GO:1902912 pyruvate kinase complex: Components, Assembly and Research Methods, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:1902912 (pyruvate kinase complex) is a cellular component defined as a protein complex capable of pyruvate kinase activity, catalyzing the transfer of a phosphate group from phosphoenolpyruvate to ADP, yielding pyruvate and ATP.
• The complex is best known through its PKM2 isoform, which forms tetramers and dimers and is central to the Warburg effect in cancer and activated immune cells.
• PKM2 activity and complex assembly are regulated by post-translational modifications including succinylation, citrullination, and lactylation-driven deubiquitination.
• The pyruvate kinase complex participates in diverse physiological and pathological processes, including macrophage IL-1beta production, colitis, heart failure, traumatic brain injury, and pain modulation.
• Divalent cations and allosteric regulators modulate the complex equilibrium of human liver pyruvate kinase, illustrating complex regulation beyond simple Michaelis-Menten kinetics.
• Studying GO:1902912 requires integrated approaches such as knockout, point-mutation, knock-in, and overexpression cell models combined with proteomics, metabolomics, and functional assays.
Description
The pyruvate kinase complex (GO:1902912) is a cellular component defined by its capacity to catalyze the final step of glycolysis, the transfer of a phosphate group from phosphoenolpyruvate to ADP to produce pyruvate and ATP. This complex is not a single static entity; it comprises multiple isoforms and oligomeric states, most notably the PKM2 isoform, which exists in equilibrium between tetrameric and dimeric forms with distinct kinetic and non-glycolytic functions. Because glycolysis is central to energy production and biosynthetic metabolism, the pyruvate kinase complex sits at a critical metabolic node that influences cell proliferation, immune activation, and stress responses. Beyond its canonical role in glycolysis, the pyruvate kinase complex has emerged as a signaling hub. PKM2 within the complex can interact with hypoxia-inducible factor 1-alpha (HIF-1alpha) and modulate interleukin-1beta (IL-1beta) induction in lipopolysaccharide-activated macrophages, linking metabolism to inflammation. Post-translational modifications such as succinylation, citrullination, and ubiquitination directly affect the complex's activity and stability, with consequences for colitis, cancer cell proliferation, and neuronal survival after traumatic brain injury. These findings have positioned the pyruvate kinase complex as a therapeutic target and a biomarker across oncology, immunology, and neuroscience. For researchers, GO:1902912 provides a precise ontological handle for annotating proteins and experimental models that reconstitute pyruvate kinase activity. Understanding its composition, assembly, and regulation is essential for designing CRISPR-based knockout, knock-in, and point-mutation studies that dissect isoform-specific and modification-specific functions in health and disease.
pyruvate kinase complex At A Glance
| GO ID | GO:1902912 |
|---|---|
| GO term | pyruvate kinase complex |
| Ontology | cellular_component |
| Synonym | none |
| Major function | Catalysis of the transfer of a phosphate group from phosphoenolpyruvate to ADP, producing pyruvate and ATP |
| Primary isoforms | PKM1 and PKM2 (PKM2 is the most studied in the context of this complex) |
| Oligomeric states | Tetrameric and dimeric forms, with distinct kinetic and non-glycolytic roles |
| Key regulators | Post-translational modifications (succinylation, citrullination, ubiquitination), divalent cations, allosteric effectors |
| Associated processes | Glycolysis, Warburg effect, inflammatory cytokine production, mitophagy, pain modulation |
What Is GO:1902912?
According to the Gene Ontology, GO:1902912 (pyruvate kinase complex) is a protein complex which is capable of pyruvate kinase activity. In other words, it is an assembly of proteins, typically including pyruvate kinase isoforms such as PKM, that together catalyze the transfer of a phosphate group from phosphoenolpyruvate to ADP, forming pyruvate and ATP. The term describes the structural entity (the complex) rather than the isolated enzymatic activity, and it encompasses different oligomeric states and isoform compositions that retain the capacity for this catalytic function.
Why Is pyruvate kinase complex Important in Cell Biology?
The pyruvate kinase complex is important because it occupies a pivotal position in cellular metabolism and has been directly implicated in major human diseases. Its activity determines the rate of glycolytic flux and ATP production, and its non-glycolytic functions influence gene expression, inflammation, and cell survival. Dysregulation of the complex contributes to cancer metabolism, inflammatory bowel disease, heart failure, traumatic brain injury, and pain sensitization, making it a high-value target for mechanistic studies and therapeutic development.
• Central to glycolysis and ATP generation, affecting cellular energy homeostasis.
• Drives the Warburg effect in cancer cells and activated macrophages.
• Regulates IL-1beta production and inflammation in macrophages.
• Protects against DSS-induced colitis in mouse models.
• Supports neuronal survival after traumatic brain injury via mitophagy regulation.
• Modulates cancer cell proliferation through citrullination-dependent regulation.
• Protects the heart from pressure overload-induced heart failure.
• Involved in pain modulation through metabolic pathways.
• Exhibits complex allosteric and divalent cation regulation.
• Forms a stable complex with prolyl hydroxylase 3, expanding its functional repertoire.
What Happens During pyruvate kinase complex?
Glycolytic catalysis
In simple terms: The complex performs the last step of glycolysis, turning phosphoenolpyruvate into pyruvate while making ATP.
The pyruvate kinase complex catalyzes the transfer of a phosphate group from phosphoenolpyruvate to ADP, yielding pyruvate and ATP. This reaction is essentially irreversible under physiological conditions and represents a key regulatory point in glycolysis. The catalytic efficiency of the complex depends on its oligomeric state and isoform composition, with PKM2 tetramers exhibiting high affinity for phosphoenolpyruvate and dimers showing lower affinity and altered regulation.
Oligomeric equilibrium and allosteric regulation
In simple terms: The complex can switch between different shapes (tetramers and dimers), and this switch changes how well it works.
Human liver pyruvate kinase exemplifies the combined effects of complex-equilibrium and allosteric regulation, where divalent cations and allosteric effectors shift the equilibrium between active and inactive oligomeric states. This dynamic assembly allows the complex to respond to metabolic demands and signaling cues, fine-tuning glycolytic flux and non-glycolytic functions.
Post-translational modification and functional diversification
In simple terms: Chemical tags added to the complex can change what it does beyond glycolysis.
Succinylation by SIRT5 desuccinylates and activates PKM2 to block macrophage IL-1beta production and prevent DSS-induced colitis in mice. Citrullination of PKM2 by PADI1 and PADI3 regulates glycolysis and cancer cell proliferation. Lactylation-stimulated upregulation of PSMD14 alleviates neuron PANoptosis through deubiquitinating PKM2 to activate PINK1-mediated mitophagy after traumatic brain injury. These modifications demonstrate that the pyruvate kinase complex is a dynamic signaling node.
Interaction with other protein complexes
In simple terms: The complex can partner with other proteins to perform additional jobs.
PKM2 forms a complex with prolyl hydroxylase 3 (PHD3), and this interaction has been purified and characterized, suggesting that the pyruvate kinase complex can integrate with oxygen-sensing pathways. Such interactions expand the functional repertoire of the complex beyond glycolysis and highlight its role in cellular adaptation.
Key Genes Involved in GO:1902912 pyruvate kinase complex
The following genes and proteins are experimentally implicated in the composition, regulation, or function of the pyruvate kinase complex (GO:1902912).
| Gene | Major Role | Research Relevance |
|---|---|---|
| PKM | Encodes pyruvate kinase M1/M2 isoforms; core catalytic component of the complex | Central to glycolysis, Warburg effect, and non-glycolytic functions |
| SIRT5 | Desuccinylates and activates PKM2 | Regulates macrophage IL-1beta and colitis |
| PADI1 | Citrullinates PKM2 | Regulates glycolysis and cancer cell proliferation |
| PADI3 | Citrullinates PKM2 | Regulates glycolysis and cancer cell proliferation |
| PSMD14 | Deubiquitinates PKM2 | Alleviates neuron PANoptosis after traumatic brain injury |
| PINK1 | Mediates mitophagy downstream of PKM2 | Neuroprotection after traumatic brain injury |
| HIF1A | Interacts with PKM2 to regulate Hif-1alpha activity | Links metabolism to inflammation |
| IL1B | Cytokine induced by PKM2-dependent pathways | Inflammatory readout in macrophages |
| RAC1 | Phosphorylated by PKM2 | Protects heart from pressure overload-induced heart failure |
| PHD3 | Forms a complex with PKM2 | Oxygen-sensing and metabolic regulation |
| ADP | Substrate of the pyruvate kinase reaction | Core catalytic mechanism |
| PEP | Substrate of the pyruvate kinase reaction | Core catalytic mechanism |
| ATP | Product of the pyruvate kinase reaction | Energy homeostasis |
| Pyruvate | Product of the pyruvate kinase reaction | Metabolic flux and biosynthesis |
| Divalent cations | Modulate complex equilibrium and allosteric regulation | Enzyme kinetics and regulation |
| Lactate | Drives lactylation and PSMD14 upregulation | Neuronal survival after TBI |
How Is pyruvate kinase complex Regulated?
The pyruvate kinase complex is regulated at multiple levels. Allosteric regulation by divalent cations and metabolic intermediates shifts the equilibrium between active and inactive oligomeric states, as demonstrated for human liver pyruvate kinase. Post-translational modifications provide another layer: SIRT5-mediated desuccinylation activates PKM2 to suppress IL-1beta production, while citrullination by PADI1 and PADI3 modulates glycolysis and cancer cell proliferation. Ubiquitination and deubiquitination, exemplified by PSMD14, control PKM2 stability and downstream mitophagy. These regulatory mechanisms allow the complex to adapt to inflammatory, metabolic, and stress signals.
pyruvate kinase complex and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| PKM | Cancer, inflammation, heart failure, TBI | PKM knockout and knock-in cell lines; mouse models |
| SIRT5 | Colitis | SIRT5 knockout mice and macrophages |
| PADI1/PADI3 | Cancer proliferation | PADI1/3 knockdown or knockout cancer cells |
| PSMD14 | Traumatic brain injury | PSMD14 knockout neurons and TBI mouse models |
| RAC1 | Heart failure | RAC1 phospho-mutant knock-in mice |
Cancer metabolism and the Warburg effect
The pyruvate kinase complex, particularly the PKM2 isoform, is a critical determinant of the Warburg effect in cancer cells and activated macrophages. Citrullination of PKM2 by PADI1 and PADI3 regulates glycolysis and cancer cell proliferation, suggesting that targeting this modification could alter tumor growth. The complex's role in HIF-1alpha activity and IL-1beta induction further links it to the inflammatory tumor microenvironment.
Inflammatory bowel disease and colitis
SIRT5 desuccinylates and activates PKM2 to block macrophage IL-1beta production and prevent DSS-induced colitis in mice. This positions the pyruvate kinase complex as a protective factor in intestinal inflammation and a potential therapeutic target for inflammatory bowel disease.
Heart failure and cardiovascular stress
PKM2 protects the heart from pressure overload-induced heart failure by phosphorylating RAC1. This non-glycolytic function of the pyruvate kinase complex highlights its importance in cardiac stress responses and suggests that modulating its activity could be cardioprotective.
Traumatic brain injury and neurodegeneration
Histone lactylation stimulated upregulation of PSMD14 alleviates neuron PANoptosis through deubiquitinating PKM2 to activate PINK1-mediated mitophagy after traumatic brain injury. This pathway places the pyruvate kinase complex at the center of neuroprotective mitophagy and cell death regulation after brain trauma.
From pyruvate kinase complex-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of PKM2 affect glycolytic flux and IL-1beta production? | PKM2 knockout macrophages |
| Does citrullination of PKM2 regulate cancer cell proliferation? | PADI1/PADI3 knockout cancer cell lines |
| Does PSMD14-mediated deubiquitination of PKM2 protect neurons after TBI? | PSMD14 knockout neurons and TBI mouse models |
| Does PKM2 phosphorylation of RAC1 protect against heart failure? | RAC1 phospho-mutant knock-in mice |
| How do divalent cations regulate pyruvate kinase complex equilibrium? | Recombinant human liver pyruvate kinase with point mutations |
| Does PKM2 interact with PHD3 to modulate oxygen sensing? | PHD3 knockout or tagged knock-in cells |
How to Study the pyruvate kinase complex Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Affinity purification-mass spectrometry | Protein composition and interactions | Identifying PKM2-PHD3 complex |
| Seahorse extracellular flux analysis | Glycolytic rate and ATP production | Assessing Warburg effect |
| Isotope tracing | Metabolic flux through pyruvate kinase | Quantifying glycolytic intermediates |
| Immunoblotting | Protein levels and post-translational modifications | Detecting PKM2 succinylation, citrullination, ubiquitination |
| Immunofluorescence | Subcellular localization | Tracking PKM2 during mitophagy |
| Enzyme kinetics assays | Catalytic activity and allosteric regulation | Studying divalent cation effects |
| CRISPR screening | Gene requirements for complex function | Identifying regulators of PKM2 |
Proteomic and interactomic analysis
Affinity purification coupled with mass spectrometry can identify components of the pyruvate kinase complex, including PKM2 and its interacting partners such as PHD3. This approach helps define the composition and stoichiometry of the complex under different conditions.
Metabolic flux analysis
Seahorse extracellular flux analysis and isotope tracing measure glycolytic rate and ATP production, providing functional readouts of pyruvate kinase complex activity. These methods are essential for linking complex composition to metabolic output.
Post-translational modification profiling
Immunoblotting with modification-specific antibodies and mass spectrometry-based proteomics detect succinylation, citrullination, and ubiquitination of PKM2, revealing how these modifications regulate complex function.
Imaging and subcellular localization
Fluorescence microscopy and subcellular fractionation determine where the pyruvate kinase complex localizes and how it redistributes under stress, such as during mitophagy after traumatic brain injury.
How CRISPR Can Be Used to Study GO:1902912 pyruvate kinase complex
Knockout
CRISPR knockout of PKM, SIRT5, PADI1, PADI3, or PSMD14 can abolish specific functions of the pyruvate kinase complex, such as IL-1beta production or cancer cell proliferation, providing causal evidence for gene involvement.
Point Mutation
Point mutations in PKM can mimic or prevent post-translational modifications, such as succinylation or citrullination sites, allowing precise dissection of how these modifications regulate complex activity and downstream phenotypes.
Knock-in
Knock-in of tagged PKM2 (e.g., FLAG or HA) enables affinity purification and interactome studies of the pyruvate kinase complex under endogenous conditions.
Overexpression
Overexpression of wild-type or mutant PKM2 in cancer or immune cells can enhance glycolytic flux and modulate inflammatory cytokine production, helping to establish sufficiency in disease models.
How EDITGENE Supports pyruvate kinase complex Research
Researchers studying pyruvate kinase complex-related genes often need to determine whether a candidate gene is causally involved in complex assembly, catalysis, or downstream disease phenotypes. EDITGENE provides a comprehensive suite of CRISPR-based services to accelerate this discovery process.
Contact EDITGENE today to design your custom CRISPR model for pyruvate kinase complex research.
Frequently Asked Questions About pyruvate kinase complex
What is GO:1902912?
GO:1902912 is the Gene Ontology cellular component term for pyruvate kinase complex, defined as a protein complex capable of pyruvate kinase activity.
What genes are involved in the pyruvate kinase complex?
Key genes include PKM, SIRT5, PADI1, PADI3, PSMD14, PINK1, HIF1A, IL1B, RAC1, and PHD3, among others.
What is the function of the pyruvate kinase complex?
It catalyzes the final step of glycolysis, converting phosphoenolpyruvate and ADP to pyruvate and ATP, and also has non-glycolytic signaling roles.
How is the pyruvate kinase complex regulated?
It is regulated by allosteric effectors, divalent cations, and post-translational modifications such as succinylation, citrullination, and ubiquitination.
What diseases are associated with the pyruvate kinase complex?
It is linked to cancer, inflammatory bowel disease, heart failure, traumatic brain injury, and pain.
What is the role of PKM2 in the pyruvate kinase complex?
PKM2 is a key isoform that forms the complex, regulates the Warburg effect, and modulates inflammation and mitophagy.
How can I study the pyruvate kinase complex using CRISPR?
CRISPR knockout, point mutation, knock-in, and overexpression models can be used to dissect gene function and regulation.
What methods are used to measure pyruvate kinase complex activity?
Enzyme kinetics, Seahorse flux analysis, isotope tracing, and immunoblotting are commonly used.
Is the pyruvate kinase complex a therapeutic target?
Yes, its roles in cancer, inflammation, and heart failure make it a promising target for drug development.
What is the difference between PKM1 and PKM2 in the complex?
PKM1 and PKM2 are splice isoforms with different kinetic properties and regulatory modifications; PKM2 is more extensively studied in disease contexts.
Conclusion
The pyruvate kinase complex (GO:1902912) is a dynamic cellular component that catalyzes a key step in glycolysis and serves as a signaling hub in health and disease. Its composition, oligomeric state, and post-translational modifications are tightly regulated and have been implicated in cancer, inflammation, heart failure, and neurodegeneration. Continued research using advanced CRISPR models and multi-omics approaches will further clarify its mechanistic roles and therapeutic potential.
References
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- 2. Wang F et al.. 2017. SIRT5 Desuccinylates and Activates Pyruvate Kinase M2 to Block Macrophage IL-1β Production and to Prevent DSS-Induced Colitis in Mice.. Cell Rep 19(11):2331-2344 PMID: 28614718
- 3. Xu L et al.. 2025. Histone lactylation stimulated upregulation of PSMD14 alleviates neuron PANoptosis through deubiquitinating PKM2 to activate PINK1-mediated mitophagy after traumatic brain injury.. Autophagy 21(7):1473-1491 PMID: 40000916
- 4. Coassolo S et al.. 2021. Citrullination of pyruvate kinase M2 by PADI1 and PADI3 regulates glycolysis and cancer cell proliferation.. Nat Commun 12(1):1718 PMID: 33741961
- 5. Martin TA et al.. 2023. Divalent cations in human liver pyruvate kinase exemplify the combined effects of complex-equilibrium and allosteric regulation.. Sci Rep 13(1):10557 PMID: 37386072
- 6. Kumar S et al.. 2020. Purification and Characterization of Prolyl Hydroxylase 3/Pyruvate Kinase Isoform 2 Protein Complex.. Mol Biotechnol 62(2):111-118 PMID: 31760602
- 7. Ni L et al.. 2022. Pyruvate Kinase M2 Protects Heart from Pressure Overload-Induced Heart Failure by Phosphorylating RAC1.. J Am Heart Assoc 11(11):e024854 PMID: 35656980
- 8. Kalmegh V et al.. 2026. Pyruvate kinase M2 - linked metabolic pathways in pain modulation.. Drug Discov Today 31(1):104557 PMID: 41290088
