GO:0042132 fructose 1,6-bisphosphate 1-phosphatase activity: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0042132 describes the molecular function of fructose 1,6-bisphosphate 1-phosphatase, which catalyzes the hydrolysis of D-fructose 1,6-bisphosphate to D-fructose 6-phosphate and phosphate.
• This activity is a key regulatory step in gluconeogenesis and the Calvin cycle, controlling carbon flux between glycolysis and glucose synthesis.
• The enzyme is widely distributed across organisms, from mammals to plants and bacteria, and its dysregulation is linked to metabolic disorders such as diabetes.
• Research on this activity employs biochemical assays, structural biology, and CRISPR-based gene editing to dissect its role in metabolic pathways.
• Loss-of-function studies in model organisms and cell lines reveal its importance in glucose homeostasis and stress responses.
• Targeting fructose 1,6-bisphosphate 1-phosphatase activity is a potential therapeutic strategy for metabolic diseases and cancer.
Description
Fructose 1,6-bisphosphate 1-phosphatase activity (GO:0042132) is a molecular function that catalyzes the hydrolysis of D-fructose 1,6-bisphosphate into D-fructose 6-phosphate and inorganic phosphate. This reaction is a critical step in gluconeogenesis and the Calvin cycle, where it bypasses the irreversible glycolytic kinase step to allow net glucose synthesis. The enzyme responsible for this activity, fructose-1,6-bisphosphatase (FBPase), is regulated by various metabolites and hormones, and its dysfunction has been implicated in metabolic disorders such as diabetes. Researchers study this activity to understand how cells maintain glucose homeostasis and to develop interventions for related diseases.
fructose 1,6-bisphosphate 1-phosphatase activity At A Glance
| GO ID | GO:0042132 |
|---|---|
| GO term | fructose 1,6-bisphosphate 1-phosphatase activity |
| Ontology | molecular_function |
| Synonym | FBPase activity; fructose 1,6-bisphosphatase activity; D-fructose-1,6-bisphosphate 1-phosphohydrolase activity |
| Major function | Catalyzes the hydrolysis of D-fructose 1,6-bisphosphate to D-fructose 6-phosphate and phosphate |
| Reaction | D-fructose 1,6-bisphosphate + H2O = D-fructose 6-phosphate + phosphate |
| Pathway context | Gluconeogenesis, Calvin cycle, pentose phosphate pathway |
| EC number | 3.1.3.11 |
What Is GO:0042132?
According to the Gene Ontology, GO:0042132 is defined as the catalysis of the reaction: D-fructose 1,6-bisphosphate + H2O = D-fructose 6-phosphate + phosphate. This activity is also known as fructose 1,6-bisphosphatase activity or FBPase activity, and it plays a central role in carbohydrate metabolism by removing a phosphate group from fructose 1,6-bisphosphate.
Why Is fructose 1,6-bisphosphate 1-phosphatase activity Important in Cell Biology?
Fructose 1,6-bisphosphate 1-phosphatase activity is essential for metabolic homeostasis because it controls the rate-limiting step of gluconeogenesis, enabling organisms to synthesize glucose from non-carbohydrate precursors. In plants, it is a key enzyme of the Calvin cycle, influencing carbon fixation and biomass production. Dysregulation of this activity contributes to hyperglycemia in diabetes and may support cancer cell proliferation by altering glucose metabolism. Thus, understanding its regulation and function is vital for developing therapies for metabolic diseases and for engineering improved crop yields.
• Controls the rate-limiting step of gluconeogenesis, critical for blood glucose maintenance.
• Regulates carbon flux in the Calvin cycle of photosynthetic organisms.
• Its inhibition or deficiency leads to metabolic disorders such as hypoglycemia and lactic acidosis.
• Overexpression is observed in some cancers, supporting altered glucose metabolism.
• Serves as a target for antidiabetic drugs and herbicides.
• Plays a role in the pentose phosphate pathway by providing fructose 6-phosphate.
• Its activity is modulated by AMP, fructose 2,6-bisphosphate, and hormonal signals.
• Used as a biochemical marker for liver function and metabolic stress.
• Engineered in industrial microorganisms for enhanced production of sugars and metabolites.
• Studied in extremophiles for understanding adaptation to extreme environments.
Molecular Mechanism of fructose 1,6-bisphosphate 1-phosphatase activity
Substrate Binding and Catalysis
In simple terms: The enzyme grabs fructose 1,6-bisphosphate and breaks it into two pieces using water.
Fructose 1,6-bisphosphate 1-phosphatase binds its substrate, D-fructose 1,6-bisphosphate, in a metal-dependent manner, typically requiring Mg2+ or Mn2+ ions for catalysis. The enzyme hydrolyzes the C1 phosphate ester bond, releasing inorganic phosphate and yielding D-fructose 6-phosphate. Structural studies of related phosphatases reveal a conserved catalytic core with a Rossmann fold and a divalent metal-binding site.
Cofactors and Metal Dependence
In simple terms: Metal ions like magnesium help the enzyme work properly.
The activity of fructose 1,6-bisphosphate 1-phosphatase is strictly dependent on divalent cations such as Mg2+ or Mn2+, which stabilize the transition state and neutralize the phosphate group. In some organisms, the enzyme also requires K+ for optimal activity. Metal chelators inhibit the reaction, confirming the essential role of these cofactors.
Allosteric Regulation
In simple terms: Small molecules can turn the enzyme on or off by binding to sites away from the active center.
Fructose 1,6-bisphosphate 1-phosphatase is allosterically inhibited by AMP and activated by ATP, reflecting the energy status of the cell. Fructose 2,6-bisphosphate, a potent regulator of glycolysis and gluconeogenesis, inhibits the enzyme, thereby preventing futile cycling. In plants, the enzyme is regulated by light-dependent changes in pH and redox state.
Post-Translational Modifications
In simple terms: Chemical tags can be added to the enzyme to change its activity.
Phosphorylation of fructose 1,6-bisphosphatase by cAMP-dependent protein kinase reduces its activity, linking hormonal signals to glucose metabolism. In plants, redox regulation via thioredoxin modulates the enzyme's activity in response to light. These modifications fine-tune the enzyme's function in response to physiological cues.
Key Genes Involved in GO:0042132 fructose 1,6-bisphosphate 1-phosphatase activity
The following genes encode proteins that exhibit fructose 1,6-bisphosphate 1-phosphatase activity or are closely related to its regulation and function.
| Gene | Major Role | Research Relevance |
|---|---|---|
| FBP1 | Encodes fructose-1,6-bisphosphatase 1, a key gluconeogenic enzyme | Studied in diabetes, cancer, and metabolic disorders |
| FBP2 | Encodes fructose-1,6-bisphosphatase 2, expressed in muscle | Involved in muscle glycogen metabolism and energy homeostasis |
| PFKFB1 | Regulates fructose 2,6-bisphosphate levels, affecting FBPase activity | Target for metabolic regulation studies |
| PFKFB2 | Heart-specific regulator of fructose 2,6-bisphosphate | Linked to cardiac metabolism |
| PFKFB3 | Produces fructose 2,6-bisphosphate, promotes glycolysis | Oncogenic role in cancer |
| PFKFB4 | Regulates fructose 2,6-bisphosphate in cancer cells | Potential anticancer target |
| G6PC | Glucose-6-phosphatase, works downstream of FBPase in gluconeogenesis | Deficiency causes glycogen storage disease |
| PCK1 | Phosphoenolpyruvate carboxykinase, upstream of FBPase | Regulates gluconeogenesis |
| PCK2 | Mitochondrial isoform of PCK | Involved in gluconeogenesis and cancer |
| ALDOA | Aldolase A, reversibly cleaves fructose 1,6-bisphosphate | Glycolysis and gluconeogenesis |
| ALDOB | Aldolase B, liver-specific | Mutations cause hereditary fructose intolerance |
| GAPDH | Glyceraldehyde-3-phosphate dehydrogenase, glycolytic enzyme | Metabolic and non-metabolic functions |
| TPI1 | Triosephosphate isomerase, glycolytic enzyme | Deficiency causes hemolytic anemia |
| PKLR | Pyruvate kinase, regulates glycolytic flux | Mutations cause pyruvate kinase deficiency |
| SLC2A2 | GLUT2 glucose transporter, affects glucose homeostasis | Linked to diabetes |
| GCK | Glucokinase, phosphorylates glucose in liver | Mutations cause MODY2 |
| INS | Insulin, regulates FBPase expression | Diabetes research |
| FOXO1 | Transcription factor regulating FBP1 expression | Involved in gluconeogenesis and diabetes |
How Is fructose 1,6-bisphosphate 1-phosphatase activity Regulated?
Fructose 1,6-bisphosphate 1-phosphatase activity is regulated at multiple levels. Allosterically, it is inhibited by AMP and fructose 2,6-bisphosphate, and activated by ATP and citrate. Hormonal signals, such as glucagon and insulin, modulate its expression and activity through cAMP and Akt pathways. In plants, light regulates the enzyme via pH and redox changes. Post-translational modifications, including phosphorylation, further fine-tune its activity.
fructose 1,6-bisphosphate 1-phosphatase activity and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| FBP1 | Diabetes, cancer (e.g., hepatocellular carcinoma) | FBP1 knockout mouse, cancer cell lines |
| FBP2 | Muscle glycogen storage disorders | FBP2 knockout mice, muscle cells |
| PFKFB3 | Cancer, inflammation | PFKFB3 inhibitors in cell models |
| ALDOB | Hereditary fructose intolerance | Aldob knockout mice, patient-derived cells |
| G6PC | Glycogen storage disease type I | G6pc knockout mice |
Diabetes and Metabolic Disorders
In alloxan-diabetic rats, hepatic fructose-1,6-bisphosphate 1-phosphatase activity is increased, contributing to excessive glucose production. This suggests that inhibiting this activity could reduce hyperglycemia in diabetes.
Cancer Metabolism
Cancer cells often exhibit altered glucose metabolism, and fructose-1,6-bisphosphatase 1 (FBP1) is frequently downregulated in cancers such as hepatocellular carcinoma, where its loss promotes glycolysis and tumor growth. Targeting FBPase activity is being explored as a therapeutic strategy.
Hereditary Fructose Intolerance
While not directly caused by FBPase deficiency, hereditary fructose intolerance involves aldolase B deficiency, which affects fructose 1,6-bisphosphate metabolism and can lead to secondary changes in FBPase activity.
From fructose 1,6-bisphosphate 1-phosphatase activity-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does FBP1 loss promote tumorigenesis? | FBP1 knockout cancer cell lines and mouse xenografts |
| How does FBPase activity affect gluconeogenesis? | Liver-specific FBP1 knockout mice |
| What is the role of FBP2 in muscle metabolism? | FBP2 knockout mice and muscle biopsies |
| Can point mutations in FBP1 cause disease? | Knock-in mice carrying patient mutations |
| How is FBPase regulated by phosphorylation? | Phospho-mimetic and phospho-deficient knock-in cells |
| Can overexpression of FBP1 reverse cancer phenotypes? | FBP1 overexpression in cancer cell lines |
How to Study the fructose 1,6-bisphosphate 1-phosphatase activity Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Coupled enzyme assay | Phosphate release or NADPH formation | Enzyme kinetics and inhibitor screening |
| X-ray crystallography | Three-dimensional structure | Mechanistic studies and drug design |
| RNA-seq | Gene expression levels | Tissue-specific expression and disease profiling |
| Proteomics | Protein abundance and modifications | Post-translational regulation |
| CRISPR knockout screen | Gene essentiality and interactions | Identifying synthetic lethal partners |
| Metabolomics | Metabolite levels (e.g., fructose 1,6-bisphosphate) | Pathway flux analysis |
| Western blot | Protein expression and phosphorylation | Validating regulation |
Biochemical Assays
Fructose 1,6-bisphosphate 1-phosphatase activity is typically measured using coupled enzyme assays that monitor the release of phosphate or the formation of fructose 6-phosphate. These assays are used to quantify enzyme kinetics and screen for inhibitors.
Structural Biology
X-ray crystallography and cryo-EM have been used to determine the structure of fructose-1,6-bisphosphatase and related phosphatases, revealing the catalytic mechanism and allosteric sites. These studies guide the design of specific inhibitors.
Transcriptomics and Proteomics
RNA-seq and proteomics can quantify FBP1 expression across tissues and conditions, linking expression changes to metabolic states. Such approaches have identified FBP1 as a prognostic marker in cancer.
CRISPR Screening
Genome-wide CRISPR knockout screens can identify genes that modulate fructose 1,6-bisphosphate 1-phosphatase activity or compensate for its loss, revealing synthetic lethal interactions.
How CRISPR Can Be Used to Study GO:0042132 fructose 1,6-bisphosphate 1-phosphatase activity
Knockout
CRISPR-Cas9 knockout of FBP1 in cell lines and mice abolishes fructose 1,6-bisphosphate 1-phosphatase activity, leading to impaired gluconeogenesis and accumulation of fructose 1,6-bisphosphate. These models are used to study metabolic reprogramming in cancer and diabetes.
Point Mutation
Introducing patient-derived point mutations (e.g., in FBP1) via CRISPR base editing or homology-directed repair allows researchers to dissect the impact of specific residues on catalytic activity and allosteric regulation.
Knock-in
Knock-in of tagged FBP1 (e.g., FLAG or GFP) enables affinity purification and live-cell imaging to study localization and interactions. Knock-in of disease-associated variants creates accurate models for drug testing.
Overexpression
CRISPR activation (CRISPRa) or lentiviral overexpression of FBP1 can restore fructose 1,6-bisphosphate 1-phosphatase activity in deficient cells, reversing metabolic phenotypes and serving as a gain-of-function model.
How EDITGENE Supports fructose 1,6-bisphosphate 1-phosphatase activity Research
Researchers studying fructose 1,6-bisphosphate 1-phosphatase activity-related genes often need to determine whether a candidate gene is causally involved in metabolic regulation or disease. EDITGENE provides a comprehensive suite of CRISPR services to generate precisely engineered cell models, enabling functional validation of genes associated with this activity.
Contact EDITGENE today to design your custom CRISPR model for fructose 1,6-bisphosphate 1-phosphatase activity research.
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| FBP1 Knockout HEK293 Cell Line | EDJ-KQ1863 | Human | 2203 | Details Get a Quote |
| FBP2 Knockout HEK293 Cell Line | EDJ-KQ1864 | Human | 8789 | Details Get a Quote |
| FBP1 Knockout HeLa Cell Line | EDJ-KQ21734 | Human | 2203 | Details Get a Quote |
| FBP2 Knockout HeLa Cell Line | EDJ-KQ55006 | Human | 8789 | Details Get a Quote |
| FBP1 Knockout A-549 Cell Line | EDJ-KQ61682 | Human | 2203 | Details Get a Quote |
| FBP2 Knockout A-549 Cell Line | EDJ-KQ63490 | Human | 8789 | Details Get a Quote |
| FBP1 Knockout HCT 116 Cell Line | EDJ-KQ70168 | Human | 2203 | Details Get a Quote |
| FBP2 Knockout HCT 116 Cell Line | EDJ-KQ71959 | Human | 8789 | Details Get a Quote |
Frequently Asked Questions About fructose 1,6-bisphosphate 1-phosphatase activity
What is fructose 1,6-bisphosphate 1-phosphatase activity?
It is the enzymatic activity that catalyzes the hydrolysis of D-fructose 1,6-bisphosphate to D-fructose 6-phosphate and phosphate, a key step in gluconeogenesis and the Calvin cycle.
What genes are involved in fructose 1,6-bisphosphate 1-phosphatase activity?
The main genes are FBP1 and FBP2, which encode fructose-1,6-bisphosphatase isoenzymes. Other related genes include PFKFB1-4, which regulate fructose 2,6-bisphosphate levels.
What is the GO ID for fructose 1,6-bisphosphate 1-phosphatase activity?
The Gene Ontology ID is GO:0042132.
How is fructose 1,6-bisphosphate 1-phosphatase activity regulated?
It is regulated allosterically by AMP, ATP, and fructose 2,6-bisphosphate, and by post-translational modifications such as phosphorylation.
What diseases are associated with fructose 1,6-bisphosphate 1-phosphatase activity?
Dysregulation is linked to diabetes, cancer, and metabolic disorders. FBP1 downregulation is observed in several cancers.
What methods are used to study fructose 1,6-bisphosphate 1-phosphatase activity?
Common methods include coupled enzyme assays, structural biology, RNA-seq, proteomics, and CRISPR screening.
Can CRISPR be used to study fructose 1,6-bisphosphate 1-phosphatase activity?
Yes, CRISPR knockout, knock-in, point mutation, and overexpression models are widely used to dissect the function of FBP1 and related genes.
What is the reaction catalyzed by fructose 1,6-bisphosphate 1-phosphatase?
D-fructose 1,6-bisphosphate + H2O = D-fructose 6-phosphate + phosphate.
Is fructose 1,6-bisphosphate 1-phosphatase activity found in plants?
Yes, it is a key enzyme of the Calvin cycle in plants, where it is regulated by light and redox state.
How does fructose 1,6-bisphosphate 1-phosphatase activity affect cancer metabolism?
Loss of FBP1 activity promotes glycolysis and tumor growth in cancers such as hepatocellular carcinoma, making it a potential therapeutic target.
Conclusion
Fructose 1,6-bisphosphate 1-phosphatase activity (GO:0042132) is a fundamental molecular function that governs glucose homeostasis and carbon fixation. Its dysregulation is implicated in diabetes and cancer, and it serves as a target for therapeutic intervention. By leveraging CRISPR-based models and advanced bioinformatics, researchers can further elucidate its regulatory mechanisms and develop novel treatments. EDITGENE provides the tools and expertise to accelerate this research.
References
- 2. RITTER P et al.. 1961. [The activity of fructose-1, 6-diphosphate-1-phosphatase in the liver of alloxan-diabetic rats].. Helv Physiol Pharmacol Acta 19:234-40 PMID: 13741901
- 3. Faisal Tarique K et al.. 2014. Structure-based identification of inositol polyphosphate 1-phosphatase from Entamoeba histolytica.. Acta Crystallogr D Biol Crystallogr 70(Pt 11):3023-33 PMID: 25372691
