GO:2001295 malonyl-CoA biosynthetic process: Metabolic Hub, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:2001295 (malonyl-CoA biosynthetic process) describes the biochemical reactions that produce malonyl-CoA, the S-malonyl derivative of coenzyme A.
• Malonyl-CoA is a central metabolite that serves as the committed substrate for de novo fatty acid synthesis and as a key regulator of mitochondrial fatty acid oxidation through inhibition of CPT1.
• Hepatic malonyl-CoA synthesis restrains gluconeogenesis by suppressing fat oxidation, pyruvate carboxylation, and amino acid availability.
• Malonyl-CoA promotes prostate cancer progression and castration resistance by enhancing lipogenesis and Ran activation.
• FASN-derived malonyl-CoA regulates STING palmitoylation in macrophages and alleviates sepsis-induced liver injury.
• Advanced tools such as ReaL-MGE enable enhanced multiplex genome engineering and application to malonyl-CoA anabolism.
Description
Malonyl-CoA is a pivotal metabolite at the crossroads of fatty acid synthesis and oxidation. The Gene Ontology term GO:2001295, malonyl-CoA biosynthetic process, is defined as the chemical reactions and pathways resulting in the formation of malonyl-CoA, the S-malonyl derivative of coenzyme A. This process is essential for cellular energy homeostasis, membrane biogenesis, and signaling. In hepatocytes, malonyl-CoA synthesis restrains gluconeogenesis by suppressing fat oxidation, pyruvate carboxylation, and amino acid availability, highlighting its role in metabolic regulation. In cancer, malonyl-CoA promotes prostate cancer progression and castration resistance by enhancing lipogenesis and Ran activation. Furthermore, malonyl-CoA produced by FASN regulates STING palmitoylation in macrophages to alleviate sepsis-induced liver injury. Given its broad impact on metabolism, cancer, and immunity, understanding the malonyl-CoA biosynthetic process is critical for researchers in cell biology, oncology, and metabolic diseases.
malonyl-CoA biosynthetic process At A Glance
| GO ID | GO:2001295 |
|---|---|
| GO term | malonyl-CoA biosynthetic process |
| Ontology | biological_process |
| Synonym | malonyl-CoA anabolism, malonyl-CoA biosynthesis, malonyl-CoA formation, malonyl-CoA synthesis |
| Major function | Production of malonyl-CoA, a key substrate for fatty acid synthesis and regulator of fatty acid oxidation |
| Key enzymes | Acetyl-CoA carboxylase (ACC), malonyl-CoA synthetase (ACSF3) |
| Pathways | Fatty acid biosynthesis, mitochondrial fatty acid oxidation regulation, gluconeogenesis suppression |
| Disease relevance | Cancer, insulin resistance, sepsis-induced liver injury, metabolic disorders |
What Is GO:2001295?
The malonyl-CoA biosynthetic process (GO:2001295) encompasses the enzymatic reactions that synthesize malonyl-CoA from acetyl-CoA and bicarbonate, primarily catalyzed by acetyl-CoA carboxylase (ACC). This process is a biological process that provides malonyl-CoA for fatty acid synthesis and other metabolic pathways. The QuickGO definition states: 'The chemical reactions and pathways resulting in the formation of malonyl-CoA, the S-malonyl derivative of coenzyme A.' Synonyms include malonyl-CoA anabolism, biosynthesis, formation, and synthesis.
Why Is malonyl-CoA biosynthetic process Important in Cell Biology?
The malonyl-CoA biosynthetic process is fundamentally important because malonyl-CoA acts as a metabolic hub. It is the committed substrate for de novo fatty acid synthesis and a potent inhibitor of carnitine palmitoyltransferase 1 (CPT1), thereby controlling mitochondrial fatty acid oxidation. In the liver, malonyl-CoA synthesis restrains gluconeogenesis by suppressing fat oxidation, pyruvate carboxylation, and amino acid availability, which is critical for whole-body glucose homeostasis. Dysregulation of this process contributes to insulin resistance, cancer progression, and inflammatory conditions such as sepsis-induced liver injury. Therefore, understanding the regulation and function of malonyl-CoA biosynthesis offers therapeutic opportunities for metabolic diseases and cancer.
• Central to fatty acid synthesis and energy storage.
• Regulates mitochondrial fatty acid oxidation via CPT1 inhibition.
• Suppresses hepatic gluconeogenesis and controls blood glucose.
• Promotes prostate cancer progression and castration resistance.
• Modulates immune responses through STING palmitoylation in macrophages.
• Implicated in insulin resistance and type 2 diabetes.
• Target for metabolic engineering to enhance malonyl-CoA anabolism.
• Involved in mitochondrial metabolism via ACSF3.
• Potential therapeutic target for sepsis-induced liver injury.
• Key node for understanding fuel sensing and metabolic regulation.
What Happens During malonyl-CoA biosynthetic process?
Synthesis from Acetyl-CoA by Acetyl-CoA Carboxylase
In simple terms: The main way cells make malonyl-CoA is by adding a carboxyl group to acetyl-CoA.
The primary route for malonyl-CoA biosynthesis is the carboxylation of acetyl-CoA to malonyl-CoA, catalyzed by acetyl-CoA carboxylase (ACC). This reaction requires bicarbonate and ATP. ACC is a biotin-dependent enzyme and is regulated by phosphorylation and allosteric modulators. In hepatocytes, this process is essential for providing malonyl-CoA for fatty acid synthesis and for signaling to suppress gluconeogenesis. The malonyl-CoA produced then acts as a substrate for fatty acid synthase (FASN) and as a regulator of CPT1.
Alternative Route via Malonyl-CoA Synthetase (ACSF3)
In simple terms: Another enzyme, ACSF3, can directly make malonyl-CoA from malonate.
ACSF3 (acyl-CoA synthetase family member 3) catalyzes the ATP-dependent ligation of malonate and CoA to form malonyl-CoA. This enzyme is localized in mitochondria and plays a role in mitochondrial metabolism. The malonyl-CoA produced by ACSF3 can be used for fatty acid synthesis or can regulate mitochondrial fatty acid oxidation. This pathway is particularly important in tissues where ACC activity is low or in specific metabolic conditions.
Regulation by Malonyl-CoA Decarboxylase
In simple terms: Malonyl-CoA can be broken down by MCD, balancing its levels.
Malonyl-CoA decarboxylase (MCD) catalyzes the conversion of malonyl-CoA to acetyl-CoA, thereby reducing malonyl-CoA levels. This enzyme is important for regulating the cellular concentration of malonyl-CoA and thus the rate of fatty acid synthesis and oxidation. The balance between ACC and MCD activities determines the flux through the malonyl-CoA biosynthetic process. Dysregulation of this balance can lead to metabolic disorders.
Role in Fatty Acid Oxidation Control
In simple terms: Malonyl-CoA stops fats from being burned in mitochondria.
Malonyl-CoA inhibits carnitine palmitoyltransferase 1 (CPT1), the enzyme that controls the entry of long-chain fatty acids into mitochondria for oxidation. This inhibition is a key mechanism by which malonyl-CoA regulates fatty acid oxidation. Mitochondrial morphology can also control fatty acid utilization by changing CPT1 sensitivity to malonyl-CoA. Thus, the malonyl-CoA biosynthetic process directly influences energy homeostasis and fuel selection.
Integration with Gluconeogenesis and Amino Acid Metabolism
In simple terms: Malonyl-CoA helps control how the liver makes glucose and uses amino acids.
In the liver, malonyl-CoA synthesis restrains gluconeogenesis by suppressing fat oxidation, pyruvate carboxylation, and amino acid availability. This integration ensures that glucose production is not inappropriately activated when fatty acid synthesis is ongoing. The malonyl-CoA biosynthetic process therefore serves as a critical node linking lipid and carbohydrate metabolism.
Key Genes Involved in GO:2001295 malonyl-CoA biosynthetic process
The following genes and proteins are key players in the malonyl-CoA biosynthetic process and its regulation.
| Gene | Major Role | Research Relevance |
|---|---|---|
| ACACA | Catalyzes the carboxylation of acetyl-CoA to malonyl-CoA | Rate-limiting enzyme in fatty acid synthesis; target for metabolic regulation |
| ACACB | Isoform of ACC in mitochondria; regulates fatty acid oxidation | Involved in energy sensing and insulin resistance |
| FASN | Uses malonyl-CoA for fatty acid synthesis; also regulates STING palmitoylation | Links malonyl-CoA to immune response and sepsis |
| ACSF3 | Mitochondrial malonyl-CoA synthetase | Alternative route for malonyl-CoA production; mitochondrial metabolism |
| CPT1A | Inhibited by malonyl-CoA; controls fatty acid entry into mitochondria | Key regulator of fatty acid oxidation; target of malonyl-CoA |
| CPT1B | Muscle isoform of CPT1; sensitive to malonyl-CoA | Regulates fatty acid oxidation in muscle |
| MLYCD | Malonyl-CoA decarboxylase; degrades malonyl-CoA | Balances malonyl-CoA levels; involved in metabolic disorders |
| SLC25A17 | Peroxisomal carrier; may transport malonyl-CoA precursors | Potential role in peroxisomal metabolism |
| ACLY | Produces acetyl-CoA for malonyl-CoA synthesis | Links citrate metabolism to lipogenesis |
| PDHX | Pyruvate dehydrogenase complex component; provides acetyl-CoA | Connects glucose metabolism to malonyl-CoA synthesis |
| PC | Pyruvate carboxylase; provides oxaloacetate for gluconeogenesis | Suppressed by malonyl-CoA in liver |
| G6PC | Glucose-6-phosphatase; gluconeogenic enzyme | Downregulated by malonyl-CoA synthesis |
| PCK1 | Phosphoenolpyruvate carboxykinase; gluconeogenic enzyme | Regulated by malonyl-CoA levels |
| STING1 | Palmitoylated by malonyl-CoA-derived lipids; immune signaling | Links malonyl-CoA to innate immunity |
| RAN | GTPase activated by malonyl-CoA; promotes cancer progression | Target in prostate cancer |
| mTOR | Regulates ACC and lipogenesis | Central regulator of malonyl-CoA synthesis |
| AMPK | Phosphorylates and inhibits ACC | Energy sensor that controls malonyl-CoA levels |
| SREBP1 | Transcription factor inducing ACC and FASN | Master regulator of lipogenesis |
How Is malonyl-CoA biosynthetic process Regulated?
The malonyl-CoA biosynthetic process is tightly regulated at multiple levels. Acetyl-CoA carboxylase (ACC) is allosterically activated by citrate and inhibited by long-chain acyl-CoAs. Phosphorylation by AMP-activated protein kinase (AMPK) inhibits ACC activity, reducing malonyl-CoA synthesis when energy is low. Conversely, insulin and mTOR signaling promote ACC activity and lipogenesis. Transcription factors such as SREBP1 induce the expression of ACC and FASN, enhancing malonyl-CoA production. Malonyl-CoA decarboxylase (MCD) provides a counter-regulatory mechanism by degrading malonyl-CoA. Additionally, mitochondrial morphology can influence CPT1 sensitivity to malonyl-CoA, thereby affecting fatty acid oxidation. This multilayered regulation ensures that malonyl-CoA levels are matched to cellular energy needs and biosynthetic demands.
malonyl-CoA biosynthetic process and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| ACACA | Cancer, insulin resistance | Knockout or point mutation in cancer cell lines; overexpression in hepatocytes |
| FASN | Sepsis-induced liver injury, cancer | Macrophage-specific knockout; knock-in of palmitoylation sites |
| ACSF3 | Combined malonic and methylmalonic aciduria | Knockout in HEK293 or patient-derived fibroblasts |
| CPT1A | Fatty acid oxidation disorders | Point mutation to alter malonyl-CoA sensitivity; knockout in liver cells |
| RAN | Prostate cancer castration resistance | Overexpression or knockout in prostate cancer cell lines |
Cancer
Malonyl-CoA promotes prostate cancer progression and castration resistance by enhancing lipogenesis and Ran activation. In many cancers, upregulation of ACC and FASN leads to increased malonyl-CoA synthesis, supporting rapid cell proliferation and membrane biogenesis. Targeting the malonyl-CoA biosynthetic process is therefore a potential therapeutic strategy in oncology.
Metabolic Disorders and Insulin Resistance
Dysregulation of malonyl-CoA metabolism is implicated in insulin resistance and type 2 diabetes. Malonyl-CoA acts as a fuel sensor, and its accumulation in muscle and liver can lead to impaired fatty acid oxidation and glucose uptake. Hepatic malonyl-CoA synthesis restrains gluconeogenesis, and its dysregulation contributes to hyperglycemia.
Sepsis-Induced Liver Injury
FASN-derived malonyl-CoA regulates STING palmitoylation in macrophages, which alleviates sepsis-induced liver injury. This highlights the role of malonyl-CoA biosynthesis in inflammatory and immune responses, suggesting that modulating this pathway could be beneficial in sepsis.
Mitochondrial Metabolism and Rare Diseases
ACSF3, a malonyl-CoA synthetase, is involved in mitochondrial metabolism, and mutations in ACSF3 cause combined malonic and methylmalonic aciduria (CMAMMA). This rare metabolic disorder underscores the importance of malonyl-CoA biosynthesis in mitochondrial function and human health.
From malonyl-CoA biosynthetic process-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does ACC isoform specifically regulate gluconeogenesis? | Liver-specific ACC knockout mice or CRISPR knockout in HepG2 cells |
| How does malonyl-CoA binding to CPT1 affect fatty acid oxidation? | Point mutations in CPT1A at malonyl-CoA binding site; knock-in mice |
| What is the role of ACSF3 in mitochondrial metabolism? | ACSF3 knockout cell lines; rescue with wild-type or mutant ACSF3 |
| Can malonyl-CoA levels be monitored in live cells? | Knock-in of fluorescent malonyl-CoA biosensor; overexpression of ACC |
| Does FASN-derived malonyl-CoA regulate STING signaling? | Macrophage-specific FASN knockout; STING palmitoylation mutants |
| What genes enhance malonyl-CoA anabolism? | CRISPR library screening; ReaL-MGE multiplex engineering |
How to Study the malonyl-CoA biosynthetic process Process
| Method | What It Measures | Typical Application |
|---|---|---|
| LC-MS metabolomics | Malonyl-CoA concentration | Quantify changes in cells or tissues |
| 13C isotope tracing | Flux through malonyl-CoA synthesis | Assess pathway activity |
| CRISPR knockout library screening | Genes affecting malonyl-CoA levels | Identify novel regulators |
| Western blot | Protein expression of ACC, FASN, ACSF3 | Validate knockout or overexpression |
| Co-immunoprecipitation | Protein interactions | Study ACC complex formation |
| Fluorescent biosensor imaging | Real-time malonyl-CoA dynamics | Live-cell monitoring |
| Palmitoylation assays | STING palmitoylation | Link malonyl-CoA to immune signaling |
| Seahorse assay | Fatty acid oxidation | Measure CPT1 activity |
Metabolomics and Flux Analysis
Mass spectrometry-based metabolomics allows direct measurement of malonyl-CoA levels in cells and tissues. Stable isotope tracing with 13C-labeled substrates can quantify flux through the malonyl-CoA biosynthetic process. These methods are essential for understanding how genetic or pharmacological interventions alter malonyl-CoA production.
Genetic Screens and CRISPR Libraries
CRISPR knockout libraries can be used to identify genes that regulate malonyl-CoA levels. For example, ReaL-MGE is a tool for enhanced multiplex genome engineering and has been applied to malonyl-CoA anabolism. Such screens can uncover novel regulators and therapeutic targets.
Protein-Protein Interaction and Modification Studies
Co-immunoprecipitation, proximity labeling, and mass spectrometry can identify proteins that interact with ACC, FASN, or ACSF3. Palmitoylation of STING by malonyl-CoA-derived lipids can be studied using click chemistry or acyl-biotin exchange assays.
Imaging and Biosensors
Genetically encoded fluorescent biosensors for malonyl-CoA enable real-time monitoring of its dynamics in living cells. These tools can be combined with CRISPR knock-in to tag endogenous enzymes or to express biosensors under specific promoters.
How CRISPR Can Be Used to Study GO:2001295 malonyl-CoA biosynthetic process
Knockout
CRISPR knockout of ACACA, ACACB, or FASN can abolish malonyl-CoA biosynthesis, leading to reduced lipogenesis and increased fatty acid oxidation. Such models are valuable for studying the role of malonyl-CoA in cancer, metabolic diseases, and immune responses [1,2,4].
Point Mutation
Point mutations can be introduced into ACC to mimic phosphorylation sites or alter catalytic activity. Similarly, mutations in CPT1A at the malonyl-CoA binding site can disrupt regulation of fatty acid oxidation. These models help dissect specific regulatory mechanisms.
Knock-in
Knock-in of tagged ACC or ACSF3 allows for affinity purification and interaction studies. Knock-in of fluorescent biosensors enables real-time monitoring of malonyl-CoA levels. Additionally, knock-in of disease-associated mutations can model rare metabolic disorders.
Overexpression
Overexpression of ACC or FASN increases malonyl-CoA production and lipogenesis, which can drive cancer cell proliferation or alter immune cell function. Overexpression models are useful for studying the consequences of malonyl-CoA accumulation [2,4].
How EDITGENE Supports malonyl-CoA biosynthetic process Research
Researchers studying malonyl-CoA biosynthetic process-related genes often need to determine whether a candidate gene is causally involved in metabolite production, metabolic regulation, or disease progression. EDITGENE provides comprehensive CRISPR services to create precisely engineered cell models for such investigations.
Contact EDITGENE today to design your custom CRISPR model for malonyl-CoA biosynthetic process research.
Frequently Asked Questions About malonyl-CoA biosynthetic process
What is malonyl-CoA biosynthetic process?
It is the set of biochemical reactions that produce malonyl-CoA, the S-malonyl derivative of coenzyme A, as defined by GO:2001295.
What genes are involved in malonyl-CoA biosynthetic process?
Key genes include ACACA, ACACB, FASN, ACSF3, and MLYCD, which encode enzymes that synthesize or degrade malonyl-CoA [1,4,6].
How is malonyl-CoA synthesized?
Malonyl-CoA is primarily synthesized by acetyl-CoA carboxylase (ACC) from acetyl-CoA and bicarbonate, and alternatively by ACSF3 from malonate and CoA [1,6].
What is the role of malonyl-CoA in fatty acid oxidation?
Malonyl-CoA inhibits CPT1, preventing fatty acid entry into mitochondria and thus reducing fatty acid oxidation.
Why is malonyl-CoA important in cancer?
Malonyl-CoA promotes lipogenesis and activates Ran, contributing to prostate cancer progression and castration resistance.
How does malonyl-CoA affect gluconeogenesis?
Hepatic malonyl-CoA synthesis restrains gluconeogenesis by suppressing fat oxidation, pyruvate carboxylation, and amino acid availability.
What diseases are associated with malonyl-CoA dysregulation?
Cancer, insulin resistance, sepsis-induced liver injury, and combined malonic and methylmalonic aciduria are linked to malonyl-CoA metabolism [2,4,6,7].
What methods are used to study malonyl-CoA biosynthesis?
LC-MS metabolomics, isotope tracing, CRISPR screens, and fluorescent biosensors are commonly used [1,3,5].
Can CRISPR be used to study malonyl-CoA biosynthesis?
Yes, CRISPR knockout, knock-in, and overexpression models enable precise manipulation of genes like ACACA, FASN, and ACSF3.
What is the GO ID for malonyl-CoA biosynthetic process?
The Gene Ontology ID is GO:2001295.
Conclusion
The malonyl-CoA biosynthetic process (GO:2001295) is a central metabolic pathway with profound implications for energy homeostasis, cancer, immunity, and metabolic diseases. Understanding its regulation and function requires precise genetic tools. EDITGENE provides comprehensive CRISPR services to create knockout, point mutation, knock-in, and overexpression models, as well as library screening and bioinformatics support. By leveraging these services, researchers can accelerate discoveries in malonyl-CoA biology and develop novel therapeutic strategies.
References
- 1. Deja S et al.. 2024. Hepatic malonyl-CoA synthesis restrains gluconeogenesis by suppressing fat oxidation, pyruvate carboxylation, and amino acid availability.. Cell Metab 36(5):1088-1104.e12 PMID: 38447582
- 2. Dai Y et al.. 2025. Malonyl-CoA Promotes Prostate Cancer Progression and Castration Resistance by Enhancing Lipogenesis and Ran Activation.. Cancer Res 85(22):4504-4520 PMID: 40865048
- 3. Ngo J et al.. 2023. Mitochondrial morphology controls fatty acid utilization by changing CPT1 sensitivity to malonyl-CoA.. EMBO J 42(11):e111901 PMID: 36917141
- 4. Kang J et al.. 2024. FASN regulates STING palmitoylation via malonyl-CoA in macrophages to alleviate sepsis-induced liver injury.. Biochim Biophys Acta Mol Basis Dis 1870(7):167299 PMID: 38878833
- 5. Zheng W et al.. 2024. ReaL-MGE is a tool for enhanced multiplex genome engineering and application to malonyl-CoA anabolism.. Nat Commun 15(1):9790 PMID: 39532871
- 6. Bowman CE et al.. 2019. Role of the malonyl-CoA synthetase ACSF3 in mitochondrial metabolism.. Adv Biol Regul 71:34-40 PMID: 30201289
- 7. Ruderman NB et al.. 1999. Malonyl-CoA, fuel sensing, and insulin resistance.. Am J Physiol 276(1):E1-E18 PMID: 9886945
