GO:0005310 dicarboxylic acid transmembrane transporter activity: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0005310 describes the molecular function of moving dicarboxylic acids, organic acids with two COOH groups, across a membrane.
• The term covers mitochondrial carriers such as the dicarboxylate carrier and plasma-membrane sodium-coupled transporters for Krebs cycle intermediates.
• Transport can occur by antiport, symport, or uniport, and the mitochondrial ADP/ATP carrier provides the structural paradigm for the carrier superfamily.
• Substrates include succinate, fumarate, malate, oxalate, and itaconate, linking the function to immunometabolism and inflammation [2,7].
• Dysregulation is associated with cystic fibrosis airway clearance defects and oxalate-related stone disease [4,7].
• CRISPR knockout, point-mutation, knock-in, and overexpression models are essential to test causality of candidate transporters.
Description
GO:0005310, dicarboxylic acid transmembrane transporter activity, is a molecular function that enables the transfer of dicarboxylic acids from one side of a membrane to the other. Dicarboxylic acids are organic acids carrying two carboxyl groups, and they include central Krebs cycle intermediates such as succinate, fumarate, and malate as well as oxalate and itaconate [2,3,7]. Because these metabolites participate in energy metabolism, immune signaling, and epithelial ion transport, the proteins that move them across membranes are of broad physiological and pathological interest [2,4,7]. The function is not restricted to a single protein family; it is carried out by mitochondrial carriers, sodium-coupled symporters, and antiporters that share the ability to recognize a two-carboxyl substrate [1,3]. Understanding GO:0005310 therefore requires integrating structural biology, transport kinetics, and metabolic phenotyping [1,3]. Researchers studying this term ask how substrate specificity is achieved, how transport is energized, and how loss or gain of transport activity alters cellular metabolism and disease phenotypes [1,3,7]. The sections below summarize the definition, mechanism, key genes, disease links, and experimental strategies used to interrogate this function.
dicarboxylic acid transmembrane transporter activity At A Glance
| GO ID | GO:0005310 |
|---|---|
| GO term | dicarboxylic acid transmembrane transporter activity |
| Ontology | molecular_function |
| Synonym | dicarboxylate carrier; dicarboxylate (succinate/fumarate/malate) antiporter activity; dicarboxylic acid permease activity; sodium:dicarboxylate/tricarboxylate symporter activity |
| Major function | Transfer of dicarboxylic acids across a membrane |
| Substrate class | Organic acids with two COOH groups, e.g. succinate, fumarate, malate, oxalate, itaconate |
| Transport modes | Antiport, symport, and uniport |
| Representative families | Mitochondrial carrier family and sodium-coupled transporter families |
What Is GO:0005310?
In plain terms, GO:0005310 is the activity of a protein that carries a dicarboxylic acid, a molecule with two COOH groups, across a biological membrane. The function is defined at the level of the transporter activity itself rather than the downstream metabolic pathway, and it includes antiport, symport, and uniport modes. Synonyms such as dicarboxylate carrier, dicarboxylate (succinate/fumarate/malate) antiporter activity, dicarboxylic acid permease activity, and sodium:dicarboxylate/tricarboxylate symporter activity reflect the historical and mechanistic diversity of proteins annotated to this term.
Why Is dicarboxylic acid transmembrane transporter activity Important in Cell Biology?
GO:0005310 is important because dicarboxylic acid transport sits at the intersection of mitochondrial energy metabolism, cytosolic signaling, and epithelial physiology [2,3,7]. Mitochondrial carriers that exchange dicarboxylates supply the cytosol and mitochondria with Krebs cycle intermediates, and the structural principles of this family are exemplified by the ADP/ATP carrier. In parallel, sodium-coupled transporters for Krebs cycle intermediates control the availability of succinate and related metabolites that can act as signaling molecules [3,4]. Recent work shows that succinate chemosensing can drive CFTR-dependent airway clearance, and this process is impaired in cystic fibrosis, directly linking dicarboxylate transport to lung disease. Oxalate secretion in the gut is stimulated by a cAMP-dependent pathway, connecting this function to calcium oxalate stone risk. The IRG1-itaconate axis further demonstrates that a dicarboxylic acid can act as an immunometabolic signal, so transporters that move it are potential therapeutic targets in inflammatory disease.
• Supplies mitochondria and cytosol with Krebs cycle intermediates such as succinate, fumarate, and malate.
• Provides a structural and mechanistic model through the mitochondrial carrier family, including the ADP/ATP carrier.
• Links succinate sensing to CFTR-dependent airway clearance, which is impaired in cystic fibrosis.
• Contributes to oxalate handling in the gut, with implications for calcium oxalate stone disease.
• Supports itaconate transport and the IRG1-itaconate immunometabolic axis in inflammation.
• Is relevant to bacterial acid acclimation and urea transport in gastric Helicobacter species.
• Provides targets for metabolic engineering and for modulating immune cell function [2,3].
• Enables studies of transporter specificity through CRISPR knockout and knock-in models.
• Connects membrane transport to cystic fibrosis therapeutic strategies such as iminosugars.
• Offers a route to understand connexin hemichannel regulation where metabolite flux is involved.
Molecular Mechanism of dicarboxylic acid transmembrane transporter activity
Substrate recognition and binding
In simple terms: The transporter must first grab the dicarboxylic acid on one side of the membrane.
Dicarboxylic acid transporters recognize substrates that carry two carboxyl groups, and the spacing and chemistry of these groups determine specificity for succinate, fumarate, malate, oxalate, or itaconate [3,7]. Mitochondrial carriers use a central cavity with conserved residues that coordinate the substrate, as illustrated by structural and mechanistic studies of the ADP/ATP carrier. Sodium-coupled transporters for Krebs cycle intermediates couple substrate binding to sodium ions, which stabilizes the substrate in the binding site.
Conformational cycle and translocation
In simple terms: The protein changes shape to move the substrate through the membrane.
After binding, the transporter undergoes a conformational cycle that exposes the substrate to the opposite side of the membrane. In mitochondrial carriers, this cycle is described by a single-binding-center gating mechanism in which the carrier alternates between cytoplasmic and matrix-facing states. Antiporters exchange one dicarboxylic acid for another, while symporters move the substrate together with sodium or another ion.
Energetics and transport modes
In simple terms: Some transporters use ion gradients, while others simply exchange one molecule for another.
Transport can be driven by ion gradients in sodium-coupled symporters, or it can be electroneutral exchange in antiporters such as the dicarboxylate carrier. The mitochondrial ADP/ATP carrier uses the membrane potential and adenine nucleotide gradients to drive exchange, providing a paradigm for how carrier proteins couple conformational changes to energy. The mode of energization determines whether the transporter can concentrate a substrate or merely equilibrate it across the membrane.
Regulation by signaling and post-translational modification
In simple terms: Cells can tune transport activity by modifying the transporter or its environment.
Transport activity can be regulated by phosphorylation and other post-translational modifications, as shown for connexin hemichannels where isoform-specific phosphorylation controls channel behavior. cAMP-dependent pathways stimulate oxalate secretion in the mouse cecum, indicating that transport can be acutely regulated by second messengers. In immunometabolism, the IRG1-itaconate axis influences inflammatory responses, and transporters that move itaconate are part of this regulatory network.
Physiological integration with metabolism and ion transport
In simple terms: Moving dicarboxylic acids affects whole-cell metabolism and ion balance.
Dicarboxylic acid transport is integrated with mitochondrial energy metabolism because succinate, fumarate, and malate are Krebs cycle intermediates. Succinate chemosensing can induce CFTR-dependent airway clearance, linking dicarboxylate transport to epithelial ion and fluid transport. In bacteria, urea transport and acid acclimation by gastric Helicobacter species illustrate how related transport functions support survival in hostile environments.
Key Genes Involved in GO:0005310 dicarboxylic acid transmembrane transporter activity
The following genes and proteins represent major experimental entry points for studying GO:0005310, based on published transport and metabolism literature [1,2,3,4,6,7,8].
| Gene | Major Role | Research Relevance |
|---|---|---|
| SLC25A10 | Mitochondrial dicarboxylate carrier | Model for antiport of succinate, fumarate, and malate |
| SLC25A11 | Mitochondrial oxoglutarate/malate carrier | Links dicarboxylate transport to amino acid metabolism |
| SLC25A12 | Mitochondrial aspartate/glutamate carrier | Supports malate-aspartate shuttle studies |
| SLC25A13 | Mitochondrial aspartate/glutamate carrier isoform | Relevant to urea cycle and malate exchange |
| SLC13A1 | Sodium-dependent dicarboxylate transporter | Plasma membrane symporter for Krebs cycle intermediates |
| SLC13A2 | Sodium-dependent dicarboxylate transporter | Kidney and intestinal transport studies |
| SLC13A3 | Sodium-dependent dicarboxylate transporter | Succinate and malate uptake assays |
| SLC13A5 | Sodium-dependent citrate transporter | Related tricarboxylate transport comparison |
| SLC26A6 | Anion exchanger for oxalate and other anions | Oxalate secretion and stone disease models |
| CFTR | Chloride channel involved in airway clearance | Succinate chemosensing and cystic fibrosis |
| ACOD1 (IRG1) | Itaconate-producing enzyme | Immunometabolism and inflammation studies |
| GJA1 (Cx43) | Connexin hemichannel | Phosphorylation-dependent regulation of metabolite flux |
| GJB1 (Cx32) | Connexin hemichannel | Isoform-specific regulation studies |
| SLC25A4 | Mitochondrial ADP/ATP carrier | Structural paradigm for carrier mechanism |
| SLC25A5 | Mitochondrial ADP/ATP carrier isoform | Comparative transport assays |
| SLC25A6 | Mitochondrial ADP/ATP carrier isoform | Comparative transport assays |
| Helicobacter urease cluster | Urea transport and acid acclimation | Bacterial survival and gastric disease models |
How Is dicarboxylic acid transmembrane transporter activity Regulated?
Regulation of dicarboxylic acid transmembrane transporter activity occurs at multiple levels. Post-translational phosphorylation can alter transporter or channel behavior, as demonstrated for connexin hemichannels where isoform-specific phosphorylation controls activity. cAMP-dependent signaling stimulates oxalate secretion in the mouse cecum, showing that second-messenger pathways can acutely increase transport. In immunometabolism, the IRG1-itaconate axis is regulated by inflammatory cues, and this regulation influences how much itaconate is available for transport. Mitochondrial carriers are also regulated by substrate availability and by the electrochemical gradient across the inner membrane, as described for the ADP/ATP carrier. Together, these mechanisms allow cells to match dicarboxylic acid flux to metabolic demand and environmental signals [1,2,7,8].
dicarboxylic acid transmembrane transporter activity and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| CFTR | Cystic fibrosis airway clearance | CFTR knockout or knock-in airway epithelial cells [4,5] |
| SLC26A6 | Oxalate secretion and stone disease | Intestinal epithelial knockout and transport assays |
| ACOD1 (IRG1) | Inflammatory immunometabolism | Macrophage knockout and itaconate flux assays |
| SLC25A10 | Mitochondrial dicarboxylate transport | Knockout cells with metabolic phenotyping |
| GJA1 (Cx43) | Connexin hemichannel regulation | Phospho-mutant knock-in and flux assays |
Cystic fibrosis and airway clearance
Succinate chemosensing can induce CFTR-dependent airway clearance, and this response is impaired in cystic fibrosis, linking dicarboxylate transport and sensing to lung disease. Therapeutic strategies for cystic fibrosis include iminosugars that modulate CFTR function, providing a context in which transport-related pathways are being targeted.
Oxalate-related stone disease
Oxalate secretion in the mouse cecum is stimulated by a cAMP-dependent pathway, and altered oxalate handling is relevant to calcium oxalate stone formation. Transporters such as SLC26A6 are studied in this context because they mediate oxalate movement across epithelia.
Inflammatory and immunometabolic disease
The IRG1-itaconate axis has mechanistic roles and therapeutic potential in inflammatory diseases, and itaconate is a dicarboxylic acid whose transport influences immune cell function. This places dicarboxylic acid transporters in the broader network of immunometabolism.
Gastric infection and acid acclimation
Urea transport in bacteria supports acid acclimation by gastric Helicobacter species, illustrating how transport of small acids and related molecules contributes to bacterial survival and gastric disease.
From dicarboxylic acid transmembrane transporter activity-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Is a candidate transporter required for succinate uptake? | CRISPR knockout cell line |
| Does a specific residue control substrate specificity? | Point-mutation knock-in cell line [1,3] |
| Can a tagged transporter be tracked in live cells? | Tagged knock-in cell line |
| Does overexpression increase dicarboxylate flux? | Overexpression cell line |
| Does loss of transport alter inflammatory signaling? | Knockout macrophages and cytokine assays |
| Does transport modulation affect airway clearance? | CFTR-dependent epithelial models |
How to Study the dicarboxylic acid transmembrane transporter activity Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Radiolabeled substrate uptake | Transport rate and specificity | Characterizing SLC25A10 or SLC13A transporters |
| Metabolomics | Intracellular metabolite levels | Krebs cycle and itaconate changes [2,3] |
| Isotope tracing | Metabolic flux | Pathway activity after knockout |
| Electrophysiology | Ion currents | Sodium-coupled transport studies |
| Live-cell imaging | Protein localization | Tagged transporter trafficking |
| Phospho-specific immunoblotting | Post-translational modification | Connexin regulation studies |
| CFTR functional assay | Airway chloride transport | Succinate chemosensing in cystic fibrosis |
| Oxalate secretion assay | Epithelial oxalate flux | cAMP-dependent transport studies |
Transport assays with radiolabeled or fluorescent substrates
Direct transport assays using radiolabeled succinate, malate, or oxalate measure uptake or efflux in cells and isolated membrane vesicles [3,7]. These assays define substrate specificity and kinetics for candidate transporters.
Metabolic profiling and flux analysis
Metabolomics and isotope tracing can quantify changes in Krebs cycle intermediates and itaconate when transporters are knocked out or overexpressed [2,3]. Such experiments connect transport activity to cellular metabolism.
Electrophysiology and ion flux measurements
Electrophysiological and ion flux methods can detect sodium-coupled transport and CFTR-dependent ion movement in epithelial cells [3,4]. These approaches link dicarboxylate transport to ion transport physiology.
Imaging and protein interaction studies
Tagged transporters can be imaged to determine localization and trafficking, and phosphorylation-dependent regulation can be studied with phospho-specific reagents [1,8]. These methods reveal how transport activity is controlled in space and time.
How CRISPR Can Be Used to Study GO:0005310 dicarboxylic acid transmembrane transporter activity
Knockout
CRISPR knockout of candidate genes such as SLC25A10, SLC13A1, or SLC26A6 can test whether a transporter is required for dicarboxylic acid uptake or secretion [3,7]. Knockout cells are then analyzed by transport assays and metabolomics to define the contribution of each gene.
Point Mutation
Point mutations in substrate-binding or gating residues can be introduced to test structure-function hypotheses derived from mitochondrial carrier mechanisms. Such mutants help distinguish residues required for substrate recognition from those required for conformational cycling.
Knock-in
Knock-in of epitope or fluorescent tags allows localization and interaction studies of endogenous transporters. Knock-in of disease-associated variants can also model how specific alleles alter transport activity.
Overexpression
Overexpression of a transporter can increase dicarboxylate flux and reveal rate-limiting roles in metabolism or signaling. Overexpression models are useful when knockout phenotypes are masked by redundant transporters.
How EDITGENE Supports dicarboxylic acid transmembrane transporter activity Research
Researchers studying dicarboxylic acid transmembrane transporter activity-related genes often need to determine whether a candidate gene is causally involved in substrate transport, metabolic rewiring, or disease phenotypes. EDITGENE provides CRISPR-based cell model services that allow precise manipulation of these genes in relevant cell backgrounds.
Contact EDITGENE today to design your custom CRISPR model for dicarboxylic acid transmembrane transporter activity research.
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| SLC13A3 Knockout HEK293 Cell Line | EDJ-KQ14507 | Human | 64849 | Details Get a Quote |
| SLC13A3 Knockout HeLa Cell Line | EDJ-KQ57087 | Human | 64849 | Details Get a Quote |
| SLC13A3 Knockout A-549 Cell Line | EDJ-KQ65599 | Human | 64849 | Details Get a Quote |
| SLC13A3 Knockout HCT 116 Cell Line | EDJ-KQ74027 | Human | 64849 | Details Get a Quote |
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Frequently Asked Questions About dicarboxylic acid transmembrane transporter activity
What is GO:0005310?
GO:0005310 is the molecular function of transferring dicarboxylic acids, organic acids with two COOH groups, across a membrane.
What genes are involved in dicarboxylic acid transmembrane transporter activity?
Genes include SLC25A10, SLC25A11, SLC13A1, SLC13A2, SLC13A3, SLC26A6, and CFTR, among others [3,4,7].
What are dicarboxylic acids?
Dicarboxylic acids are organic acids with two carboxyl groups, such as succinate, fumarate, malate, oxalate, and itaconate [2,3,7].
How is dicarboxylic acid transport energized?
Transport can be driven by ion gradients in sodium-coupled symporters or by exchange in antiporters such as mitochondrial carriers [1,3].
Is dicarboxylic acid transport linked to cystic fibrosis?
Yes, succinate chemosensing can induce CFTR-dependent airway clearance, and this response is impaired in cystic fibrosis.
What diseases involve dicarboxylic acid transporters?
They are linked to cystic fibrosis, oxalate-related stone disease, inflammatory conditions, and gastric infection biology [2,4,6,7].
How can I study dicarboxylic acid transport in the lab?
Common methods include radiolabeled substrate uptake, metabolomics, electrophysiology, and imaging of tagged transporters [1,3,7].
What is the role of SLC25A10?
SLC25A10 is a mitochondrial dicarboxylate carrier that exchanges substrates such as succinate, fumarate, and malate.
Can CRISPR be used to study these transporters?
Yes, CRISPR knockout, point mutation, knock-in, and overexpression models are widely used to test transporter function [1,3].
What is the connection to itaconate?
Itaconate is a dicarboxylic acid produced by the IRG1 enzyme, and its transport is part of the IRG1-itaconate immunometabolic axis.
Conclusion
GO:0005310 defines a fundamental membrane transport function that moves dicarboxylic acids such as succinate, fumarate, malate, oxalate, and itaconate across membranes [2,3,7]. Its mechanistic basis is best understood through mitochondrial carrier and sodium-coupled transporter families, with the ADP/ATP carrier serving as a structural paradigm [1,3]. The function is increasingly linked to human disease, including cystic fibrosis airway clearance defects, oxalate-related stone disease, and inflammatory immunometabolism [2,4,7]. CRISPR-based cell models provide a rigorous way to test causality and to dissect the residues and regulatory pathways that control transport [1,3].
References
- 1. Kunji ER et al.. 2016. The transport mechanism of the mitochondrial ADP/ATP carrier.. Biochim Biophys Acta 1863(10):2379-93 PMID: 27001633
- 2. Liu Y et al.. 2026. IRG1-itaconate axis in immunometabolism: mechanistic roles and therapeutic potential in inflammatory diseases.. Front Immunol 17:1767601 PMID: 41743716
- 3. Pajor AM. 1999. Sodium-coupled transporters for Krebs cycle intermediates.. Annu Rev Physiol 61:663-82 PMID: 10099705
- 4. Apablaza T et al.. 2025. Succinate Chemosensing Induces Cystic Fibrosis Transmembrane Conductance Regulator-dependent Airway Clearance that Is Impaired in Cystic Fibrosis.. Am J Respir Cell Mol Biol 73(5):769-779 PMID: 40239014
- 5. Esposito A et al.. 2020. Synthesis and Therapeutic Applications of Iminosugars in Cystic Fibrosis.. Int J Mol Sci 21(9) PMID: 32397443
- 6. Sachs G et al.. 2006. Urea transport in bacteria: acid acclimation by gastric Helicobacter spp.. J Membr Biol 212(2):71-82 PMID: 17264989
- 7. Whittamore JM et al.. 2023. Oxalate secretion is stimulated by a cAMP-dependent pathway in the mouse cecum.. Pflugers Arch 475(2):249-266 PMID: 36044064
- 8. Alstrøm JS et al.. 2015. Isoform-specific phosphorylation-dependent regulation of connexin hemichannels.. J Neurophysiol 114(5):3014-22 PMID: 26400258
