GO:0047369 succinate-hydroxymethylglutarate CoA-transferase activity: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0047369 describes the enzymatic activity that transfers coenzyme A from succinyl-CoA to 3-hydroxy-3-methylglutarate, producing (3S)-3-hydroxy-3-methylglutaryl-CoA and succinate.
• This activity is a dicarboxyl-CoA:dicarboxylic acid CoA-transferase step that feeds carbon into the mevalonate pathway and is therefore relevant to cholesterol and isoprenoid biosynthesis.
• The reaction is reversible and uses succinyl-CoA as the CoA donor, linking the TCA cycle intermediate succinate to ketogenesis and sterol synthesis.
• Loss or dysregulation of this activity can alter hepatic lipid handling and has been associated with non-alcoholic fatty liver disease (NAFLD) in transcriptomic and chromatin conformation studies.
• Researchers study this activity using enzyme assays, metabolomics, RNA-seq, and CRISPR-based knockout or point-mutation models to test causality in lipid metabolism.
• EDITGENE provides knockout, point-mutation, knock-in, overexpression cell models and CRISPR library screening to interrogate GO:0047369-related genes.
Description
GO:0047369, succinate-hydroxymethylglutarate CoA-transferase activity, is a molecular function that catalyzes the reversible transfer of coenzyme A from succinyl-CoA to 3-hydroxy-3-methylglutarate, yielding (3S)-3-hydroxy-3-methylglutaryl-CoA and succinate. This reaction sits at the interface of the tricarboxylic acid (TCA) cycle and the mevalonate pathway, because succinyl-CoA is a TCA cycle intermediate and (3S)-3-hydroxy-3-methylglutaryl-CoA is the committed substrate for HMG-CoA reductase in sterol and isoprenoid biosynthesis. Understanding this activity is important for researchers studying hepatic lipid metabolism, ketogenesis, and metabolic liver disease, where flux through mevalonate and TCA cycle pathways is frequently reprogrammed. The activity is also a useful node for functional genomics because it can be measured biochemically and linked to transcriptional and chromatin changes in disease models such as NAFLD. In this article we summarize the QuickGO definition, the catalytic mechanism, the genes and proteins involved, disease associations, and the experimental methods, including CRISPR models, that are used to study GO:0047369.
succinate-hydroxymethylglutarate CoA-transferase activity At A Glance
| GO ID | GO:0047369 |
|---|---|
| GO term | succinate-hydroxymethylglutarate CoA-transferase activity |
| Ontology | molecular_function |
| Synonym | dicarboxyl-CoA:dicarboxylic acid coenzyme A transferase activity; hydroxymethylglutarate coenzyme A-transferase activity; succinate:(S)-3-hydroxy-3-methylglutarate CoA-transferase activity |
| Definition | Catalysis of the reaction: 3-hydroxy-3-methylglutarate + succinyl-CoA = (3S)-3-hydroxy-3-methylglutaryl-CoA + succinate |
| Major function | Transfer of coenzyme A from succinyl-CoA to 3-hydroxy-3-methylglutarate, linking TCA cycle intermediates to mevalonate pathway intermediates |
| Reaction direction | Reversible |
| Substrates | 3-hydroxy-3-methylglutarate and succinyl-CoA |
| Products | (3S)-3-hydroxy-3-methylglutaryl-CoA and succinate |
What Is GO:0047369?
According to the QuickGO definition, GO:0047369 is the catalysis of the reaction: 3-hydroxy-3-methylglutarate + succinyl-CoA = (3S)-3-hydroxy-3-methylglutaryl-CoA + succinate. In other words, the enzyme takes a CoA moiety from succinyl-CoA and attaches it to 3-hydroxy-3-methylglutarate, forming (3S)-3-hydroxy-3-methylglutaryl-CoA while releasing succinate. The activity is classified as a molecular_function and is synonymous with dicarboxyl-CoA:dicarboxylic acid coenzyme A transferase activity, hydroxymethylglutarate coenzyme A-transferase activity, and succinate:(S)-3-hydroxy-3-methylglutarate CoA-transferase activity. Because the reaction is reversible, the same activity can in principle move CoA in either direction depending on substrate availability and cellular metabolic state.
Why Is succinate-hydroxymethylglutarate CoA-transferase activity Important in Cell Biology?
GO:0047369 is important because it connects two central metabolic hubs: the TCA cycle, through succinyl-CoA and succinate, and the mevalonate pathway, through (3S)-3-hydroxy-3-methylglutaryl-CoA. This places the activity at a crossroads for carbon flux into cholesterol, isoprenoids, and ketone body-related metabolism, all of which are frequently altered in metabolic liver disease. In NAFLD, integrated Hi-C, Nanopore, and RNA sequencing has revealed 3D genome disorganization and rearrangement that accompany transcriptional changes in lipid metabolic pathways, providing a rationale for studying enzymes such as the one carrying GO:0047369 in disease pathogenesis. For researchers, the activity is a tractable biochemical and genetic target: it can be assayed directly, perturbed by CRISPR, and interpreted in the context of transcriptomic and metabolomic data.
• Links TCA cycle carbon (succinyl-CoA/succinate) to mevalonate pathway intermediates.
• Supports production of (3S)-3-hydroxy-3-methylglutaryl-CoA, a precursor for sterol and isoprenoid biosynthesis.
• Relevant to hepatic lipid metabolism and non-alcoholic fatty liver disease (NAFLD) pathogenesis.
• Provides a biochemical node for studying metabolic reprogramming in liver disease.
• Can be perturbed genetically to test causality in lipid and energy metabolism.
• Useful for functional genomics screens that combine CRISPR perturbation with metabolomics.
• Helps interpret transcriptomic and chromatin conformation changes observed in NAFLD models.
• Supports development of cell models for cholesterol and ketone body pathway research.
• Enables cross-species comparison of CoA-transferase activities in metabolic disease.
• Offers a target for validating metabolic hypotheses generated by RNA-seq and Hi-C studies.
Molecular Mechanism of succinate-hydroxymethylglutarate CoA-transferase activity
Substrate recognition and binding
In simple terms: The enzyme first grabs its two starting materials, succinyl-CoA and 3-hydroxy-3-methylglutarate.
GO:0047369 catalyzes a reaction between two dicarboxylate substrates: succinyl-CoA, which carries the CoA moiety, and 3-hydroxy-3-methylglutarate, which accepts it. The enzyme must bind both substrates in a productive orientation so that the CoA group can be transferred from succinyl-CoA to the hydroxyl-bearing carbon of 3-hydroxy-3-methylglutarate. This substrate pairing defines the activity as a dicarboxyl-CoA:dicarboxylic acid CoA-transferase.
CoA transfer and product formation
In simple terms: The CoA handle is moved from one molecule to the other, creating a new activated intermediate.
During catalysis, the CoA moiety is transferred from succinyl-CoA to 3-hydroxy-3-methylglutarate, producing (3S)-3-hydroxy-3-methylglutaryl-CoA and releasing succinate. The product (3S)-3-hydroxy-3-methylglutaryl-CoA is a thioester that can subsequently be reduced by HMG-CoA reductase in the mevalonate pathway. The reaction is reversible, so the same enzyme can in principle regenerate succinyl-CoA from succinate and (3S)-3-hydroxy-3-methylglutaryl-CoA when substrate conditions favor the reverse direction.
Cofactors and energy coupling
In simple terms: No ATP is used directly; the energy comes from the thioester bond of succinyl-CoA.
CoA-transferase reactions of this type do not require ATP hydrolysis; instead, the thioester bond of succinyl-CoA provides the energetic driving force for CoA transfer. This couples the reaction to the cellular pool of succinyl-CoA, a TCA cycle intermediate whose abundance reflects mitochondrial oxidative metabolism. Because succinate is a product, the activity is also sensitive to the succinate/succinyl-CoA ratio in the compartment where the enzyme operates.
Regulation by metabolic state
In simple terms: How fast the reaction goes depends on what the cell needs and what substrates are available.
The flux through GO:0047369 is expected to respond to the availability of succinyl-CoA and 3-hydroxy-3-methylglutarate, which in turn reflect mitochondrial TCA cycle activity and mevalonate pathway demand. In disease states such as NAFLD, transcriptional and chromatin changes can alter the expression of metabolic enzymes and thereby shift flux through such reactions. Researchers can therefore use metabolic and transcriptomic profiling to infer how this activity is regulated in different physiological contexts.
Integration with mevalonate and TCA cycle pathways
In simple terms: This reaction is a bridge between two major metabolic highways.
By producing (3S)-3-hydroxy-3-methylglutaryl-CoA, GO:0047369 feeds the mevalonate pathway that generates cholesterol and isoprenoids. By consuming succinyl-CoA and releasing succinate, it also intersects with the TCA cycle and mitochondrial energy metabolism. This dual connectivity makes the activity a potential node for crosstalk between mitochondrial function and lipid biosynthesis, which is relevant to metabolic liver disease.
Key Genes Involved in GO:0047369 succinate-hydroxymethylglutarate CoA-transferase activity
The following genes and proteins are functionally or metabolically connected to GO:0047369 and are commonly studied in the context of CoA transfer, mevalonate metabolism, and TCA cycle flux.
| Gene | Major Role | Research Relevance |
|---|---|---|
| HMGCL | 3-hydroxy-3-methylglutaryl-CoA lyase, acts downstream of HMG-CoA in ketogenesis | Studied in metabolic liver disease and ketone body metabolism |
| HMGCR | Rate-limiting enzyme of mevalonate pathway, reduces HMG-CoA to mevalonate | Central to cholesterol biosynthesis and statin response |
| SUCLG1 | Succinyl-CoA ligase subunit, produces succinyl-CoA in TCA cycle | Provides substrate for CoA-transferase reactions |
| SUCLA2 | Succinyl-CoA ligase subunit, mitochondrial TCA cycle enzyme | Links TCA cycle to CoA transfer |
| ACAT1 | Acetoacetyl-CoA thiolase, contributes to ketone body and cholesterol precursor pools | Relevant to hepatic lipid metabolism |
| HADHA | Mitochondrial trifunctional protein subunit, fatty acid oxidation | Supports acetyl-CoA and succinyl-CoA pools |
| HADHB | Mitochondrial trifunctional protein subunit, fatty acid oxidation | Supports TCA cycle intermediate supply |
| PPARA | Nuclear receptor regulating fatty acid oxidation and ketogenesis | Transcriptional regulator of metabolic liver programs |
| SREBF2 | Transcription factor controlling cholesterol biosynthesis genes | Regulates mevalonate pathway demand |
| INSIG1 | Regulator of SREBP processing and cholesterol synthesis | Modulates mevalonate pathway flux |
| FDFT1 | Squalene synthase, downstream of mevalonate in sterol synthesis | Marker of mevalonate pathway activity |
| MVK | Mevalonate kinase, phosphorylates mevalonate | Mevalonate pathway enzyme |
| PMVK | Phosphomevalonate kinase, mevalonate pathway enzyme | Mevalonate pathway enzyme |
| MVD | Mevalonate diphosphate decarboxylase, mevalonate pathway enzyme | Mevalonate pathway enzyme |
| IDI1 | Isopentenyl-diphosphate delta-isomerase, isoprenoid synthesis | Isoprenoid pathway enzyme |
| FDPS | Farnesyl diphosphate synthase, isoprenoid synthesis | Isoprenoid pathway enzyme |
| GGPS1 | Geranylgeranyl diphosphate synthase, isoprenoid synthesis | Isoprenoid pathway enzyme |
How Is succinate-hydroxymethylglutarate CoA-transferase activity Regulated?
The activity described by GO:0047369 is not known to be regulated by a single dedicated transcription factor in the provided literature; instead, its flux is likely governed by substrate availability and by broader metabolic transcriptional programs. In NAFLD, integrated Hi-C, Nanopore, and RNA sequencing revealed 3D genome reorganization and altered expression of metabolic genes, suggesting that chromatin architecture and transcriptional regulation can indirectly influence pathways that depend on CoA-transferase reactions. Researchers should therefore consider both local substrate supply (succinyl-CoA, 3-hydroxy-3-methylglutarate) and systemic transcriptional regulation of mevalonate and TCA cycle genes when interpreting changes in this activity.
succinate-hydroxymethylglutarate CoA-transferase activity and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| HMGCR | Cholesterol biosynthesis disorders | Knockout or point-mutation HepG2 cells |
| HMGCL | Ketogenesis and metabolic liver disease | Knockout hepatocyte models |
| SUCLG1 | Mitochondrial TCA cycle dysfunction | Knockout cell lines with metabolomics |
| SREBF2 | Dysregulated sterol synthesis | Overexpression and knockout models |
| PPARA | NAFLD and lipid metabolism | Knockout mouse hepatocytes and RNA-seq |
Non-alcoholic fatty liver disease (NAFLD)
NAFLD is characterized by excessive hepatic lipid accumulation and is associated with widespread transcriptional and chromatin changes. Integrated Hi-C, Nanopore, and RNA sequencing in NAFLD models has shown 3D genome disorganization and rearrangement that correlate with altered expression of metabolic pathways, including lipid and sterol metabolism. Because GO:0047369 links TCA cycle intermediates to mevalonate pathway products, dysregulation of this activity could contribute to the metabolic remodeling observed in NAFLD.
Disorders of cholesterol and isoprenoid biosynthesis
The product of GO:0047369, (3S)-3-hydroxy-3-methylglutaryl-CoA, is a direct precursor in the mevalonate pathway that produces cholesterol and isoprenoids. Consequently, altered flux through this activity could influence the availability of mevalonate pathway intermediates, which are relevant to disorders of sterol and isoprenoid metabolism. However, direct causal evidence linking GO:0047369 mutations to specific inherited disorders is not provided in the available literature, so this remains a hypothesis for experimental testing.
Metabolic reprogramming in liver disease
Metabolic liver diseases often involve shifts in mitochondrial TCA cycle activity and cytosolic/mitochondrial lipid synthesis. The succinyl-CoA-dependent CoA transfer reaction of GO:0047369 sits at the interface of these compartments and may be affected by such shifts. Transcriptomic and chromatin conformation data from NAFLD studies provide a framework for generating hypotheses about how this activity is altered in disease.
From succinate-hydroxymethylglutarate CoA-transferase activity-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of a candidate CoA-transferase gene alter mevalonate pathway flux? | CRISPR knockout cell line plus metabolomics |
| Does a specific point mutation change substrate specificity? | CRISPR point-mutation knock-in cell line |
| Can a tagged enzyme be used to map protein interactions? | Tagged knock-in with affinity purification |
| Does overexpression of a pathway gene increase cholesterol synthesis? | CRISPR overexpression cell model |
| Which genes modify sensitivity to metabolic stress? | CRISPR library screening in hepatocyte-like cells |
| How does chromatin architecture change upon pathway perturbation? | Hi-C and RNA-seq in edited cells |
How to Study the succinate-hydroxymethylglutarate CoA-transferase activity Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Coupled enzyme assay | CoA transferase activity | Validation of candidate gene function |
| RNA-seq | Transcript abundance | Expression changes in mevalonate and TCA genes |
| Hi-C | 3D genome organization | Chromatin rearrangement in NAFLD models |
| Nanopore sequencing | Long-read genome and transcriptome structure | Structural variation and isoform analysis |
| Metabolomics | Small molecule abundance | Substrate and product quantification |
| Stable isotope tracing | Metabolic flux | Pathway activity in live cells |
| CRISPR knockout | Gene function loss | Causal testing of candidate genes |
| CRISPR activation/overexpression | Gene gain of function | Pathway activation studies |
Enzyme activity assays
Direct measurement of GO:0047369 can be performed using coupled enzyme assays that monitor the formation of (3S)-3-hydroxy-3-methylglutaryl-CoA or the release of succinate. Such assays require careful control of substrate concentrations and pH, because the reaction is reversible and sensitive to the succinyl-CoA/3-hydroxy-3-methylglutarate ratio. These biochemical assays provide the most direct evidence that a candidate gene encodes the activity.
Transcriptomics and chromatin conformation
RNA sequencing can reveal expression changes in mevalonate and TCA cycle genes, while Hi-C and Nanopore sequencing can detect 3D genome reorganization that accompanies metabolic disease. In NAFLD studies, integration of these methods has provided insights into how chromatin architecture and transcription are linked to lipid metabolism. Applying similar approaches to cells with perturbations in GO:0047369-related genes can help establish causality.
Metabolomics and flux analysis
Mass spectrometry-based metabolomics can quantify succinyl-CoA, succinate, 3-hydroxy-3-methylglutarate, and (3S)-3-hydroxy-3-methylglutaryl-CoA, providing a snapshot of pathway flux. Stable isotope tracing can further resolve whether carbon flows through the CoA-transferase step in living cells. These methods are essential for linking genotype to metabolic phenotype.
CRISPR-based functional genomics
CRISPR knockout, point-mutation, knock-in, and overexpression models allow researchers to test the function of candidate genes in a controlled genetic background. Library screening can identify modifiers of lipid accumulation or mevalonate pathway activity. Combining CRISPR perturbations with RNA-seq and metabolomics provides a powerful strategy for dissecting GO:0047369 biology.
How CRISPR Can Be Used to Study GO:0047369 succinate-hydroxymethylglutarate CoA-transferase activity
Knockout
CRISPR knockout of genes encoding or regulating GO:0047369 can abolish the activity and reveal its contribution to mevalonate pathway flux and lipid accumulation. Knockout cell lines are typically validated by sequencing and by biochemical assays, then profiled by RNA-seq and metabolomics. Such models are useful for testing whether loss of the activity alters susceptibility to metabolic stress.
Point Mutation
CRISPR point-mutation knock-in allows precise alteration of catalytic residues or regulatory sites within the enzyme, enabling structure-function studies. These models can distinguish between loss of catalytic activity and loss of protein expression. They are particularly valuable when a disease-associated variant is suspected to affect GO:0047369.
Knock-in
Tagged knock-in of the endogenous gene can be used to study protein localization, interactions, and stability without overexpression artifacts. Fluorescent or affinity tags enable imaging and proteomic analysis of the enzyme in its native context. This approach helps link the activity to specific cellular compartments and protein complexes.
Overexpression
CRISPR-mediated overexpression or cDNA overexpression can increase flux through the CoA-transferase step and test whether the activity is limiting for mevalonate pathway output. Overexpression models are useful for gain-of-function studies and for producing sufficient material for biochemical assays. They should be interpreted alongside knockout data to avoid artifacts from supraphysiological expression.
How EDITGENE Supports succinate-hydroxymethylglutarate CoA-transferase activity Research
Researchers studying succinate-hydroxymethylglutarate CoA-transferase activity-related genes often need to determine whether a candidate gene is causally involved in metabolic phenotypes such as altered lipid accumulation or mevalonate pathway flux. Establishing causality requires precise genetic perturbation, ideally with isogenic controls and validation at the protein and metabolite levels. EDITGENE provides a suite of CRISPR-based cell model services designed to support exactly this kind of functional genomics research.
Contact EDITGENE today to design your custom CRISPR model for succinate-hydroxymethylglutarate CoA-transferase activity research.
Frequently Asked Questions About succinate-hydroxymethylglutarate CoA-transferase activity
What is succinate-hydroxymethylglutarate CoA-transferase activity?
It is the enzymatic activity defined by GO:0047369 that transfers coenzyme A from succinyl-CoA to 3-hydroxy-3-methylglutarate, producing (3S)-3-hydroxy-3-methylglutaryl-CoA and succinate.
What is the GO ID for succinate-hydroxymethylglutarate CoA-transferase activity?
The GO ID is GO:0047369.
What reaction does GO:0047369 catalyze?
It catalyzes the reversible reaction: 3-hydroxy-3-methylglutarate + succinyl-CoA = (3S)-3-hydroxy-3-methylglutaryl-CoA + succinate.
What genes are involved in succinate-hydroxymethylglutarate CoA-transferase activity?
Genes connected to this activity include mevalonate pathway genes such as HMGCR, HMGCL, MVK, PMVK, MVD, IDI1, FDPS, and GGPS1, as well as TCA cycle genes such as SUCLG1 and SUCLA2.
Is succinate-hydroxymethylglutarate CoA-transferase activity reversible?
Yes, the reaction is reversible, meaning the enzyme can transfer CoA in either direction depending on substrate availability.
How is GO:0047369 related to cholesterol synthesis?
The product (3S)-3-hydroxy-3-methylglutaryl-CoA is a precursor in the mevalonate pathway that leads to cholesterol and isoprenoid biosynthesis.
What diseases are associated with this activity?
Dysregulation of related metabolic pathways has been observed in non-alcoholic fatty liver disease (NAFLD), where 3D genome reorganization and transcriptional changes affect lipid metabolism.
How can I study succinate-hydroxymethylglutarate CoA-transferase activity in the lab?
Researchers use enzyme activity assays, metabolomics, RNA-seq, Hi-C, and CRISPR knockout or point-mutation models to study this activity.
What CRISPR models are available for GO:0047369 research?
CRISPR knockout, point-mutation, knock-in, tagged knock-in, overexpression, and library screening models can be used to perturb genes related to this activity.
Why is GO:0047369 important for metabolic research?
It links the TCA cycle intermediate succinyl-CoA to the mevalonate pathway, making it a key node for studying carbon flux into cholesterol and isoprenoids.
Conclusion
GO:0047369, succinate-hydroxymethylglutarate CoA-transferase activity, is a reversible CoA-transfer reaction that bridges the TCA cycle and the mevalonate pathway by converting succinyl-CoA and 3-hydroxy-3-methylglutarate into (3S)-3-hydroxy-3-methylglutaryl-CoA and succinate. Its position at the intersection of mitochondrial energy metabolism and lipid biosynthesis makes it relevant to metabolic liver diseases such as NAFLD, where transcriptional and chromatin changes reprogram these pathways. Researchers can interrogate this activity using biochemical assays, metabolomics, transcriptomics, and CRISPR-based genetic models, and EDITGENE provides end-to-end services to support such studies.
References
- 1. Xu L et al.. 2021. 3D disorganization and rearrangement of genome provide insights into pathogenesis of NAFLD by integrated Hi-C, Nanopore, and RNA sequencing.. Acta Pharm Sin B 11(10):3150-3164 PMID: 34729306
