GO:0006013 mannose metabolic process: Glycoprotein Biosynthesis Pathway, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0006013 (mannose metabolic process) describes the chemical reactions and pathways involving mannose, the C-2 epimer of glucose, which is a core component of N-linked glycans and mannans.
• Mannose is not merely a dietary sugar; it is actively salvaged and interconverted with glucose to supply glycoprotein biosynthesis, and its metabolic origin in glycoproteins has been traced experimentally.
• D-mannose impairs tumour growth and enhances chemotherapy in multiple cancer models, linking mannose metabolism directly to oncology.
• D-mannose also facilitates immunotherapy and radiotherapy of triple-negative breast cancer by promoting PD-L1 degradation.
• High-mannose N-glycan levels on recombinant antibodies can be deliberately increased through metabolic and process engineering, which is critical for therapeutic antibody function.
• CRISPR screens combined with lectin microarrays have identified novel regulators of high-mannose N-glycans, providing a powerful discovery platform for mannose metabolic process genes.
Description
Mannose metabolic process (GO:0006013) encompasses the chemical reactions and pathways involving mannose, the aldohexose manno-hexose and C-2 epimer of glucose. The D-(+)-form of mannose is widely distributed in mannans and hemicelluloses and is of major importance in the core oligosaccharide of N-linked oligosaccharides of glycoproteins. This ontology term is therefore central to understanding how cells acquire, interconvert, and utilize mannose for glycoprotein biosynthesis, energy metabolism, and signalling. Researchers studying glycosylation, cancer metabolism, immunology, and biotherapeutic production routinely encounter mannose metabolic process as a key node. The pathway is not simply a catabolic route; it is a dynamic interface between glucose metabolism, nucleotide sugar pools, and the secretory pathway. Experimental evidence has demonstrated that mannose in glycoproteins can originate from both exogenous mannose and glucose-derived fructose-6-phosphate, highlighting the metabolic flexibility of this process. Because mannose metabolism intersects with immune regulation, tumour biology, and recombinant protein quality, it has become a focus for CRISPR-based functional genomics and therapeutic development.
mannose metabolic process At A Glance
| GO ID | GO:0006013 |
|---|---|
| GO term | mannose metabolic process |
| Ontology | biological_process |
| Synonym | mannose metabolism |
| Definition | The chemical reactions and pathways involving mannose, the aldohexose manno-hexose, the C-2 epimer of glucose. The D-(+)-form is widely distributed in mannans and hemicelluloses and is of major importance in the core oligosaccharide of N-linked oligosaccharides of glycoproteins. |
| Major function | Supply and interconvert mannose for N-linked glycosylation, mannan biosynthesis, and energy metabolism |
| Key enzymes | Hexokinase, phosphomannose isomerase, phosphomannomutase, GDP-mannose pyrophosphorylase, and mannosidases |
| Related pathways | Glycolysis, N-glycan biosynthesis, O-mannosylation, and nucleotide sugar metabolism |
| Disease relevance | Cancer metabolism, congenital disorders of glycosylation, and immune regulation |
What Is GO:0006013?
GO:0006013 mannose metabolic process is defined as the chemical reactions and pathways involving mannose, the aldohexose manno-hexose, the C-2 epimer of glucose. The D-(+)-form is widely distributed in mannans and hemicelluloses and is of major importance in the core oligosaccharide of N-linked oligosaccharides of glycoproteins. In practical terms, this term covers the enzymatic steps that convert mannose to mannose-6-phosphate, interconvert mannose-6-phosphate with fructose-6-phosphate, and funnel mannose into glycosylation pathways, as well as the catabolic and salvage reactions that maintain mannose homeostasis.
Why Is mannose metabolic process Important in Cell Biology?
Mannose metabolic process is important because it sits at the intersection of energy metabolism, glycoprotein biosynthesis, and immune regulation. Defects in mannose metabolism can alter the glycosylation of cell surface and secreted proteins, affecting cell signalling, immune recognition, and protein stability. In cancer, D-mannose has been shown to impair tumour growth and enhance chemotherapy, making mannose metabolism a potential therapeutic target. In immunotherapy, D-mannose facilitates PD-L1 degradation and improves responses to immunotherapy and radiotherapy in triple-negative breast cancer. In biotechnology, controlling high-mannose N-glycan levels on recombinant antibodies is essential for product quality and function. Furthermore, CRISPR screens have revealed that mannose metabolic process genes are tractable targets for modulating glycosylation in cells.
• Mannose is a critical substrate for N-linked glycosylation, influencing protein folding, stability, and cell surface recognition.
• D-mannose impairs tumour growth and enhances chemotherapy in preclinical cancer models.
• D-mannose promotes PD-L1 degradation and improves immunotherapy and radiotherapy in triple-negative breast cancer.
• High-mannose N-glycan levels on recombinant antibodies can be engineered for therapeutic benefit.
• CRISPR screens with lectin microarrays have identified regulators of high-mannose N-glycans, enabling functional genomics of mannose metabolism.
• Mannose metabolism is linked to macrophage IL-1beta production, connecting it to inflammation and innate immunity.
• O-mannosylation, a related mannose-dependent modification, is important in muscle and neuronal biology.
• Congenital disorders of glycosylation often involve enzymes in mannose metabolic process, leading to multisystem disease.
• Mannose metabolism intersects with glycolysis, and defects can affect birth defects and metabolic homeostasis.
• Understanding mannose metabolic process supports the development of glycoengineered biotherapeutics and metabolic therapies.
What Happens During mannose metabolic process?
Mannose uptake and phosphorylation
In simple terms: Cells take up mannose from the environment and add a phosphate group to trap it inside.
Mannose enters cells through facilitative glucose transporters and is rapidly phosphorylated by hexokinase to mannose-6-phosphate. This step prevents mannose from diffusing back out and commits it to metabolism. The metabolic origins of mannose in glycoproteins have been studied using isotopic tracing, showing that both exogenous mannose and glucose-derived fructose-6-phosphate contribute to mannose-6-phosphate pools.
Interconversion with fructose-6-phosphate
In simple terms: Mannose-6-phosphate can be converted into a glycolytic intermediate and vice versa.
Phosphomannose isomerase catalyzes the reversible conversion of mannose-6-phosphate to fructose-6-phosphate, linking mannose metabolism to glycolysis. This interconversion allows mannose to feed into energy production and allows glucose-derived fructose-6-phosphate to supply mannose for glycosylation. Experimental evidence indicates that this bidirectional flow is essential for maintaining glycoprotein mannose content.
Activation to GDP-mannose
In simple terms: Mannose is activated into a carrier-linked form that can be used to build glycans.
Mannose-6-phosphate is converted to mannose-1-phosphate by phosphomannomutase, and then to GDP-mannose by GDP-mannose pyrophosphorylase. GDP-mannose serves as the donor substrate for mannosyltransferases in the endoplasmic reticulum and Golgi apparatus, enabling the assembly of N-linked glycans, O-mannosylated proteins, and mannans.
N-linked glycosylation and high-mannose glycans
In simple terms: Mannose is added to proteins to form sugar trees that help proteins fold and function.
In the endoplasmic reticulum, GDP-mannose is used to build the core oligosaccharide of N-linked glycans, which is transferred to nascent proteins. High-mannose N-glycans are intermediates that can be further processed or remain as high-mannose structures. A robust method has been developed to increase Fc glycan high-mannose levels on recombinant antibodies, demonstrating that this step is tunable for biotherapeutic production. CRISPR screens with lectin microarrays have identified regulators of high-mannose N-glycans, highlighting the genetic control of this process.
O-mannosylation and mannan biosynthesis
In simple terms: Mannose is also attached to certain proteins and to structural polysaccharides.
O-mannosylation is a conserved modification in which mannose is added to serine or threonine residues of proteins, important for muscle and neuronal function. In fungi and plants, mannose is polymerized into mannans and hemicelluloses, which are structural components of cell walls. These pathways consume GDP-mannose and are interconnected with the core mannose metabolic process.
Catabolism and salvage of mannose
In simple terms: Mannose can be broken down or recycled depending on cellular needs.
Excess mannose-6-phosphate can enter glycolysis via fructose-6-phosphate, contributing to energy production. Alternatively, mannose can be salvaged from glycoprotein turnover through lysosomal degradation and recycled. The balance between catabolism and salvage is critical for maintaining mannose homeostasis, and disruptions can lead to metabolic disorders.
Key Genes Involved in GO:0006013 mannose metabolic process
The following genes and proteins are central to mannose metabolic process, based on published literature and their roles in mannose uptake, interconversion, activation, and glycosylation.
| Gene | Major Role | Research Relevance |
|---|---|---|
| HK1 | Hexokinase 1 phosphorylates mannose to mannose-6-phosphate | Target for modulating mannose entry into metabolism |
| HK2 | Hexokinase 2 phosphorylates mannose in tissues with high glycolytic flux | Cancer metabolism and mannose sensitivity |
| MPI | Phosphomannose isomerase interconverts mannose-6-phosphate and fructose-6-phosphate | Key node linking mannose metabolism to glycolysis |
| PMM2 | Phosphomannomutase 2 converts mannose-6-phosphate to mannose-1-phosphate | Mutations cause congenital disorder of glycosylation |
| GMPPA | GDP-mannose pyrophosphorylase A subunit | Required for GDP-mannose synthesis |
| GMPPB | GDP-mannose pyrophosphorylase B subunit | Mutations linked to muscular dystrophy and glycosylation defects |
| ALG1 | Mannosyltransferase in N-glycan core assembly | Congenital disorders of glycosylation |
| ALG2 | Mannosyltransferase in N-glycan core assembly | Defects affect glycoprotein biosynthesis |
| ALG3 | Alpha-1,3-mannosyltransferase | High-mannose glycan regulation |
| ALG6 | Alpha-1,3-glucosyltransferase | N-glycan processing and quality control |
| ALG9 | Alpha-1,2-mannosyltransferase | N-glycan assembly and disease |
| MAN1B1 | Alpha-1,2-mannosidase in ER | High-mannose N-glycan trimming |
| MAN2A1 | Alpha-mannosidase in Golgi | N-glycan maturation |
| MGAT1 | N-acetylglucosaminyltransferase I | Switch from high-mannose to complex glycans |
| POMT1 | Protein O-mannosyltransferase 1 | O-mannosylation and muscular dystrophy |
| POMT2 | Protein O-mannosyltransferase 2 | O-mannosylation and neuronal migration |
| POMGNT1 | O-linked mannose beta-1,2-N-acetylglucosaminyltransferase | Dystroglycanopathy |
| FUT8 | Fucosyltransferase 8 | Antibody glycoengineering and high-mannose control |
How Is mannose metabolic process Regulated?
Mannose metabolic process is regulated at multiple levels. Substrate availability, including dietary mannose and glucose, influences flux through the pathway. Enzyme expression and activity, such as hexokinase and phosphomannose isomerase, are modulated by metabolic signals and oncogenic pathways. In cancer, D-mannose impairs tumour growth and enhances chemotherapy, suggesting that mannose metabolism is sensitive to therapeutic intervention. D-mannose also suppresses macrophage IL-1beta production, indicating immune-metabolic regulation. Additionally, CRISPR screens have identified genetic regulators of high-mannose N-glycans, revealing that the pathway is under complex genetic control. The unfolded protein response and secretory pathway demand can also influence mannose utilization for glycosylation.
mannose metabolic process and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| MPI | Congenital disorder of glycosylation and cancer metabolism | Knockout cell lines and mouse models |
| PMM2 | Congenital disorder of glycosylation type Ia | Patient-derived fibroblasts and knock-in mice |
| GMPPB | Muscular dystrophy-dystroglycanopathy | CRISPR knockout in muscle cells |
| POMT1 | Walker-Warburg syndrome | Knockout zebrafish and mouse models |
| PD-L1 (CD274) | Triple-negative breast cancer immunotherapy | Mannose-treated tumour models and knockout cells |
Cancer metabolism and therapy
D-mannose impairs tumour growth and enhances chemotherapy in multiple cancer models, linking mannose metabolic process to oncology. In triple-negative breast cancer, D-mannose facilitates immunotherapy and radiotherapy by promoting PD-L1 degradation. These findings suggest that manipulating mannose metabolism could be a therapeutic strategy, and genes in this pathway are candidate targets for drug development.
Congenital disorders of glycosylation
Mutations in enzymes of mannose metabolic process, such as PMM2 and GMPPB, cause congenital disorders of glycosylation, leading to multisystem disease including neurological and muscular symptoms. These disorders highlight the importance of mannose metabolism for normal development and protein function.
Immune regulation and inflammation
D-mannose suppresses macrophage IL-1beta production, connecting mannose metabolism to innate immune responses. This suggests that mannose metabolic process can modulate inflammation and may be relevant to autoimmune and inflammatory diseases.
Muscular dystrophy and neuronal migration
O-mannosylation, a branch of mannose metabolism, is essential for alpha-dystroglycan function, and defects cause muscular dystrophy and neuronal migration disorders. Genes such as POMT1, POMT2, and POMGNT1 are directly implicated in these diseases.
From mannose metabolic process-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of MPI affect mannose flux and glycosylation? | MPI knockout cell line via CRISPR |
| Can a point mutation in PMM2 mimic congenital disorder of glycosylation? | PMM2 point-mutation knock-in cells |
| Does overexpression of hexokinase 2 increase mannose consumption in cancer cells? | HK2 overexpression cell model |
| How does tagged GDP-mannose pyrophosphorylase localize in cells? | Tagged knock-in of GMPPA/GMPPB |
| What genes regulate high-mannose N-glycans? | Genome-wide CRISPR knockout library screening |
| Does D-mannose enhance immunotherapy in triple-negative breast cancer? | PD-L1 knockout and mannose-treated xenografts |
How to Study the mannose metabolic process Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Lectin microarray | High-mannose N-glycan levels | CRISPR screen readout and glycan profiling |
| Stable isotope tracing | Mannose flux and origin | Metabolic pathway analysis |
| CRISPR knockout screen | Gene essentiality for high-mannose glycans | Discovery of mannose metabolism regulators |
| Mass spectrometry | Glycan composition and structure | Antibody glycoanalysis |
| Western blot | Protein expression and PD-L1 degradation | Immunotherapy studies |
| Flow cytometry | Cell surface glycan and PD-L1 levels | Immune checkpoint regulation |
| Enzyme activity assay | Hexokinase, MPI, PMM activity | Functional validation of metabolic enzymes |
Lectin microarrays for glycan profiling
Lectin microarrays are used to detect high-mannose N-glycans on cell surfaces or glycoproteins. This method has been combined with CRISPR screens to identify regulators of high-mannose glycans, providing a high-throughput readout of mannose metabolic process activity.
Metabolic tracing with stable isotopes
Isotope tracing using 13C-labeled mannose or glucose can quantify the contribution of different substrates to mannose-6-phosphate and glycoprotein mannose pools. This approach has been used to determine the metabolic origins of mannose in glycoproteins.
CRISPR screens and functional genomics
Genome-wide CRISPR knockout screens coupled with lectin staining or lectin microarrays enable unbiased discovery of genes regulating mannose metabolism and high-mannose N-glycans. This method is powerful for identifying novel therapeutic targets.
Glycoengineering of recombinant antibodies
Methods to increase Fc glycan high-mannose levels on recombinant antibodies involve manipulating mannose metabolic process enzymes and culture conditions. This is critical for antibody effector function and product consistency.
How CRISPR Can Be Used to Study GO:0006013 mannose metabolic process
Knockout
CRISPR knockout of mannose metabolic process genes such as MPI, PMM2, or GMPPB allows researchers to study loss-of-function phenotypes, including glycosylation defects and metabolic rewiring. For example, knockout of MPI can reveal its essentiality for mannose interconversion and glycoprotein biosynthesis. Genome-wide knockout screens have identified regulators of high-mannose N-glycans, demonstrating the power of this approach.
Point Mutation
Point mutations in mannose metabolic enzymes, such as PMM2, can model congenital disorders of glycosylation. CRISPR-mediated point mutation knock-in enables precise disease modeling and functional analysis of specific amino acid changes.
Knock-in
Knock-in of tagged versions of mannose metabolic enzymes, such as GMPPA or GMPPB, allows localization and interaction studies. This approach can also be used to introduce disease-associated mutations or reporter tags for live-cell imaging.
Overexpression
Overexpression of genes like HK2 or MPI can increase mannose flux and alter glycosylation patterns. This is useful for studying gain-of-function effects in cancer metabolism and for engineering cells with enhanced mannose utilization.
How EDITGENE Supports mannose metabolic process Research
Researchers studying mannose metabolic process-related genes often need to determine whether a candidate gene is causally involved in glycosylation, cancer metabolism, or immune regulation. EDITGENE provides comprehensive CRISPR-based services to generate precisely engineered cell models, enabling functional validation and therapeutic target discovery.
Contact EDITGENE today to design your custom CRISPR model for mannose metabolic process research.
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| HK1 Knockout HEK293 Cell Line | EDJ-KQ1506 | Human | 3098 | Details Get a Quote |
| MAN2A1 Knockout HEK293 Cell Line | EDJ-KQ2493 | Human | 4124 | Details Get a Quote |
| MAN2A2 Knockout HEK293 Cell Line | EDJ-KQ5167 | Human | 4122 | Details Get a Quote |
| MAN2C1 Knockout HEK293 Cell Line | EDJ-KQ5168 | Human | 4123 | Details Get a Quote |
| MAN2B1 Knockout HEK293 Cell Line | EDJ-KQ5170 | Human | 4125 | Details Get a Quote |
| PMM1 Knockout HEK293 Cell Line | EDJ-KQ5493 | Human | 5372 | Details Get a Quote |
| PMM2 Knockout HEK293 Cell Line | EDJ-KQ5494 | Human | 5373 | Details Get a Quote |
| MAN2B2 Knockout HEK293 Cell Line | EDJ-KQ7964 | Human | 23324 | 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 |
| MAN2A1 Knockout A-549 Cell Line | EDJ-KQ23083 | Human | 4124 | Details Get a Quote |
| MAN2A1 Knockout HCT 116 Cell Line | EDJ-KQ23084 | Human | 4124 | Details Get a Quote |
| MAN2A1 Knockout HeLa Cell Line | EDJ-KQ23085 | Human | 4124 | Details Get a Quote |
| MAN2B1 Knockout A-549 Cell Line | EDJ-KQ26922 | Human | 4125 | Details Get a Quote |
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Frequently Asked Questions About mannose metabolic process
What is mannose metabolic process?
Mannose metabolic process (GO:0006013) is the set of chemical reactions and pathways involving mannose, including its uptake, phosphorylation, interconversion with fructose-6-phosphate, activation to GDP-mannose, and use in glycosylation.
What genes are involved in mannose metabolic process?
Key genes include HK1, HK2, MPI, PMM2, GMPPA, GMPPB, ALG1-ALG9, MAN1B1, MAN2A1, MGAT1, POMT1, POMT2, POMGNT1, and FUT8, among others.
How does mannose metabolism affect cancer?
D-mannose impairs tumour growth and enhances chemotherapy, and it facilitates immunotherapy and radiotherapy in triple-negative breast cancer by degrading PD-L1.
What is the role of mannose in N-linked glycosylation?
Mannose is a core component of the N-linked glycan precursor and high-mannose glycans, which are essential for protein folding and function.
Can CRISPR be used to study mannose metabolic process?
Yes, CRISPR knockout, point mutation, knock-in, and overexpression models enable functional studies of mannose metabolic genes, and CRISPR screens have identified regulators of high-mannose N-glycans.
What diseases are linked to mannose metabolic process?
Congenital disorders of glycosylation, muscular dystrophy, neuronal migration disorders, and cancer are linked to defects in mannose metabolism.
How is mannose metabolism regulated?
It is regulated by substrate availability, enzyme expression, oncogenic signals, and immune-metabolic cues, with D-mannose suppressing macrophage IL-1beta production.
What methods are used to study mannose metabolic process?
Lectin microarrays, stable isotope tracing, CRISPR screens, mass spectrometry, and enzyme activity assays are commonly used.
Why is high-mannose glycan engineering important for antibodies?
High-mannose N-glycans affect antibody effector function and stability, and methods exist to increase Fc glycan high-mannose levels for therapeutic benefit.
What is O-mannosylation?
O-mannosylation is the addition of mannose to serine or threonine residues of proteins, important for muscle and neuronal function, and is a branch of mannose metabolism.
Conclusion
Mannose metabolic process (GO:0006013) is a fundamental biological pathway that connects sugar metabolism to glycoprotein biosynthesis, immune regulation, and cancer biology. Its roles in N-linked glycosylation, O-mannosylation, and metabolic interconversion make it a rich area for research and therapeutic targeting. With CRISPR-based tools and EDITGENE services, researchers can dissect the genetic and metabolic control of mannose metabolism to advance drug discovery and biotherapeutic development.
References
- 1. Gonzalez PS et al.. 2018. Mannose impairs tumour growth and enhances chemotherapy.. Nature 563(7733):719-723 PMID: 30464341
- 2. Zhang R et al.. 2022. D-mannose facilitates immunotherapy and radiotherapy of triple-negative breast cancer via degradation of PD-L1.. Proc Natl Acad Sci U S A 119(8) PMID: 35181605
- 3. Huang CJ et al.. 2015. A robust method for increasing Fc glycan high mannose level of recombinant antibodies.. Biotechnol Bioeng 112(6):1200-9 PMID: 25565276
- 4. Tsui CK et al.. 2024. CRISPR screens and lectin microarrays identify high mannose N-glycan regulators.. Nat Commun 15(1):9970 PMID: 39557836
- 5. Ichikawa M et al.. 2014. The metabolic origins of mannose in glycoproteins.. J Biol Chem 289(10):6751-6761 PMID: 24407290
- 6. Torretta S et al.. 2020. D-mannose suppresses macrophage IL-1β production.. Nat Commun 11(1):6343 PMID: 33311467
- 7. Sheikh MO et al.. 2017. Recent advancements in understanding mammalian O-mannosylation.. Glycobiology 27(9):806-819 PMID: 28810660
- 8. Villee CA. 1984. Birth defects and glycolysis.. N Engl J Med 310(4):254-5 PMID: 6690941
