GO:0120226 succinyl-CoA binding: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0120226 succinyl-CoA binding is a molecular function defined as binding to succinyl-CoA, an omega-carboxyacyl-CoA with succinoyl as the S-acyl component.
• Key proteins that bind succinyl-CoA include KAT2A, succinyl-CoA synthetase subunits (SUCLG1, SUCLG2, SUCLA2), and various acyltransferases and thiolases [1,2,3,5,6].
• Succinyl-CoA binding is central to the TCA cycle, lysine succinylation, heme biosynthesis, and ketone body metabolism [1,4,8].
• Dysregulation of succinyl-CoA-binding proteins is linked to cancer metastasis, antibiotic resistance, and metabolic disorders [3,4,8].
• Studying succinyl-CoA binding requires structural biology, enzymology, and CRISPR-based models to dissect its role in health and disease [2,5,6].
• EDITGENE provides CRISPR knockout, point mutation, knock-in, overexpression, and library screening services to investigate succinyl-CoA-binding proteins.
Description
Succinyl-CoA binding (GO:0120226) is a molecular function that enables proteins to interact with succinyl-CoA, a key metabolite at the intersection of the TCA cycle, amino acid metabolism, and heme synthesis. This binding event is essential for numerous enzymatic reactions and regulatory processes, including histone succinylation and metabolic signaling [1,4]. Understanding the proteins that bind succinyl-CoA is critical for deciphering metabolic reprogramming in cancer and infectious diseases [3,4]. Recent studies have identified KAT2A as a histone succinyltransferase that binds succinyl-CoA to modify chromatin and regulate gene expression. Additionally, succinyl-CoA synthetase (SCS) subunits bind succinyl-CoA as part of their catalytic cycle, influencing stress granule assembly and redox homeostasis. The structural basis of succinyl-CoA binding has been elucidated for several enzymes, revealing conserved binding pockets and conformational changes [2,6]. This article provides a comprehensive overview of GO:0120226, covering its definition, biological significance, key genes, and research methodologies, with a focus on CRISPR-based approaches for functional studies.
succinyl-CoA binding At A Glance
| GO ID | GO:0120226 |
|---|---|
| GO term | succinyl-CoA binding |
| Ontology | molecular_function |
| Synonym | succinyl-coenzyme A binding |
| Definition | Binding to succinyl-CoA, an omega-carboxyacyl-CoA having succinoyl as the S-acyl component. |
| Major function | Enables proteins to recognize and interact with succinyl-CoA for catalysis, regulation, or substrate channeling. |
| Related metabolites | Succinyl-CoA, succinate, CoA, acetyl-CoA |
| Representative proteins | KAT2A, SUCLG1, SUCLG2, SUCLA2, Tfu_0875 |
| Associated processes | TCA cycle, lysine succinylation, heme biosynthesis, ketone body metabolism |
What Is GO:0120226?
According to the Gene Ontology, succinyl-CoA binding (GO:0120226) is the molecular function of selectively interacting with succinyl-CoA, an omega-carboxyacyl-CoA having succinoyl as the S-acyl component. This binding can be non-covalent and is often a prerequisite for enzymatic catalysis or regulatory modulation. Proteins that bind succinyl-CoA typically possess a conserved binding pocket that accommodates the succinyl moiety and the CoA nucleotide, as seen in succinyl-CoA synthetase and related acyltransferases [2,6].
Why Is succinyl-CoA binding Important in Cell Biology?
Succinyl-CoA binding is fundamental to cellular metabolism because succinyl-CoA is a pivotal metabolite in the TCA cycle and a substrate for various biosynthetic pathways. Proteins that bind succinyl-CoA regulate energy production, post-translational modifications, and metabolic signaling [1,4]. Dysregulation of these proteins has been implicated in cancer progression, where succinylation affects stress granule assembly and redox balance. Moreover, succinyl-CoA binding is essential for antibiotic resistance mechanisms in bacteria, highlighting its broad biological relevance. Thus, understanding this molecular function offers insights into metabolic diseases and potential therapeutic targets.
• Succinyl-CoA binding is required for the catalytic activity of succinyl-CoA synthetase in the TCA cycle [2,6].
• KAT2A binds succinyl-CoA to succinylate histone H3, linking metabolism to gene expression.
• Succinyl-CoA synthetase subunit beta (SUCLG2) promotes stress granule assembly and cancer metastasis.
• Bacterial proteins binding succinyl-CoA mediate antibiotic resistance through metabolic resource allocation.
• Succinyl-CoA binding is involved in heme biosynthesis and regulation of pyroptosis.
• Mutations in succinyl-CoA-binding proteins can lead to metabolic disorders and neurodegeneration.
• Succinyl-CoA binding is a target for engineering enzymes with altered substrate specificity.
• Studying succinyl-CoA binding aids in understanding lysine succinylation and its role in epigenetics.
• It is critical for ketone body metabolism and energy homeostasis.
• CRISPR-based models enable precise dissection of succinyl-CoA binding in disease contexts.
Molecular Mechanism of succinyl-CoA binding
Substrate Recognition and Binding Pocket
In simple terms: Proteins that bind succinyl-CoA have a pocket that fits the molecule like a lock and key.
The binding of succinyl-CoA typically occurs in a conserved pocket that recognizes the succinyl moiety and the CoA nucleotide. Structural studies of succinyl-CoA synthetase reveal that the binding site undergoes conformational changes upon succinyl-CoA binding, facilitating catalysis [2,6]. For example, the binding of succinate to succinyl-CoA synthetase provides insights into substrate specificity and the role of key residues. In KAT2A, the binding pocket accommodates succinyl-CoA to transfer the succinyl group to histone H3. Engineering of the thiolase Tfu_0875 has shown that rational modification of the binding pocket can enhance succinyl-CoA specificity.
Catalytic Mechanism and Cofactors
In simple terms: Once bound, succinyl-CoA is often converted into other molecules, with help from cofactors.
Succinyl-CoA binding is often coupled to catalysis. In succinyl-CoA synthetase, the binding of succinyl-CoA leads to phosphorylation of a histidine residue and subsequent transfer of the succinyl group to a nucleotide, producing succinate and CoA [2,7]. This reaction requires magnesium ions and is essential for the TCA cycle. In KAT2A, succinyl-CoA serves as a cofactor for histone succinylation, a post-translational modification that regulates chromatin structure. The binding of succinyl-CoA to enzymes can also be regulated by metabolites such as tartryl-CoA, which inhibits succinyl-CoA synthetase.
Regulation by Metabolites and Post-translational Modifications
In simple terms: The ability of proteins to bind succinyl-CoA can be turned on or off by other molecules.
Succinyl-CoA binding can be modulated by the availability of succinyl-CoA itself, which is influenced by metabolic flux. For instance, tartryl-CoA acts as an inhibitor of succinyl-CoA synthetase by competing with succinyl-CoA binding. Additionally, post-translational modifications of the binding proteins, such as phosphorylation, can affect their affinity for succinyl-CoA. In cancer cells, the expression levels of succinyl-CoA synthetase subunits are altered, impacting succinyl-CoA binding and downstream signaling. The nuclear receptor Nur77 disrupts heme homeostasis, which may indirectly affect succinyl-CoA metabolism and binding.
Role in Lysine Succinylation and Epigenetics
In simple terms: Succinyl-CoA binding by enzymes like KAT2A can add succinyl marks to histones, affecting gene activity.
KAT2A, a histone acetyltransferase, also functions as a succinyltransferase by binding succinyl-CoA and transferring the succinyl group to histone H3 at lysine 79. This succinylation is coupled to the α-ketoglutarate dehydrogenase complex, linking TCA cycle activity to chromatin modification. This epigenetic mark can influence gene expression and has implications for cancer and stem cell biology. The binding of succinyl-CoA to KAT2A is therefore a key mechanism connecting metabolism to gene regulation.
Structural Insights and Engineering
In simple terms: Scientists can change how proteins bind succinyl-CoA by altering their structure.
Structural studies have revealed the atomic details of succinyl-CoA binding in several enzymes. The crystal structure of succinyl-CoA synthetase with bound succinate and CoA analogs has elucidated the nucleotide-binding site and conformational changes [6,7]. Rational engineering of the thiolase Tfu_0875 has demonstrated that modifying the binding pocket can increase activity and specificity for succinyl-CoA. These insights are valuable for designing inhibitors or engineering enzymes for biotechnological applications.
Key Genes Involved in GO:0120226 succinyl-CoA binding
The following genes encode proteins that bind succinyl-CoA or are directly involved in succinyl-CoA-dependent processes.
| Gene | Major Role | Research Relevance |
|---|---|---|
| KAT2A | Histone succinyltransferase; binds succinyl-CoA to succinylate H3K79 | Links metabolism to epigenetics; cancer |
| SUCLG1 | Succinyl-CoA synthetase alpha subunit; binds succinyl-CoA | TCA cycle; metabolic disorders [2,6] |
| SUCLG2 | Succinyl-CoA synthetase beta subunit; binds succinyl-CoA | Stress granule assembly; cancer metastasis |
| SUCLA2 | Succinyl-CoA synthetase beta subunit (ADP-forming); binds succinyl-CoA | Mitochondrial DNA depletion syndromes |
| Tfu_0875 | Thiolase engineered for enhanced succinyl-CoA specificity | Biocatalysis; synthetic biology |
| Nur77 (NR4A1) | Nuclear receptor; disrupts heme homeostasis, may affect succinyl-CoA metabolism | Pyroptosis; inflammation |
| DLST | Dihydrolipoamide succinyltransferase; component of α-KGDH complex | TCA cycle; histone succinylation |
| OGDH | α-ketoglutarate dehydrogenase; produces succinyl-CoA | TCA cycle; cancer metabolism |
| ACAT1 | Acetyl-CoA acetyltransferase; can bind succinyl-CoA | Ketone body metabolism |
| HMGCS2 | HMG-CoA synthase; uses succinyl-CoA? No, uses acetyl-CoA | Ketogenesis |
| ALAS1 | Delta-aminolevulinate synthase; uses succinyl-CoA? No, uses glycine and succinyl-CoA | Heme biosynthesis |
| ALAS2 | Delta-aminolevulinate synthase 2; uses succinyl-CoA | Heme biosynthesis; erythropoiesis |
| SCS | Succinyl-CoA synthetase complex | TCA cycle; cancer [2,3,6] |
| KAT2B | Histone acetyltransferase; may bind succinyl-CoA | Epigenetics |
| SIRT5 | Desuccinylase; removes succinyl groups | Mitochondrial metabolism |
| GSDMC | Gasdermin C; cleaved by granzyme B in pyroptosis | Cell death; inflammation |
| GZMB | Granzyme B; cleaves GSDMC | Immune response; pyroptosis |
How Is succinyl-CoA binding Regulated?
Succinyl-CoA binding is regulated at multiple levels. The availability of succinyl-CoA, which is influenced by TCA cycle flux and amino acid catabolism, directly affects binding. Enzymes such as succinyl-CoA synthetase are inhibited by metabolites like tartryl-CoA. Post-translational modifications, including phosphorylation and succinylation, can modulate the affinity of proteins for succinyl-CoA. In cancer, the expression of SUCLG2 is upregulated, leading to increased succinyl-CoA binding and stress granule assembly. Additionally, the nuclear receptor Nur77 can disrupt heme homeostasis, potentially altering succinyl-CoA levels and binding. These regulatory mechanisms ensure that succinyl-CoA binding is tightly coupled to cellular metabolic status.
succinyl-CoA binding and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| SUCLG2 | Cancer metastasis | Knockout in cancer cell lines; mouse xenograft |
| SUCLA2 | Mitochondrial DNA depletion syndrome | Patient-derived fibroblasts; knock-in of patient mutations |
| KAT2A | Cancer, epigenetic regulation | Histone succinylation assays; knockout mice |
| Nur77 | Inflammation, pyroptosis | Knockout macrophages; overexpression models |
| Tfu_0875 | Antibiotic resistance (bacterial) | Bacterial knockout; engineered variants |
Succinyl-CoA binding in cancer
Succinyl-CoA synthetase subunit beta (SUCLG2) promotes stress granule assembly to regulate redox and drive cancer metastasis. KAT2A-mediated histone succinylation links metabolic state to gene expression, contributing to tumorigenesis. Dysregulated succinyl-CoA binding can alter metabolic pathways that support cancer cell growth and survival.
Succinyl-CoA binding in metabolic disorders
Mutations in succinyl-CoA synthetase subunits (SUCLG1, SUCLA2) cause mitochondrial DNA depletion syndromes and encephalomyopathies. Impaired succinyl-CoA binding affects TCA cycle function and energy production [2,6].
Succinyl-CoA binding in infectious diseases
Metabolism-dependent succinylation governs resource allocation for antibiotic resistance in bacteria. Proteins that bind succinyl-CoA may be targets for novel antimicrobials.
Succinyl-CoA binding in inflammation and cell death
Disruption of heme homeostasis by Nur77 induces pyroptosis through granzyme B-dependent GSDMC cleavage, a process that may involve succinyl-CoA metabolism. Succinyl-CoA binding proteins could modulate inflammatory responses.
From succinyl-CoA binding-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of SUCLG2 affect stress granule assembly? | CRISPR knockout in cancer cell lines |
| How does a point mutation in SUCLG1 affect succinyl-CoA binding? | Point mutation knock-in in HEK293 cells |
| Can KAT2A succinyltransferase activity be monitored? | Tagged knock-in of KAT2A with FLAG epitope |
| Does overexpression of SUCLA2 rescue mitochondrial function? | Overexpression in patient fibroblasts |
| What is the role of succinyl-CoA binding in antibiotic resistance? | CRISPR interference knockdown in bacteria |
| Can engineered Tfu_0875 improve succinyl-CoA specificity? | Site-directed mutagenesis and enzyme assays |
How to Study the succinyl-CoA binding Process
| Method | What It Measures | Typical Application |
|---|---|---|
| X-ray crystallography | 3D structure of protein-succinyl-CoA complex | Binding pocket mapping [2,6] |
| Isothermal titration calorimetry | Binding affinity (Kd) | Quantify succinyl-CoA binding |
| Enzyme kinetics | Catalytic activity | Succinyl-CoA synthetase assays [2,7] |
| CRISPR knockout | Loss-of-function phenotype | Gene function in metabolism |
| CRISPR knock-in | Point mutations or tags | Disease modeling |
| Succinylome profiling | Global succinylation sites | Epigenetics and metabolism |
| RNA-seq | Transcriptional changes | Pathway analysis |
| Proximity ligation assay | Protein-protein interactions | Complex assembly |
Structural biology
X-ray crystallography and cryo-EM can determine the structure of proteins bound to succinyl-CoA, revealing binding pocket residues and conformational changes [2,6]. These methods are essential for understanding the molecular basis of succinyl-CoA binding.
Enzymatic assays
Kinetic assays using succinyl-CoA as a substrate measure binding affinity and catalytic activity. For example, succinyl-CoA synthetase activity can be monitored by NADH consumption or CoA release [2,7].
CRISPR-based functional genomics
CRISPR knockout, point mutation, and knock-in models allow precise dissection of succinyl-CoA-binding proteins in cells. These models can be used to study metabolic reprogramming, stress granule assembly, and drug resistance [3,4].
Proteomics and succinylome analysis
Mass spectrometry-based proteomics can identify proteins that bind succinyl-CoA and map succinylation sites. This approach has revealed widespread lysine succinylation in mitochondria and chromatin.
How CRISPR Can Be Used to Study GO:0120226 succinyl-CoA binding
Knockout
CRISPR knockout of genes encoding succinyl-CoA-binding proteins (e.g., SUCLG2, KAT2A) can reveal their essential roles in metabolism and disease. For instance, SUCLG2 knockout reduces stress granule assembly and cancer metastasis.
Point Mutation
Introducing point mutations in the succinyl-CoA binding pocket (e.g., in SUCLG1 or Tfu_0875) can dissect the contribution of specific residues to binding affinity and catalysis [5,6].
Knock-in
Knock-in of tagged versions (e.g., FLAG-KAT2A) allows purification and interaction studies. Knock-in of patient mutations in SUCLA2 can model mitochondrial DNA depletion syndromes.
Overexpression
Overexpression of succinyl-CoA-binding proteins (e.g., SUCLG2) can drive phenotypes such as stress granule formation and redox regulation, providing gain-of-function insights.
How EDITGENE Supports succinyl-CoA binding Research
Researchers studying succinyl-CoA binding-related genes often need to determine whether a candidate gene is causally involved in metabolic regulation, disease progression, or drug resistance. EDITGENE provides a comprehensive suite of CRISPR services to enable precise genetic manipulation and functional interrogation of succinyl-CoA-binding proteins.
Contact EDITGENE today to design your custom CRISPR model for succinyl-CoA binding research.
Frequently Asked Questions About succinyl-CoA binding
What is succinyl-CoA binding?
Succinyl-CoA binding is a molecular function (GO:0120226) where a protein interacts with succinyl-CoA, a key metabolite in the TCA cycle and other pathways.
What genes are involved in succinyl-CoA binding?
Key genes include KAT2A, SUCLG1, SUCLG2, SUCLA2, and Tfu_0875, which encode proteins that bind succinyl-CoA [1,2,3,5].
How does succinyl-CoA binding relate to cancer?
SUCLG2 promotes stress granule assembly and cancer metastasis, while KAT2A-mediated histone succinylation links metabolism to gene expression [1,3].
What diseases are associated with succinyl-CoA binding?
Mutations in succinyl-CoA synthetase subunits cause mitochondrial DNA depletion syndromes; dysregulation is linked to cancer and antibiotic resistance [2,3,4].
What methods are used to study succinyl-CoA binding?
X-ray crystallography, enzyme kinetics, CRISPR knockout/knock-in, and succinylome profiling are commonly used [1,2,6].
Can CRISPR be used to study succinyl-CoA binding?
Yes, CRISPR knockout, point mutation, knock-in, and overexpression models enable precise functional studies of succinyl-CoA-binding proteins [3,5].
What is the role of KAT2A in succinyl-CoA binding?
KAT2A binds succinyl-CoA to succinylate histone H3, linking TCA cycle activity to chromatin regulation.
How is succinyl-CoA binding regulated?
It is regulated by succinyl-CoA availability, metabolites like tartryl-CoA, and post-translational modifications [2,3].
What is the structural basis of succinyl-CoA binding?
Structural studies reveal a conserved binding pocket that recognizes the succinyl moiety and CoA, with conformational changes upon binding [2,6].
Why is succinyl-CoA binding important for antibiotic resistance?
Metabolism-dependent succinylation governs resource allocation for antibiotic resistance in bacteria, involving succinyl-CoA-binding proteins.
Conclusion
Succinyl-CoA binding (GO:0120226) is a critical molecular function that connects cellular metabolism to diverse biological processes, including the TCA cycle, epigenetic regulation, and disease progression. Key proteins such as KAT2A and succinyl-CoA synthetase subunits mediate these effects through their ability to bind succinyl-CoA [1,2,3]. Understanding the mechanisms and regulation of succinyl-CoA binding offers opportunities for therapeutic intervention in cancer, metabolic disorders, and infectious diseases. EDITGENE's CRISPR services provide powerful tools to investigate these proteins and accelerate discoveries in the field.
References
- 1. Wang Y et al.. 2017. KAT2A coupled with the α-KGDH complex acts as a histone H3 succinyltransferase.. Nature 552(7684):273-277 PMID: 29211711
- 2. Huang J et al.. 2020. Tartryl-CoA inhibits succinyl-CoA synthetase.. Acta Crystallogr F Struct Biol Commun 76(Pt 7):302-308 PMID: 32627745
- 3. Boese AC et al.. 2023. Succinyl-CoA ligase ADP-forming subunit beta promotes stress granule assembly to regulate redox and drive cancer metastasis.. Proc Natl Acad Sci U S A 120(23):e2217332120 PMID: 37253003
- 4. Wu JH et al.. 2025. Metabolism-dependent succinylation governs resource allocation for antibiotic resistance.. Sci Adv 11(34):eadu2856 PMID: 40845110
- 5. Liu L et al.. 2024. Enhancing the activity and succinyl-CoA specificity of 3-ketoacyl-CoA thiolase Tfu_0875 through rational binding pocket engineering.. Synth Syst Biotechnol 9(3):558-568 PMID: 38694995
- 6. Huang J et al.. 2016. Structural basis for the binding of succinate to succinyl-CoA synthetase.. Acta Crystallogr D Struct Biol 72(Pt 8):912-21 PMID: 27487822
- 7. Joyce MA et al.. 1999. Probing the nucleotide-binding site of Escherichia coli succinyl-CoA synthetase.. Biochemistry 38(22):7273-83 PMID: 10353839
- 8. Wu LZ et al.. 2025. Disruption of heme homeostasis by nuclear receptor Nur77 induces pyroptosis through granzyme B-dependent GSDMC cleavage.. Signal Transduct Target Ther 10(1):413 PMID: 41407678
