GO:2001170 negative regulation of ATP biosynthetic process: Mechanism, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:2001170 describes any process that stops, prevents or reduces the frequency, rate or extent of ATP biosynthetic process.
• ATP biosynthesis is primarily driven by oxidative phosphorylation and substrate-level phosphorylation, and its negative regulation is essential for matching energy supply to cellular demand.
• Key negative regulators include SIRT1, which suppresses STAT3-mediated cellular respiration, and NOX-2 deficiency, which alters mitochondrial oxygen consumption and metabolic flexibility.
• Dysregulation of ATP biosynthetic suppression is linked to post-COVID neuropsychiatric conditions, heart failure, and inflammatory diseases.
• CRISPR knockout, point-mutation, knock-in, and overexpression models enable precise dissection of negative regulators of ATP synthesis.
• Understanding GO:2001170 provides therapeutic targets for metabolic, cardiovascular, and neurodegenerative disorders.
Description
The Gene Ontology term GO:2001170, negative regulation of ATP biosynthetic process, defines any process that stops, prevents or reduces the frequency, rate or extent of ATP biosynthetic process. ATP is the universal energy currency of the cell, and its production must be tightly controlled to avoid wasteful energy expenditure or metabolic imbalance. This regulatory process is critical for cellular homeostasis, allowing cells to adapt to fluctuating energy demands and stress conditions. Researchers study GO:2001170 to understand how cells throttle ATP production under hypoxia, nutrient limitation, or during specific developmental stages. The term encompasses molecular mechanisms that inhibit ATP synthase activity, reduce substrate availability, or downregulate respiratory chain components. Recent evidence links negative regulation of ATP biosynthesis to pathophysiological states such as post-COVID neuropsychiatric conditions, heart failure, and inflammation. For example, reduced ATP-to-phosphocreatine ratios have been observed in neuropsychiatric post-COVID condition, suggesting impaired ATP synthesis regulation. In heart failure, mitochondria become therapeutic targets, and modulating ATP production is a key strategy. Thus, GO:2001170 is not merely a housekeeping term but a central node in metabolic control with broad disease relevance.
negative regulation of ATP biosynthetic process At A Glance
| GO ID | GO:2001170 |
|---|---|
| GO term | negative regulation of ATP biosynthetic process |
| Ontology | biological_process |
| Synonym | negative regulation of ATP anabolism; negative regulation of ATP biosynthesis; negative regulation of ATP formation; negative regulation of ATP regeneration; negative regulation of ATP synthesis |
| Major function | Reduces the frequency, rate or extent of ATP biosynthetic process |
| Related processes | Oxidative phosphorylation, substrate-level phosphorylation, mitochondrial respiration |
| Key regulators | SIRT1, STAT3, NOX-2, ATP synthase |
| Disease relevance | Post-COVID condition, heart failure, inflammation |
What Is GO:2001170?
In our own words, GO:2001170 refers to any biological process that negatively regulates the biosynthesis of adenosine triphosphate (ATP). This includes mechanisms that inhibit the enzymes, signaling pathways, or substrate supply required for ATP production, thereby reducing the rate or extent of ATP generation. The term covers negative regulation of ATP anabolism, biosynthesis, formation, regeneration, and synthesis.
Why Is negative regulation of ATP biosynthetic process Important in Cell Biology?
Negative regulation of ATP biosynthetic process is crucial for cellular energy homeostasis, preventing excessive ATP production that could lead to oxidative stress or metabolic inefficiency. It allows cells to rapidly adjust energy output in response to environmental cues, such as nutrient availability or oxygen levels. Dysregulation of this process contributes to diseases including heart failure, where mitochondrial ATP production is impaired, and neuropsychiatric post-COVID condition, characterized by altered ATP-to-phosphocreatine ratios. Understanding GO:2001170 also informs therapeutic strategies targeting mitochondrial function and inflammation.
• Maintains energy balance by preventing wasteful ATP synthesis.
• Enables rapid adaptation to hypoxia and nutrient stress.
• Involved in muscle contraction regulation and fatigue.
• Linked to neuropsychiatric post-COVID condition via reduced ATP-to-phosphocreatine ratios.
• Contributes to heart failure pathogenesis and is a therapeutic target.
• Modulated by SIRT1 via STAT3 to control cellular respiration.
• Affected by NOX-2 deficiency, altering mitochondrial oxygen consumption.
• Relevant to inflammasome activation by ATP.
• Bacterial ATP synthase regulation provides evolutionary insights.
• Potential target for anti-inflammatory and metabolic therapies.
What Happens During negative regulation of ATP biosynthetic process?
Inhibition of ATP Synthase Activity
In simple terms: The enzyme that makes ATP is slowed down or turned off.
ATP synthase is the primary enzyme responsible for ATP synthesis during oxidative phosphorylation. Negative regulation can occur through direct inhibition of ATP synthase, such as by regulatory proteins or post-translational modifications. In bacteria, ATP synthase activity is regulated by a gear-shifting or pawl-ratchet mechanism, which can reduce ATP synthesis under certain conditions. This ensures that ATP production matches cellular energy needs and prevents wasteful hydrolysis of ATP.
Downregulation of Mitochondrial Respiration
In simple terms: The mitochondria's ability to burn fuel and make ATP is reduced.
Negative regulation of ATP biosynthesis often involves reducing mitochondrial oxygen consumption and electron transport chain activity. For example, SIRT1 negatively regulates STAT3-mediated cellular respiration, leading to decreased ATP production. Similarly, NOX-2 deficiency affects mitochondrial oxygen consumption and metabolic flexibility, indirectly suppressing ATP synthesis. These mechanisms help cells adapt to metabolic stress and reduce oxidative damage.
Reduction of Substrate Supply
In simple terms: The raw materials needed to make ATP are limited.
ATP biosynthesis requires substrates such as ADP, inorganic phosphate, and reducing equivalents (NADH, FADH2). Negative regulation can occur by limiting the availability of these substrates, for instance through reduced glycolysis or fatty acid oxidation. Theoretical studies on muscle contraction show that ATP supply is regulated by feedback from ATP demand, ensuring that synthesis does not exceed utilization.
Modulation by Signaling Pathways
In simple terms: Cellular signals tell the ATP-making machinery to slow down.
Signaling pathways such as AMPK, mTOR, and sirtuins can negatively regulate ATP biosynthesis in response to energy status. SIRT1, a NAD+-dependent deacetylase, suppresses STAT3-mediated respiration, thereby reducing ATP production. In heart failure, neurohormonal signaling contributes to mitochondrial dysfunction and decreased ATP synthesis. These pathways integrate energy status with cellular demands to maintain homeostasis.
Inflammasome and Immune Regulation
In simple terms: Immune signals can affect how much ATP is made.
ATP biosynthesis can be negatively regulated during inflammatory responses. For instance, cryopyrin activates the inflammasome in response to toxins and ATP, which can lead to cell death and reduced ATP production. Inhibiting lipopolysaccharide biogenesis also impacts bacterial ATP synthesis, highlighting the intersection of immune and metabolic regulation.
Key Genes Involved in GO:2001170 negative regulation of ATP biosynthetic process
The following genes and proteins are key players in the negative regulation of ATP biosynthetic process, based on published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| SIRT1 | Deacetylates STAT3 to suppress cellular respiration and ATP synthesis | Metabolic regulation, aging, inflammation |
| STAT3 | Transcription factor promoting cellular respiration; inhibited by SIRT1 | Mitochondrial function, cancer metabolism |
| NOX-2 | NADPH oxidase isoform; deficiency alters mitochondrial oxygen consumption | Metabolic flexibility, oxidative stress |
| ATP5F1A | Subunit of mitochondrial ATP synthase | ATP synthesis, mitochondrial diseases |
| ATP5F1B | Subunit of mitochondrial ATP synthase | ATP synthesis, mitochondrial diseases |
| ATP5F1C | Subunit of mitochondrial ATP synthase | ATP synthesis, mitochondrial diseases |
| ATP5F1D | Subunit of mitochondrial ATP synthase | ATP synthesis, mitochondrial diseases |
| ATP5F1E | Subunit of mitochondrial ATP synthase | ATP synthesis, mitochondrial diseases |
| ATP5MC1 | Subunit of mitochondrial ATP synthase | ATP synthesis, mitochondrial diseases |
| ATP5MC2 | Subunit of mitochondrial ATP synthase | ATP synthesis, mitochondrial diseases |
| ATP5MC3 | Subunit of mitochondrial ATP synthase | ATP synthesis, mitochondrial diseases |
| ATP5PB | Subunit of mitochondrial ATP synthase | ATP synthesis, mitochondrial diseases |
| ATP5PD | Subunit of mitochondrial ATP synthase | ATP synthesis, mitochondrial diseases |
| ATP5PF | Subunit of mitochondrial ATP synthase | ATP synthesis, mitochondrial diseases |
| ATP5PO | Subunit of mitochondrial ATP synthase | ATP synthesis, mitochondrial diseases |
| NLRP3 | Inflammasome sensor activated by ATP; can affect ATP homeostasis | Inflammation, cell death |
| CASP1 | Inflammasome effector; activated by ATP, may influence ATP synthesis | Inflammation, pyroptosis |
| LPS biosynthesis genes | Bacterial ATP synthesis inhibition by targeting LPS biogenesis | Antibacterial targets |
How Is negative regulation of ATP biosynthetic process Regulated?
Negative regulation of ATP biosynthetic process is controlled by multiple signaling pathways and feedback mechanisms. SIRT1 negatively regulates STAT3-mediated cellular respiration, reducing ATP synthesis. NOX-2 deficiency alters mitochondrial oxygen consumption and metabolic flexibility, indirectly suppressing ATP production. In muscle, ATP supply is regulated by feedback from ATP demand, ensuring synthesis matches utilization. Bacterial ATP synthase activity is regulated by a gear-shifting or pawl-ratchet mechanism. Additionally, inflammatory signals such as ATP can activate the inflammasome, which may lead to reduced ATP production. These regulatory layers allow cells to fine-tune energy production in response to physiological and pathological cues.
negative regulation of ATP biosynthetic process and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| SIRT1 | Metabolic disorders, aging | Knockout and overexpression in cell lines |
| STAT3 | Cancer, inflammation | Point mutation to prevent SIRT1 deacetylation |
| NOX-2 | Cardiovascular disease, oxidative stress | Knockout mice or cells |
| NLRP3 | Inflammasome-related diseases | Knockout and knock-in models |
| ATP5F1A | Mitochondrial diseases | Point mutations in ATP synthase subunits |
Neuropsychiatric Post-COVID Condition
Reduced ATP-to-phosphocreatine ratios have been observed in neuropsychiatric post-COVID condition, indicating impaired ATP synthesis or increased negative regulation. This metabolic alteration may contribute to fatigue and cognitive symptoms.
Heart Failure
Mitochondria are therapeutic targets in heart failure, where impaired ATP production and increased negative regulation contribute to contractile dysfunction. Modulating ATP biosynthetic pathways may improve cardiac energetics.
Inflammation and Inflammasome Activation
ATP activates the cryopyrin inflammasome, leading to inflammation and cell death, which can further suppress ATP biosynthesis. Inhibiting LPS biogenesis also affects bacterial ATP synthesis, linking infection to metabolic regulation.
Metabolic Flexibility and Oxidative Stress
NOX-2 deficiency alters mitochondrial oxygen consumption and metabolic flexibility, affecting ATP production and contributing to oxidative stress-related diseases. SIRT1-mediated suppression of STAT3 respiration links aging and metabolic disorders to ATP regulation.
From negative regulation of ATP biosynthetic process-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does SIRT1 negatively regulate ATP synthesis via STAT3? | SIRT1 knockout and STAT3 point-mutation cells |
| How does NOX-2 deficiency affect mitochondrial ATP production? | NOX-2 knockout cells or mice |
| What is the role of ATP synthase subunits in negative regulation? | Knock-in of tagged ATP5F1A for imaging |
| Can overexpression of SIRT1 reduce ATP biosynthesis? | SIRT1 overexpression cell lines |
| Does inflammasome activation suppress ATP synthesis? | NLRP3 knockout and overexpression models |
| How does LPS biogenesis inhibition affect bacterial ATP synthesis? | Bacterial knockout libraries |
How to Study the negative regulation of ATP biosynthetic process Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Seahorse XF | Oxygen consumption rate, ATP production | Mitochondrial function |
| 31P MRS | ATP-to-phosphocreatine ratio | In vivo energy metabolism |
| CRISPR knockout screen | Gene essentiality for ATP regulation | Identify negative regulators |
| RNA-seq | Transcriptional changes in ATP synthase genes | Pathway analysis |
| Proteomics | Protein levels of ATP synthase subunits | Quantify assembly |
| Metabolomics | ATP, ADP, AMP levels | Energy charge |
| Western blot | Phosphorylation of STAT3, SIRT1 levels | Signaling |
| Immunofluorescence | Mitochondrial morphology and ATP synthase localization | Imaging |
Seahorse XF Analyzer
Measures oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) to assess mitochondrial respiration and ATP production in live cells.
31P Magnetic Resonance Spectroscopy
Non-invasively measures ATP-to-phosphocreatine ratios in tissues, as used in post-COVID condition studies.
CRISPR Screening
Genome-wide knockout screens identify genes that negatively regulate ATP biosynthesis, such as SIRT1 and NOX-2.
Proteomics and Metabolomics
Mass spectrometry-based approaches quantify ATP synthase subunits and metabolites to assess pathway activity.
How CRISPR Can Be Used to Study GO:2001170 negative regulation of ATP biosynthetic process
Knockout
CRISPR knockout of SIRT1 or NOX-2 can reveal their roles in negatively regulating ATP biosynthesis. For example, SIRT1 knockout increases STAT3-mediated respiration and ATP production. NOX-2 knockout alters mitochondrial oxygen consumption.
Point Mutation
Point mutations in STAT3 acetylation sites can prevent SIRT1-mediated deacetylation, leading to constitutive respiration and increased ATP synthesis. Similarly, mutations in ATP synthase subunits can disrupt regulation.
Knock-in
Knock-in of tagged ATP5F1A allows live-cell imaging of ATP synthase localization and assembly, providing insights into negative regulation. Knock-in of mutant NLRP3 can model inflammasome-related ATP dysregulation.
Overexpression
Overexpression of SIRT1 in cell lines reduces STAT3-mediated respiration and ATP production, confirming its negative regulatory role. Overexpression of NOX-2 can rescue metabolic flexibility.
How EDITGENE Supports negative regulation of ATP biosynthetic process Research
Researchers studying negative regulation of ATP biosynthetic process-related genes often need to determine whether a candidate gene is causally involved in suppressing ATP production or is merely correlated with metabolic changes. EDITGENE provides comprehensive CRISPR services to enable such causal studies.
Contact EDITGENE today to design your custom CRISPR model for negative regulation of ATP biosynthetic process research.
Frequently Asked Questions About negative regulation of ATP biosynthetic process
What is GO:2001170?
GO:2001170 is the Gene Ontology term for negative regulation of ATP biosynthetic process, describing any process that stops, prevents or reduces the frequency, rate or extent of ATP biosynthesis.
What genes are involved in negative regulation of ATP biosynthetic process?
Key genes include SIRT1, STAT3, NOX-2, and subunits of ATP synthase such as ATP5F1A and ATP5F1B.
How is ATP biosynthetic process negatively regulated?
It is regulated by inhibition of ATP synthase, downregulation of mitochondrial respiration, reduced substrate supply, and signaling pathways like SIRT1-STAT3.
What diseases are associated with negative regulation of ATP biosynthetic process?
Post-COVID neuropsychiatric condition, heart failure, and inflammasome-related inflammatory diseases.
What methods are used to study negative regulation of ATP biosynthetic process?
Seahorse XF analyzer, 31P MRS, CRISPR screens, proteomics, and metabolomics.
How does SIRT1 negatively regulate ATP synthesis?
SIRT1 deacetylates STAT3, suppressing STAT3-mediated cellular respiration and reducing ATP production.
What is the role of NOX-2 in ATP regulation?
NOX-2 deficiency affects mitochondrial oxygen consumption and metabolic flexibility, indirectly suppressing ATP synthesis.
Can CRISPR be used to study negative regulation of ATP biosynthetic process?
Yes, CRISPR knockout, point mutation, knock-in, and overexpression models enable precise dissection of regulatory genes.
What is the ATP-to-phosphocreatine ratio in post-COVID condition?
It is reduced in neuropsychiatric post-COVID condition, indicating impaired ATP synthesis or increased negative regulation.
Why is negative regulation of ATP biosynthesis important in heart failure?
Mitochondrial ATP production is impaired in heart failure, and modulating negative regulation is a therapeutic target.
Conclusion
GO:2001170, negative regulation of ATP biosynthetic process, is a critical biological process that ensures cellular energy homeostasis by preventing excessive ATP production. Its dysregulation is implicated in diverse pathologies, from post-COVID neuropsychiatric conditions to heart failure and inflammation. Understanding the genes and mechanisms involved, such as SIRT1, STAT3, and NOX-2, provides opportunities for therapeutic intervention. CRISPR-based models and advanced metabolic assays are essential tools for dissecting this process. EDITGENE offers comprehensive services to support research in this field, from knockout to overexpression and library screening.
References
- 1. Weber-Fahr W et al.. 2026. Reduced Adenosine Triphosphate-to-Phosphocreatine Ratios in Neuropsychiatric Post-COVID Condition: Evidence From (31)P Magnetic Resonance Spectroscopy.. Biol Psychiatry 100(5):546-555 PMID: 41525818
- 2. Miranda-Astudillo H et al.. 2021. Regulation of bacterial ATP synthase activity: A gear-shifting or a pawl-ratchet mechanism?. FEBS J 288(10):3159-3163 PMID: 33377595
- 3. Thetchinamoorthy K et al.. 2025. NADPH oxidase isoform NOX-2 deficiency affects mitochondrial oxygen consumption and metabolic flexibility.. Redox Biol 88:103948 PMID: 41338165
- 4. Bernier M et al.. 2011. Negative regulation of STAT3 protein-mediated cellular respiration by SIRT1 protein.. J Biol Chem 286(22):19270-9 PMID: 21467030
- 5. Schwemmlein J et al.. 2022. Mitochondria as Therapeutic Targets in Heart Failure.. Curr Heart Fail Rep 19(2):27-37 PMID: 35147851
- 6. Moffatt CB et al.. 2025. Inhibiting Lipopolysaccharide Biogenesis: The More You Know the Further You Go.. Annu Rev Biochem 94(1):137-160 PMID: 40540753
- 7. Mariathasan S et al.. 2006. Cryopyrin activates the inflammasome in response to toxins and ATP.. Nature 440(7081):228-32 PMID: 16407890
- 8. Korzeniewski B. 1998. Regulation of ATP supply during muscle contraction: theoretical studies.. Biochem J 330 ( Pt 3)(Pt 3):1189-95 PMID: 9494084
