GO:0005536 D-glucose binding: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0005536 D-glucose binding is a molecular function defined as binding to D-enantiomers of glucose, the primary sugar used for energy and signaling in cells.
• Key proteins that bind D-glucose include sodium-glucose cotransporters (SGLTs), insulin, and the bacterial D-glucose/D-galactose-binding protein, as shown by biophysical and structural studies.
• D-glucose binding is central to glucose sensing, transport, and metabolism, and its dysregulation is linked to metabolic disorders, cancer, and neurodegeneration.
• Experimental methods such as voltage-clamp fluorometry, fluorescence spectroscopy, and boronic acid-based sensors enable real-time analysis of D-glucose binding.
• CRISPR-based models (knockout, point mutation, knock-in, overexpression) are essential to dissect the causal roles of D-glucose-binding proteins in health and disease.
• EDITGENE provides comprehensive CRISPR services to accelerate research on D-glucose binding and related pathways.
Description
D-glucose binding (GO:0005536) is a fundamental molecular function that underlies glucose sensing, transport, and metabolism in organisms ranging from bacteria to humans. This function is mediated by a diverse array of proteins, including transporters, enzymes, and receptors that specifically recognize the D-enantiomer of glucose. The ability to bind D-glucose is critical for cellular energy homeostasis, signaling, and metabolic regulation, and its perturbation is associated with diseases such as diabetes, cancer, and neurodegenerative disorders. Researchers study D-glucose binding to understand how cells acquire and respond to glucose, and to develop therapeutic strategies targeting these interactions. The QuickGO definition of GO:0005536 is 'Binding to D-enantiomers of glucose,' highlighting its specificity for the D-form, which is the biologically relevant enantiomer. This article provides a comprehensive overview of the mechanisms, key genes, and research methods related to D-glucose binding, with a focus on CRISPR-based approaches for functional studies.
D-glucose binding At A Glance
| GO ID | GO:0005536 |
|---|---|
| GO term | D-glucose binding |
| Ontology | molecular_function |
| Synonym | glucose binding |
| Definition | Binding to D-enantiomers of glucose. |
| Major function | Specific recognition and interaction with D-glucose, enabling transport, signaling, or catalysis. |
| Related processes | Glucose transport, glucose sensing, glycolysis, insulin signaling. |
| Representative proteins | SGLT1, SGLT2, insulin, D-glucose/D-galactose-binding protein. |
| Disease relevance | Diabetes, cancer, Huntington's disease, metabolic disorders. |
What Is GO:0005536?
GO:0005536 D-glucose binding is a molecular function term describing the selective interaction of a protein or molecule with D-glucose, the dextrorotatory enantiomer of glucose. This binding event is non-covalent and reversible, and it is essential for processes such as glucose transport, sensing, and enzymatic catalysis. The term is defined by the Gene Ontology Consortium as 'Binding to D-enantiomers of glucose,' emphasizing stereospecificity. Proteins annotated with this function include sodium-glucose cotransporters, insulin, and periplasmic binding proteins, which use D-glucose binding to trigger conformational changes, transport, or signaling.
Why Is D-glucose binding Important in Cell Biology?
D-glucose binding is a cornerstone of cellular metabolism and energy regulation. It is the first step in glucose utilization, and its dysregulation contributes to a wide range of pathologies, including diabetes, cancer, and neurodegenerative diseases. Understanding the molecular details of D-glucose binding is therefore critical for developing diagnostics and therapeutics that target glucose metabolism.
• D-glucose is the primary energy source for most cells, and its binding to transporters and enzymes initiates its metabolic fate.
• Sodium-glucose cotransporters (SGLTs) rely on D-glucose binding to mediate active transport across membranes, a process targeted by diabetes drugs.
• Insulin binds D-glucose, which may modulate its activity and stability, linking glucose binding to hormonal regulation.
• Bacterial D-glucose/D-galactose-binding proteins are model systems for studying protein-sugar recognition and chemotaxis.
• Altered D-glucose binding and metabolism are hallmarks of cancer, supporting tumor growth and survival.
• In Huntington's disease, reduced D2/D3 receptor binding and glucose metabolism correlate with disease progression.
• Boronic acid-based sensors that bind D-glucose are used for continuous glucose monitoring and cell staining.
• High D-glucose conditions can affect membrane interactions, though not all binding events are altered.
• D-allulose, a rare sugar, can be produced from D-glucose via isomerization, highlighting biotechnological applications.
• CRISPR screening can identify genes that regulate D-glucose binding and metabolism, offering new therapeutic targets.
Molecular Mechanism of D-glucose binding
Substrate Recognition and Binding Site
In simple terms: Proteins have a specific pocket that fits D-glucose like a lock and key.
D-glucose binding typically occurs in a dedicated binding pocket formed by polar and aromatic residues that hydrogen-bond with the hydroxyl groups of glucose. For example, the bacterial D-glucose/D-galactose-binding protein undergoes a conformational change upon binding, which is essential for chemotaxis. In sodium-glucose cotransporters, the binding site coordinates glucose and sodium ions, as revealed by voltage-clamp fluorometry.
Conformational Changes and Signal Transduction
In simple terms: When glucose binds, the protein changes shape to send a signal or transport the sugar.
Binding of D-glucose induces conformational changes in transporters and receptors. In SGLTs, glucose binding triggers rearrangements that couple sodium transport to sugar uptake. Insulin, upon binding D-glucose, may undergo structural alterations that affect its function. These conformational dynamics are critical for downstream signaling and transport.
Cofactors and Ion Coupling
In simple terms: Some proteins need helper ions like sodium to bind glucose effectively.
Sodium-glucose cotransporters require sodium ions as cofactors; the binding of D-glucose is coupled to sodium influx, and this is studied using voltage-clamp fluorometry. Other proteins may use calcium or other ions to stabilize the binding site. The interplay between ion binding and sugar binding is a key regulatory mechanism.
Regulation of D-glucose Binding
In simple terms: Cells can adjust how well proteins bind glucose based on conditions.
D-glucose binding can be regulated by post-translational modifications, allosteric effectors, and membrane environment. For instance, high D-glucose concentrations do not affect alpha-tocopherol binding to erythrocytes, indicating specificity. In cancer, metabolic reprogramming can alter the expression of glucose-binding proteins, such as c-Myc-driven pathways.
Kinetics and Affinity
In simple terms: How tightly and quickly a protein binds glucose determines its function.
Binding affinity (Kd) and kinetics vary among proteins. Boronic acid-based sensors exhibit turn-on fluorescence upon D-glucose binding, allowing real-time measurement of affinity. The D-glucose/D-galactose-binding protein shows high affinity and specificity, which is modulated by crowding agents. These parameters are crucial for understanding physiological roles.
Key Genes Involved in GO:0005536 D-glucose binding
The following genes encode proteins that directly bind D-glucose or are critically involved in D-glucose-binding pathways, as supported by published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| SLC5A1 | Sodium-glucose cotransporter 1 (SGLT1); binds D-glucose for intestinal absorption | Target for diabetes and glucose transport studies |
| SLC5A2 | Sodium-glucose cotransporter 2 (SGLT2); renal glucose reabsorption | Therapeutic target for SGLT2 inhibitors in diabetes |
| INS | Insulin; binds D-glucose, affecting hormone function | Link between glucose binding and insulin regulation |
| MGAM | Maltase-glucoamylase; binds D-glucose as substrate | Digestive enzyme, potential target for glycemic control |
| G6PD | Glucose-6-phosphate dehydrogenase; binds glucose derivatives | Role in oxidative stress and cancer metabolism |
| GCK | Glucokinase; binds D-glucose as substrate | Glucose sensing in pancreatic beta cells |
| SLC2A1 | GLUT1; facilitates D-glucose transport | Widely expressed, target in cancer metabolism |
| SLC2A4 | GLUT4; insulin-responsive glucose transporter | Key in diabetes and insulin resistance |
| HK1 | Hexokinase 1; binds D-glucose for phosphorylation | First step of glycolysis, cancer target |
| HK2 | Hexokinase 2; binds D-glucose, promotes glycolysis | Overexpressed in cancers |
| PYGL | Glycogen phosphorylase; binds glucose derivatives | Glycogen metabolism |
| GYS1 | Glycogen synthase; binds UDP-glucose | Glycogen synthesis |
| AMY1A | Alpha-amylase; binds starch and glucose polymers | Digestion, genetic variation |
| SI | Sucrase-isomaltase; binds glucose-containing sugars | Digestive disorders |
| LCT | Lactase; binds lactose, releases glucose | Lactose intolerance |
| SLC5A4 | SGLT3; glucose sensor, not transporter | Glucose sensing in neurons and muscle |
| GCG | Glucagon; binds glucose indirectly | Glucose homeostasis |
| INSR | Insulin receptor; binds insulin, not glucose directly | Downstream of glucose signaling |
How Is D-glucose binding Regulated?
D-glucose binding is regulated at multiple levels. Expression of glucose transporters and enzymes is controlled by transcription factors such as c-Myc, which reprograms glucose metabolism in cancer. Post-translational modifications, such as glycosylation, can modulate binding affinity. Allosteric regulation by ions (e.g., sodium in SGLTs) is critical. Additionally, the membrane lipid environment can influence binding, as seen with alpha-tocopherol in erythrocytes. Hormones like insulin regulate glucose uptake by controlling transporter trafficking, indirectly affecting D-glucose binding.
D-glucose binding and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| SLC5A2 | Diabetes, renal glucosuria | Knockout mouse, point mutation in binding site |
| HK2 | Cancer (hepatocellular carcinoma) | Overexpression in cell lines, knockout |
| INS | Diabetes, insulin resistance | Knock-in of glucose-binding mutants |
| HTT | Huntington's disease | Knock-in macaque model, KO cells |
| MYC | Cancer metabolism | Overexpression, CRISPR activation |
D-glucose binding in Cancer Metabolism
Cancer cells often exhibit increased glucose uptake and metabolism, a phenomenon known as the Warburg effect. D-glucose binding to transporters and hexokinases is upregulated in many cancers. For example, METTL5 stabilizes c-Myc to reprogram glucose metabolism and promote hepatocellular carcinoma progression. Targeting D-glucose binding proteins is a therapeutic strategy in oncology.
D-glucose binding in Neurodegeneration
In Huntington's disease, reduced D2/D3 receptor binding and glucose metabolism are observed in a macaque model, linking impaired glucose binding and utilization to neurodegeneration. This suggests that D-glucose binding and metabolic pathways are relevant to neurodegenerative disease pathology.
D-glucose binding in Diabetes and Metabolic Disorders
Sodium-glucose cotransporters (SGLTs) are key mediators of renal glucose reabsorption. Mutations in SLC5A2 cause familial renal glucosuria, and SGLT2 inhibitors are used to treat type 2 diabetes by blocking D-glucose binding. Thus, D-glucose binding is directly linked to glucose homeostasis and diabetes.
From D-glucose binding-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does SLC5A2 mutation affect D-glucose binding affinity? | Point mutation knock-in cell line |
| What is the role of HK2 in cancer glucose metabolism? | Knockout and overexpression models |
| How does insulin binding to D-glucose modulate secretion? | Tagged knock-in for imaging |
| Can CRISPR screening identify novel D-glucose binding regulators? | Genome-wide CRISPR library screening |
| Does SGLT1 knockout alter intestinal glucose uptake? | Knockout mouse or cell line |
| What is the effect of D-glucose binding on Huntington's disease progression? | Knock-in macaque model |
How to Study the D-glucose binding Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Voltage-clamp fluorometry | Conformational changes and binding kinetics | SGLT sugar binding analysis |
| Fluorescence spectroscopy | Binding-induced fluorescence changes | Boronic acid sensors for D-glucose |
| Isothermal titration calorimetry | Binding affinity and thermodynamics | Protein-sugar interactions |
| Surface plasmon resonance | Real-time binding kinetics | Screening inhibitors |
| X-ray crystallography | Atomic structure of binding site | Structure-based drug design |
| CRISPR screening | Gene function in glucose binding | Identify novel regulators |
| RNA-seq | Gene expression changes | Pathway analysis |
| Proteomics | Protein abundance and modifications | Global analysis of glucose-binding proteins |
Voltage-Clamp Fluorometry
This technique measures conformational changes and binding events in real time by combining electrophysiology with fluorescence. It has been used to analyze sugar binding of sodium-glucose cotransporters, revealing kinetics and ion coupling.
Fluorescence Spectroscopy
Boronic acid-based fluorescent sensors exhibit turn-on fluorescence upon D-glucose binding, enabling sensitive detection and quantification in cells and solutions. This method is useful for high-throughput screening of binding modulators.
Structural Biology (X-ray, Cryo-EM)
High-resolution structures of D-glucose-binding proteins, such as the bacterial D-glucose/D-galactose-binding protein, reveal atomic details of the binding pocket and conformational changes. These insights guide mutagenesis and drug design.
CRISPR Screening and Functional Genomics
Genome-wide CRISPR knockout or activation screens can identify genes that regulate D-glucose binding and metabolism. Combined with bioinformatics, this approach uncovers novel pathways and therapeutic targets.
How CRISPR Can Be Used to Study GO:0005536 D-glucose binding
Knockout
CRISPR knockout of genes encoding D-glucose-binding proteins (e.g., SLC5A2, HK2) allows researchers to assess loss-of-function phenotypes, such as altered glucose transport or metabolism. This is critical for validating therapeutic targets.
Point Mutation
Introducing precise point mutations in the binding pocket of D-glucose-binding proteins can reveal residues essential for binding affinity and specificity. For example, mutating SGLT2 residues can mimic familial glucosuria mutations.
Knock-in
Knock-in of tagged or reporter versions of D-glucose-binding proteins enables real-time imaging and tracking of binding events in live cells. This approach is valuable for studying dynamic interactions.
Overexpression
Overexpression of D-glucose-binding proteins, such as HK2 or GLUT1, can model cancer metabolism and identify dependencies. CRISPR activation (CRISPRa) can achieve tunable overexpression for dose-response studies.
How EDITGENE Supports D-glucose binding Research
Researchers studying D-glucose binding-related genes often need to determine whether a candidate gene is causally involved in glucose sensing, transport, or metabolism. EDITGENE provides a comprehensive suite of CRISPR services to generate precisely engineered cell models, enabling rigorous functional validation and accelerating discovery in metabolic research.
Contact EDITGENE today to design your custom CRISPR model for D-glucose binding research.
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| GYS1 Knockout HEK293 Cell Line | EDJ-KQ804 | Human | 2997 | Details Get a Quote |
| HK3 Knockout HEK293 Cell Line | EDJ-KQ916 | Human | 3101 | Details Get a Quote |
| HK1 Knockout HEK293 Cell Line | EDJ-KQ1506 | Human | 3098 | Details Get a Quote |
| HK2 Knockout HEK293 Cell Line | EDJ-KQ1507 | Human | 3099 | Details Get a Quote |
| HKDC1 Knockout HEK293 Cell Line | EDJ-KQ1508 | Human | 80201 | Details Get a Quote |
| GCK Knockout HEK293 Cell Line | EDJ-KQ3139 | Human | 2645 | Details Get a Quote |
| SLC2A8 Knockout HEK293 Cell Line | EDJ-KQ3619 | Human | 29988 | Details Get a Quote |
| SLC2A3 Knockout HEK293 Cell Line | EDJ-KQ3905 | Human | 6515 | Details Get a Quote |
| PYGL Knockout HEK293 Cell Line | EDJ-KQ5618 | Human | 5836 | Details Get a Quote |
| SLC2A14 Knockout HEK293 Cell Line | EDJ-KQ9694 | Human | 144195 | Details Get a Quote |
| HK1 Knockout A-549 Cell Line | EDJ-KQ21124 | Human | 3098 | Details Get a Quote |
| HK1 Knockout HCT 116 Cell Line | EDJ-KQ21125 | Human | 3098 | Details Get a Quote |
| HK1 Knockout HeLa Cell Line | EDJ-KQ21126 | Human | 3098 | Details Get a Quote |
| HK2 Knockout HCT 116 Cell Line | EDJ-KQ21127 | Human | 3099 | Details Get a Quote |
| HK2 Knockout HeLa Cell Line | EDJ-KQ21128 | Human | 3099 | Details Get a Quote |
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Frequently Asked Questions About D-glucose binding
What is D-glucose binding?
D-glucose binding (GO:0005536) is the molecular function of selectively interacting with the D-enantiomer of glucose, a key sugar in energy metabolism and signaling.
What genes are involved in D-glucose binding?
Genes such as SLC5A1, SLC5A2, INS, HK2, and GCK encode proteins that bind D-glucose or are critical for its binding and transport.
How is D-glucose binding studied?
Common methods include voltage-clamp fluorometry, fluorescence spectroscopy, structural biology, and CRISPR screening.
Why is D-glucose binding important in cancer?
Cancer cells often upregulate D-glucose binding and metabolism to support growth, making it a therapeutic target.
What diseases are linked to D-glucose binding?
Diabetes, cancer, and neurodegenerative diseases like Huntington's disease are associated with altered D-glucose binding.
What is the GO term for glucose binding?
The Gene Ontology term for glucose binding is GO:0005536, defined as binding to D-enantiomers of glucose.
How does insulin bind D-glucose?
Insulin can bind D-glucose, which may influence its structure and function, as shown by early biophysical studies.
What are sodium-glucose cotransporters?
SGLTs are membrane proteins that couple sodium transport to D-glucose binding, essential for glucose absorption and reabsorption.
Can CRISPR be used to study D-glucose binding?
Yes, CRISPR knockout, point mutation, knock-in, and overexpression models enable precise functional studies of D-glucose-binding proteins.
What is the role of D-glucose binding in Huntington's disease?
Reduced glucose metabolism and D2/D3 receptor binding are observed in Huntington's disease models, linking D-glucose binding to neurodegeneration.
Conclusion
D-glucose binding (GO:0005536) is a fundamental molecular function with broad implications for cellular metabolism, signaling, and disease. Key proteins such as SGLTs, insulin, and hexokinases mediate this function, and their dysregulation contributes to cancer, diabetes, and neurodegeneration. Advanced experimental methods, including CRISPR-based models, are essential to dissect the mechanisms and therapeutic potential of D-glucose binding. EDITGENE's comprehensive CRISPR services empower researchers to generate precise cell models and accelerate discoveries in this critical field.
References
- 1. Weiss AR et al.. 2023. Reduced D(2) /D(3) Receptor Binding and Glucose Metabolism in a Macaque Model of Huntington's Disease.. Mov Disord 38(1):143-147 PMID: 36544385
- 2. Xia P et al.. 2023. METTL5 stabilizes c-Myc by facilitating USP5 translation to reprogram glucose metabolism and promote hepatocellular carcinoma progression.. Cancer Commun (Lond) 43(3):338-364 PMID: 36602428
- 3. Xie X et al.. 2024. Bioproduction of Rare d-Allulose from d-Glucose via Borate-Assisted Isomerization.. J Agric Food Chem 72(6):3036-3044 PMID: 38299460
- 4. Watabe E et al.. 2024. Sugar binding of sodium-glucose cotransporters analyzed by voltage-clamp fluorometry.. J Biol Chem 300(5):107215 PMID: 38522518
- 5. Anzenbacher P et al.. 1975. Binding of D-glucose to insulin.. Biochim Biophys Acta 386(2):603-7 PMID: 237539
- 6. Alkaş A et al.. 2024. BODIPYs α-appended with distyryl-linked aryl bisboronic acids: single-step cell staining and turn-on fluorescence binding with D-glucose.. Org Biomol Chem 22(36):7448-7459 PMID: 39188164
- 7. Fonin AV et al.. 2017. Structure and Conformational Properties of d-Glucose/d-Galactose-Binding Protein in Crowded Milieu.. Molecules 22(2) PMID: 28178192
- 8. Bellizzi MC et al.. 1997. High D-glucose does not affect binding of alpha-tocopherol to human erythrocytes.. Mol Cell Biochem 170(1-2):187-93 PMID: 9144334
