote tumor growth, depending on concentration and duration.
• NO regulates protein function via S-nitrosylation, affecting enzymes, channels and receptors.
• Redox regulation of protein homeostasis by NO influences protein folding and degradation.
• Epigenetic regulation by NO links metabolism to gene expression.
• NO controls cysteine N-degron proteolysis in response to oxygen availability.
• In plants, NO regulates metabolism, development and defense.
• Dysregulated NO metabolism is implicated in neurodegeneration, diabetes and cardiovascular disease.
• NO modulates connexin proteins and gap junction communication.
• Understanding NO regulation aids development of therapeutics targeting NO pathways.
What Happens During regulation of nitric oxide metabolic process?
Nitric oxide synthesis and its regulation
In simple terms: Cells make nitric oxide using enzymes called NOS, and this production is turned up or down by many signals.
Nitric oxide is synthesized from L-arginine by nitric oxide synthase (NOS) enzymes, which exist in neuronal (NOS1), inducible (NOS2) and endothelial (NOS3) isoforms. Regulation of NO metabolic process includes transcriptional control of NOS genes, post-translational modifications of NOS proteins, and availability of cofactors such as tetrahydrobiopterin and calcium/calmodulin. In plants, NO can also be produced from nitrite by nitrate reductase and other pathways, and this production is modulated by environmental factors. The activity of NOS is a primary determinant of NO levels, and its dysregulation is linked to disease.
Post-translational modification of NO targets
In simple terms: NO can attach to proteins and change their behavior, a process that is itself regulated.
NO exerts many of its effects through S-nitrosylation of cysteine residues, metal-nitrosylation of heme or iron-sulfur centers, and tyrosine nitration. These modifications are reversible and regulated by denitrosylases and redox conditions. For example, CYP2J2, a cytochrome P450 epoxygenase, is post-translationally regulated by NO, affecting its catalytic activity. Connexin proteins, which form gap junctions, are also regulated by NO-mediated redox changes. The regulation of these modifications is a core aspect of GO:0080164.
Redox-dependent protein homeostasis
In simple terms: NO influences how proteins are folded, repaired or degraded, especially under oxidative stress.
NO interacts with reactive oxygen species to form peroxynitrite and other reactive nitrogen species, which can modify proteins and trigger protective or damaging responses. Tegeder (2019) reviewed how NO-mediated redox regulation affects protein homeostasis, including the unfolded protein response and proteasomal degradation. This regulation ensures that cells adapt to nitrosative stress. Additionally, NO promotes cysteine N-degron proteolysis through control of oxygen availability, linking NO metabolism to oxygen sensing and protein turnover.
Epigenetic and transcriptional regulation
In simple terms: NO can change how genes are expressed by altering DNA packaging and transcription factor activity.
Socco et al. (2017) described epigenetics as the third pillar of NO signaling, highlighting how NO can influence DNA methylation, histone modifications and microRNA expression. These epigenetic changes can feed back to regulate NOS expression and NO production, creating a regulatory loop. In dendritic cells, NO modulates metabolic and immune gene expression, affecting T-cell activation. Thus, transcriptional and epigenetic mechanisms are integral to GO:0080164.
Integration with cellular metabolism
In simple terms: NO regulation is connected to how cells use energy and nutrients.
NO production consumes L-arginine and oxygen, and its regulation is intertwined with mitochondrial function, glycolysis and oxidative phosphorylation. In plants, NO regulates primary and secondary metabolism, including nitrogen assimilation and respiration. In the brain, NO modulates cerebral blood flow and energy supply. This integration ensures that NO levels are matched to metabolic demand and that NO does not interfere with essential metabolic processes.
Key Genes Involved in GO:0080164 regulation of nitric oxide metabolic process
The following genes and proteins are central to the regulation of nitric oxide metabolic process, based on published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| NOS1 | Neuronal nitric oxide synthase; produces NO in neurons | Neurotransmission, neurodegeneration |
| NOS2 | Inducible nitric oxide synthase; produces high-output NO in immune cells | Inflammation, cancer immunity |
| NOS3 | Endothelial nitric oxide synthase; produces NO for vasodilation | Cardiovascular disease, hypertension |
| CYP2J2 | Cytochrome P450 epoxygenase; post-translationally regulated by NO | Cardiac and vascular function |
| GAPDH | Glycolytic enzyme; undergoes S-nitrosylation affecting its activity | Metabolic regulation, cell death |
| CASP3 | Caspase-3; can be S-nitrosylated, affecting apoptosis | Neurodegeneration, apoptosis |
| HIF1A | Hypoxia-inducible factor 1-alpha; links NO to oxygen sensing | Cancer, ischemia |
| NFE2L2 | Nrf2; regulates antioxidant response, interacts with NO | Oxidative stress, inflammation |
| HSPA5 | BiP/GRP78; involved in ER stress and protein homeostasis | Protein folding, UPR |
| DNMT1 | DNA methyltransferase 1; epigenetic regulation by NO | Epigenetics, gene silencing |
| HDAC2 | Histone deacetylase 2; NO can modify its activity | Chromatin remodeling, inflammation |
| GJA1 | Connexin 43; gap junction protein regulated by NO | Cell communication, cardiac function |
| GJB1 | Connexin 32; regulated by NO in myelinating cells | Neuropathy, gap junctions |
| ARG1 | Arginase 1; competes with NOS for L-arginine | Immune regulation, cancer |
| SLC7A1 | Cationic amino acid transporter; supplies L-arginine for NOS | Metabolic regulation |
| NQO1 | NAD(P)H quinone dehydrogenase; redox regulation | Oxidative stress response |
| TXN | Thioredoxin; regulates S-nitrosylation and redox state | Protein homeostasis |
How Is regulation of nitric oxide metabolic process Regulated?
Regulation of nitric oxide metabolic process is itself regulated at multiple levels. Transcriptional regulation of NOS genes by cytokines, hypoxia and growth factors controls NO production capacity. Post-translational modifications of NOS, such as phosphorylation and S-nitrosylation, modulate enzyme activity. Substrate availability, particularly L-arginine, is controlled by arginase and cationic amino acid transporters, creating competition for NO synthesis. Redox balance, including the levels of glutathione and thioredoxin, determines the fate of NO and its derivatives. Epigenetic mechanisms, such as DNA methylation and histone acetylation, can silence or activate NOS genes. Furthermore, oxygen availability regulates NO effects on protein degradation via the N-degron pathway. These layers of regulation ensure that NO levels are appropriate for the cellular context.
regulation of nitric oxide metabolic process and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| NOS2 | Cancer, inflammation | Knockout mice, tumor cell lines |
| NOS3 | Hypertension, cardiovascular disease | Endothelial cell knockout, knock-in |
| NOS1 | Neurodegeneration, schizophrenia | Neuronal knockout, point mutation |
| CYP2J2 | Cardiac dysfunction | Overexpression in cardiomyocytes |
| GJA1 | Arrhythmia, neuropathy | Knock-in of nitrosylation-resistant mutant |
Cancer and immune evasion
In cancer, NO produced by tumor cells or immune cells can have opposing effects. Thwe et al. (2018) reviewed how NO regulates dendritic cell immune function and metabolic pathways, influencing T-cell activation and tumor immunity. High levels of NO can suppress anti-tumor immunity, while moderate levels may enhance immune-mediated killing. Dysregulated NO metabolism is therefore a target for cancer immunotherapy. Additionally, NO can promote angiogenesis and tumor progression through S-nitrosylation of signaling proteins.
Neurodegeneration
In the brain, NO is a key signaling molecule but also a mediator of neurotoxicity. Picón-Pagès et al. (2019) described how NO dysregulation contributes to Alzheimer's disease, Parkinson's disease and other neurodegenerative conditions. Excessive NO can cause mitochondrial dysfunction, protein misfolding and synaptic damage. S-nitrosylation of proteins such as GAPDH and parkin has been implicated in neuronal death. Regulation of NO metabolism is thus critical for neuronal survival.
Cardiovascular and metabolic disorders
Endothelial NO is essential for vasodilation and vascular homeostasis. Reduced NO bioavailability is a hallmark of hypertension, atherosclerosis and diabetes. NO also regulates cardiac ion channels and connexins, affecting arrhythmia risk. In metabolic disorders, NO modulates insulin sensitivity and glucose uptake. Therefore, targeting NO regulatory pathways may offer therapeutic benefits.
From regulation of nitric oxide metabolic process-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of NOS2 affect tumor immune surveillance? | NOS2 knockout mice or cancer cell lines |
| Does a specific S-nitrosylation site on GAPDH alter glycolysis? | Point mutation of cysteine to serine in GAPDH |
| Can a nitrosylation-resistant connexin prevent arrhythmia? | Knock-in of GJA1 mutant in cardiomyocytes |
| Does overexpression of NOS3 improve endothelial function? | Endothelial-specific NOS3 overexpression |
| What genes regulate NO metabolism in plants? | CRISPR knockout library in Arabidopsis |
| How does NO affect protein degradation via N-degron? | Tagged knock-in of degron substrates |
How to Study the regulation of nitric oxide metabolic process Process
| Method | What It Measures | Typical Application |
|---|---|---|
| RNA-seq | Gene expression changes | Identify NO-regulated genes |
| CRISPR library screening | Gene function at scale | Discover regulators of NO metabolism |
| S-nitrosylation proteomics | Cysteine modifications | Map NO targets |
| DAF-FM imaging | Intracellular NO levels | Live-cell NO dynamics |
| Western blot | Protein expression and modification | Validate NOS expression |
| Griess assay | Nitrite/nitrate levels | Measure NO production |
| Electrophysiology | Ion channel function | Assess NO effects on channels |
Genomic and transcriptomic approaches
RNA-seq and CRISPR library screening can identify genes that regulate NO metabolism. For example, knockout of candidate genes followed by NO measurement reveals regulators. Bioinformatics analysis of transcriptomic data can uncover pathways linked to GO:0080164.
Proteomic and redox proteomic methods
Mass spectrometry-based proteomics can detect S-nitrosylated proteins and quantify changes in response to NO. Redox proteomics identifies cysteine modifications. These methods are essential for understanding how NO regulates protein function.
Imaging and physiological assays
Fluorescent probes such as DAF-FM measure NO levels in live cells. Imaging of NO in tissues can reveal spatial and temporal dynamics. Physiological assays, such as vasodilation or synaptic plasticity, link NO regulation to function.
Genetic and pharmacological manipulation
CRISPR knockout, point mutation, knock-in and overexpression models allow causal testing of NO-regulatory genes. Pharmacological inhibitors of NOS (e.g., L-NAME) provide complementary evidence.
How CRISPR Can Be Used to Study GO:0080164 regulation of nitric oxide metabolic process
Knockout
CRISPR knockout of NOS genes or other NO-regulatory genes can abolish NO production or alter NO responses. For example, NOS2 knockout in immune cells reveals its role in tumor immunity. Knockout models are essential for loss-of-function studies.
Point Mutation
Point mutations can be introduced to prevent specific post-translational modifications, such as S-nitrosylation. For instance, mutating a cysteine to serine in GAPDH can test the role of S-nitrosylation in glycolysis. This approach provides mechanistic insight.
Knock-in
Knock-in of tagged or mutant alleles allows precise tracking and functional analysis. For example, knocking in a nitrosylation-resistant connexin can test its role in gap junction communication. Knock-in models are valuable for studying disease-associated variants.
Overexpression
Overexpression of NOS or NO-target genes can elevate NO levels or enhance signaling. Overexpressing NOS3 in endothelial cells can improve vasodilation. Overexpression models help identify gain-of-function effects.
How EDITGENE Supports regulation of nitric oxide metabolic process Research
Researchers studying regulation of nitric oxide metabolic process-related genes often need to determine whether a candidate gene is causally involved in NO production, signaling or downstream effects. EDITGENE provides a comprehensive suite of CRISPR services to generate precisely engineered cell models, enabling rigorous functional validation.
Contact EDITGENE today to design your custom CRISPR model for regulation of nitric oxide metabolic process research.
Frequently Asked Questions About regulation of nitric oxide metabolic process
What is GO:0080164?
GO:0080164 is the Gene Ontology term for regulation of nitric oxide metabolic process, defined as any process that modulates the frequency, rate or extent of the chemical reactions and pathways involving nitric oxide (NO).
What genes are involved in regulation of nitric oxide metabolic process?
Key genes include NOS1, NOS2, NOS3, CYP2J2, GAPDH, HIF1A, DNMT1, HDAC2, GJA1 and others, as reported in the literature.
How is nitric oxide metabolism regulated?
It is regulated at transcriptional, post-translational, redox and epigenetic levels, including control of NOS activity, substrate availability, S-nitrosylation and protein degradation.
Why is nitric oxide regulation important in cancer?
NO can either promote or suppress tumors depending on context; it regulates immune cell function and tumor microenvironment, making it a therapeutic target.
What diseases are linked to nitric oxide metabolic process?
Diseases include cancer, neurodegeneration, cardiovascular disease, hypertension and metabolic disorders.
How can CRISPR be used to study nitric oxide regulation?
CRISPR knockout, point mutation, knock-in and overexpression models allow causal testing of genes involved in NO metabolism and signaling.
What methods measure nitric oxide levels?
Methods include Griess assay, DAF-FM imaging, S-nitrosylation proteomics and RNA-seq.
What is the role of S-nitrosylation in NO regulation?
S-nitrosylation is a reversible post-translational modification of cysteine residues that modulates protein function and is a key mechanism of NO signaling.
How does NO regulate protein homeostasis?
NO influences protein folding, degradation and the unfolded protein response through redox-dependent mechanisms.
What model systems are used to study GO:0080164?
Model systems include knockout mice, cell lines, plant models and CRISPR-engineered cells, combined with biochemical and imaging assays.
Conclusion
Regulation of nitric oxide metabolic process (GO:0080164) is a fundamental biological process that controls the levels and effects of nitric oxide, a versatile signaling molecule. Its dysregulation is implicated in cancer, neurodegeneration, cardiovascular disease and metabolic disorders. Understanding the genes and mechanisms that regulate NO metabolism is essential for developing targeted therapies. CRISPR-based models, combined with advanced omics and imaging, provide powerful tools to dissect this process. EDITGENE offers comprehensive services to support researchers in this endeavor.
References
- 1. Gupta KJ et al.. 2022. Nitric oxide regulation of plant metabolism.. Mol Plant 15(2):228-242 PMID: 34971792
- 2. Thwe PM et al.. 2018. The role of nitric oxide in metabolic regulation of Dendritic cell immune function.. Cancer Lett 412:236-242 PMID: 29107106
- 3. Tegeder I. 2019. Nitric oxide mediated redox regulation of protein homeostasis.. Cell Signal 53:348-356 PMID: 30408515
- 4. Picón-Pagès P et al.. 2019. Functions and dysfunctions of nitric oxide in brain.. Biochim Biophys Acta Mol Basis Dis 1865(8):1949-1967 PMID: 30500433
- 5. Park JW et al.. 2018. Posttranslational regulation of CYP2J2 by nitric oxide.. Free Radic Biol Med 121:149-156 PMID: 29715548
- 6. Socco S et al.. 2017. Epigenetics: The third pillar of nitric oxide signaling.. Pharmacol Res 121:52-58 PMID: 28428114
- 7. García IE et al.. 2018. Redox-mediated regulation of connexin proteins; focus on nitric oxide.. Biochim Biophys Acta Biomembr 1860(1):91-95 PMID: 29017810
- 8. Kim H et al.. 2025. Nitric oxide promotes cysteine N-degron proteolysis through control of oxygen availability.. Proc Natl Acad Sci U S A 122(34):e2501796122 PMID: 40828020
