GO:0006637 acyl-CoA metabolic process: Metabolic Hub, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0006637 acyl-CoA metabolic process describes all chemical reactions and pathways involving acyl-CoA, a derivative of coenzyme A in which the sulfhydryl group is in thiolester linkage with an acyl group.
• Acyl-CoA metabolism is compartmentalised across cytosol, mitochondria, peroxisomes, endoplasmic reticulum and nucleus, and this spatial organisation determines whether acyl-CoA is used for energy production, membrane synthesis, protein modification or signalling [1,2].
• Acyl-CoA synthetases (ACSL, SLC27A, ACSS) activate fatty acids to acyl-CoA and thereby control substrate availability for beta-oxidation, lipid synthesis and phospholipid acyl-chain diversity [3,4,8].
• Acyl-CoA levels regulate chromatin by supplying acetyl-CoA and other short-chain acyl-CoAs to histone acetyltransferases and other lysine acyltransferases [1,6].
• Ischemia and metabolic stress alter acyl-CoA metabolism, promoting dephosphorylation of acyl-CoAs and accumulation of propionyl-CoA, which can affect mitochondrial and chromatin function.
• CRISPR knockout, point-mutation, knock-in and overexpression cell models are powerful tools to dissect causal roles of acyl-CoA metabolic genes in disease and metabolism [1,4].
Description
Acyl-CoA metabolic process (GO:0006637) is the set of chemical reactions and pathways involving acyl-CoA, any derivative of coenzyme A in which the sulfhydryl group is in thiolester linkage with an acyl group. Acyl-CoA species are central intermediates at the crossroads of fatty acid oxidation, lipid biosynthesis, amino acid catabolism and protein acylation, and their levels and subcellular distribution are tightly controlled [1,4]. Because acyl-CoAs are both metabolic substrates and signalling molecules, researchers across cancer biology, neuroscience, immunology and chromatin biology need to understand how this process is organised and regulated [1,2,6]. Recent work has shown that acyl-CoA metabolism is not a single uniform pool but is compartmentalised, with distinct pools in cytosol, mitochondria, peroxisomes, endoplasmic reticulum and nucleus [1,2]. Quantitative subcellular analysis has revealed distinct nuclear acyl-CoA metabolism and isoleucine-dependent histone propionylation, linking nutrient availability to chromatin modification. Acyl-CoA synthetases activate fatty acids to acyl-CoAs and thereby determine whether fatty acids are directed toward oxidation, storage or membrane synthesis [3,4,8]. For researchers, GO:0006637 provides a framework to interpret how genetic and pharmacological perturbations of acyl-CoA enzymes affect cellular metabolism, gene expression and disease phenotypes [1,4,5]. This article summarises the definition, mechanism, key genes, regulation, disease links and experimental methods for studying acyl-CoA metabolic process, with a focus on CRISPR-based models and functional genomics.
acyl-CoA metabolic process At A Glance
| GO ID | GO:0006637 |
|---|---|
| GO term | acyl-CoA metabolic process |
| Ontology | biological_process |
| Synonym | acyl-CoA metabolism |
| Definition | The chemical reactions and pathways involving acyl-CoA, any derivative of coenzyme A in which the sulfhydryl group is in thiolester linkage with an acyl group. |
| Major function | Synthesis, interconversion, transport and utilisation of acyl-CoA thioesters for energy production, lipid synthesis, amino acid catabolism and protein acylation. |
| Subcellular locations | Cytosol, mitochondria, peroxisomes, endoplasmic reticulum and nucleus [1,2]. |
| Key enzyme families | Acyl-CoA synthetases (ACSL, SLC27A, ACSS), acyl-CoA thioesterases, carnitine acyltransferases and acyltransferases [3,4,8]. |
| Related processes | Fatty acid beta-oxidation, lipid biosynthesis, histone acetylation and other lysine acylation reactions [1,6]. |
What Is GO:0006637?
GO:0006637 acyl-CoA metabolic process is defined as the chemical reactions and pathways involving acyl-CoA, any derivative of coenzyme A in which the sulfhydryl group is in thiolester linkage with an acyl group. In practice, this term covers the synthesis, interconversion, transport, utilisation and turnover of acyl-CoA species, including their roles in fatty acid oxidation, lipid synthesis, amino acid catabolism and protein acylation [1,4].
Why Is acyl-CoA metabolic process Important in Cell Biology?
Acyl-CoA metabolic process is important because acyl-CoAs are obligatory intermediates in fatty acid oxidation and lipid synthesis and also serve as substrates for protein acylation, thereby connecting nutrient metabolism to gene regulation and disease [1,4,6]. Perturbations in acyl-CoA metabolism have been linked to metabolic disorders, cancer, neurodegeneration and ischemia-related injury, making this process a major focus for both mechanistic and translational research [1,2,7,8].
• Acyl-CoAs are central intermediates in fatty acid beta-oxidation and lipid biosynthesis, determining cellular energy balance and membrane composition.
• Acyl-CoA synthetases control substrate availability for oxidation, storage and phospholipid acyl-chain diversity, with tissue-specific regulation [3,4,5,8].
• Short-chain acyl-CoAs such as acetyl-CoA and propionyl-CoA are substrates for histone acetyltransferases and other lysine acyltransferases, linking metabolism to chromatin [1,6].
• Compartmentalised acyl-CoA pools allow distinct metabolic and signalling functions in cytosol, mitochondria, peroxisomes, ER and nucleus [1,2].
• Ischemia and metabolic stress alter acyl-CoA metabolism, promoting propionyl-CoA accumulation and acyl-CoA dephosphorylation.
• Acyl-CoA metabolism is relevant to cancer, neurodegeneration, metabolic syndrome and ischemia-reperfusion injury [1,2,7,8].
• Acyl-CoA synthetases are potential therapeutic targets and biomarkers in brain and metabolic diseases [3,8].
• CRISPR screens and knockout models enable causal testing of acyl-CoA metabolic genes in disease phenotypes [1,4].
What Happens During acyl-CoA metabolic process?
Activation of fatty acids to acyl-CoA
In simple terms: Fatty acids are first switched on by attaching them to coenzyme A, forming acyl-CoA.
The first step in acyl-CoA metabolism is the activation of fatty acids to acyl-CoA thioesters, catalysed by acyl-CoA synthetases such as ACSL and SLC27A family members [3,4,8]. This reaction consumes ATP and produces acyl-CoA, which can then enter beta-oxidation, lipid synthesis or other pathways. Different acyl-CoA synthetases show distinct substrate preferences and tissue distributions, contributing to acyl-chain diversity in phospholipids and other lipids [3,8].
Compartmentalisation of acyl-CoA pools
In simple terms: Acyl-CoAs are kept in separate cellular compartments so they can do different jobs.
Acyl-CoA metabolism is compartmentalised across cytosol, mitochondria, peroxisomes, endoplasmic reticulum and nucleus [1,2]. Quantitative subcellular analysis has revealed distinct nuclear acyl-CoA metabolism and isoleucine-dependent histone propionylation, indicating that nuclear acyl-CoA pools can be regulated independently of cytosolic pools. This compartmentalisation allows acyl-CoAs to serve distinct functions, such as mitochondrial beta-oxidation, ER lipid synthesis and nuclear protein acylation [1,2].
Utilisation in beta-oxidation and lipid synthesis
In simple terms: Acyl-CoAs are burned for energy or used as building blocks for lipids.
Acyl-CoAs are substrates for mitochondrial and peroxisomal beta-oxidation, which generates acetyl-CoA and reducing equivalents for energy production. They are also used for the synthesis of triglycerides, phospholipids and other complex lipids, with acyl-CoA synthetases regulating acyl-chain diversity in brain phospholipids [3,8]. The balance between oxidation and lipid synthesis is controlled by acyl-CoA availability and by tissue-specific regulation of acyl-CoA metabolism [4,5].
Acyl-CoA turnover and thioesterase activity
In simple terms: Acyl-CoAs can be broken down by thioesterases to free fatty acids and coenzyme A.
Acyl-CoA levels are also controlled by acyl-CoA thioesterases, which hydrolyse acyl-CoAs to free fatty acids and coenzyme A, and by carnitine acyltransferases that convert acyl-CoAs to acylcarnitines for transport. Ischemia has been shown to promote acyl-CoA dephosphorylation and propionyl-CoA accumulation, indicating that stress conditions can alter acyl-CoA turnover. These turnover mechanisms help maintain appropriate acyl-CoA pools for metabolic and signalling functions [4,7].
Acyl-CoA as substrates for protein acylation
In simple terms: Acyl-CoAs donate acyl groups to proteins, modifying their function.
Short-chain acyl-CoAs such as acetyl-CoA and propionyl-CoA serve as cofactors for histone acetyltransferases and other lysine acyltransferases, thereby linking acyl-CoA metabolism to chromatin regulation [1,6]. Metabolic regulation of histone acetyltransferases by endogenous acyl-CoA cofactors has been demonstrated, showing that changes in acyl-CoA levels can directly affect gene expression. Nuclear acyl-CoA metabolism and isoleucine-dependent histone propionylation further highlight the connection between acyl-CoA metabolism and epigenetic regulation.
Key Genes Involved in GO:0006637 acyl-CoA metabolic process
The following genes and protein families are central to acyl-CoA metabolic process, based on published literature on acyl-CoA synthetases, thioesterases, acyltransferases and related enzymes [1,3,4,8].
| Gene | Major Role | Research Relevance |
|---|---|---|
| ACSL1 | Acyl-CoA synthetase that activates long-chain fatty acids to acyl-CoA | Key regulator of fatty acid oxidation and lipid synthesis; target for metabolic studies [4,8] |
| ACSL3 | Acyl-CoA synthetase involved in lipid synthesis and phospholipid acyl-chain diversity | Linked to brain phospholipid diversity and lipid signalling |
| ACSL4 | Acyl-CoA synthetase that activates arachidonic acid and other polyunsaturated fatty acids | Implicated in ferroptosis and lipid metabolism; studied in cancer and neurodegeneration |
| ACSL6 | Acyl-CoA synthetase enriched in brain and involved in phospholipid synthesis | Important for brain acyl-chain diversity and neuronal function |
| SLC27A1 | Fatty acid transport protein with acyl-CoA synthetase activity | Regulates fatty acid uptake and acyl-CoA formation in metabolic tissues |
| SLC27A2 | Peroxisomal acyl-CoA synthetase for very-long-chain fatty acids | Peroxisomal acyl-CoA metabolism and fatty acid oxidation |
| SLC27A4 | Acyl-CoA synthetase involved in epidermal lipid metabolism | Studied in skin barrier function and lipid metabolism |
| ACSS1 | Mitochondrial acetyl-CoA synthetase that activates acetate to acetyl-CoA | Links acetate metabolism to mitochondrial acetyl-CoA pools |
| ACSS2 | Cytosolic/nuclear acetyl-CoA synthetase that activates acetate to acetyl-CoA | Supplies acetyl-CoA for histone acetylation and lipid synthesis; cancer relevance [1,6] |
| ACOT1 | Acyl-CoA thioesterase that hydrolyses acyl-CoAs | Regulates acyl-CoA turnover and lipid metabolism |
| ACOT2 | Mitochondrial acyl-CoA thioesterase | Controls mitochondrial acyl-CoA levels and beta-oxidation |
| CPT1A | Carnitine palmitoyltransferase 1A that converts acyl-CoA to acylcarnitine | Rate-limiting step for mitochondrial fatty acid oxidation |
| CPT2 | Carnitine palmitoyltransferase 2 that regenerates acyl-CoA in mitochondria | Defects cause fatty acid oxidation disorders |
| HADHA | Mitochondrial trifunctional protein subunit involved in beta-oxidation | Catalyses acyl-CoA dehydrogenation and hydration steps |
| ACADM | Medium-chain acyl-CoA dehydrogenase | Defects cause MCAD deficiency; model for acyl-CoA oxidation disorders |
| ACAT1 | Acetyl-CoA acetyltransferase that converts acetoacetyl-CoA to acetyl-CoA | Involved in ketone body metabolism and acyl-CoA interconversion |
| HAT1 | Histone acetyltransferase that uses acetyl-CoA | Links acyl-CoA metabolism to chromatin modification |
| EP300 | Histone acetyltransferase that uses acetyl-CoA as cofactor | Metabolic regulation of chromatin by acyl-CoA levels |
How Is acyl-CoA metabolic process Regulated?
Acyl-CoA metabolic process is regulated at multiple levels, including transcriptional control of acyl-CoA synthetases and thioesterases, post-translational modification of enzymes, and allosteric regulation by acyl-CoA intermediates [4,5]. Tissue-specific regulation of acyl-CoA metabolism has been demonstrated, with different tissues showing distinct acyl-CoA profiles and enzyme expression patterns. Metabolic stress such as ischemia can alter acyl-CoA metabolism by promoting dephosphorylation of acyl-CoAs and accumulation of propionyl-CoA. In addition, acyl-CoA levels regulate histone acetyltransferases, providing a feedback mechanism linking metabolism to chromatin.
acyl-CoA metabolic process and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| ACSL4 | Cancer and ferroptosis-related lipid metabolism | Knockout and point-mutation cell models to test acyl-CoA substrate specificity |
| ACSS2 | Cancer metabolism and histone acetylation | Knockout and overexpression models to study acetyl-CoA supply for chromatin [1,6] |
| SLC27A2 | Peroxisomal disorders and very-long-chain fatty acid metabolism | Knockout models to assess peroxisomal acyl-CoA metabolism |
| ACADM | Medium-chain acyl-CoA dehydrogenase deficiency | Point-mutation knock-in models to study fatty acid oxidation disorders |
| CPT2 | Carnitine palmitoyltransferase II deficiency | Knockout and knock-in models to study mitochondrial acyl-CoA transport |
Acyl-CoA metabolism in cancer
Acyl-CoA metabolism supports cancer cell growth by supplying substrates for lipid synthesis and energy production, and by providing acetyl-CoA for histone acetylation and gene expression [1,6]. Acyl-CoA synthetases such as ACSL4 and ACSS2 have been implicated in cancer metabolism, and targeting acyl-CoA metabolism is an active area of therapeutic research [1,4]. Metabolic regulation of histone acetyltransferases by endogenous acyl-CoA cofactors suggests that acyl-CoA levels can directly influence oncogenic gene expression programs.
Acyl-CoA metabolism in neurodegeneration and brain disorders
Acyl-CoA synthetases regulate brain phospholipid acyl-chain diversity, and their dysfunction has been linked to neurological disorders. Peroxisomal acyl-CoA synthetases are essential for very-long-chain fatty acid metabolism, and defects in peroxisomal acyl-CoA metabolism cause peroxisomal disorders with neurological symptoms. Brain-specific acyl-CoA synthetases such as ACSL6 contribute to phospholipid diversity and neuronal function, making them relevant to neurodegeneration research.
Acyl-CoA metabolism in ischemia and metabolic stress
Ischemia promotes acyl-CoA dephosphorylation and propionyl-CoA accumulation, indicating that acyl-CoA metabolism is sensitive to oxygen and nutrient availability. These changes can affect mitochondrial function and chromatin modification, contributing to ischemia-reperfusion injury. Understanding how acyl-CoA metabolism responds to stress may reveal therapeutic targets for ischemic diseases.
Acyl-CoA metabolism in inherited metabolic disorders
Defects in acyl-CoA dehydrogenases and carnitine acyltransferases cause inherited fatty acid oxidation disorders, such as MCAD deficiency and CPT2 deficiency. These disorders highlight the importance of acyl-CoA metabolism for energy homeostasis, especially during fasting. Acyl-CoA synthetase deficiencies can also affect lipid metabolism and membrane composition [3,4].
From acyl-CoA metabolic process-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of an acyl-CoA synthetase alter acyl-CoA pools and lipid composition? | CRISPR knockout cell model |
| Does a specific point mutation in an acyl-CoA enzyme affect substrate specificity? | Point-mutation knock-in cell model |
| Can a disease-associated variant be rescued by wild-type enzyme? | Knock-in of wild-type or mutant cDNA |
| Where is an acyl-CoA enzyme localised within the cell? | Tagged knock-in with fluorescent or affinity tag [1,2] |
| Does overexpression of an acyl-CoA enzyme increase histone acetylation? | Overexpression cell model |
| Which acyl-CoA metabolic genes are essential for cancer cell growth? | CRISPR library screening [1,4] |
How to Study the acyl-CoA metabolic process Process
| Method | What It Measures | Typical Application |
|---|---|---|
| LC-MS metabolomics | Acyl-CoA species and related metabolites | Profiling acyl-CoA pools in cells and tissues [4,5] |
| Subcellular fractionation plus LC-MS | Compartment-specific acyl-CoA levels | Nuclear vs cytosolic acyl-CoA metabolism |
| Lipidomics | Phospholipid and triglyceride acyl-chain composition | Acyl-CoA synthetase function in lipid synthesis [3,8] |
| Histone acylation immunoblotting | Histone acetylation and propionylation | Linking acyl-CoA to chromatin [1,6] |
| CRISPR knockout screening | Gene essentiality and metabolic dependencies | Identifying acyl-CoA metabolic genes in cancer [1,4] |
| RNA-seq | Transcriptional responses to acyl-CoA perturbation | Pathway analysis and biomarker discovery [1,4] |
| Fluorescent tagging and imaging | Subcellular localisation of acyl-CoA enzymes | Validating compartmentalisation [1,2] |
| Seahorse respirometry | Mitochondrial oxidation of acyl-CoA substrates | Functional assessment of beta-oxidation |
Quantitative subcellular acyl-CoA analysis
Quantitative subcellular acyl-CoA analysis using mass spectrometry can measure acyl-CoA species in isolated organelles or subcellular fractions, revealing distinct nuclear metabolism and isoleucine-dependent histone propionylation. This method is essential for understanding compartmentalised acyl-CoA pools [1,2].
Metabolomics and lipidomics
Metabolomics and lipidomics can profile acyl-CoA species and their downstream lipid products, providing a systems-level view of acyl-CoA metabolism [4,5]. These approaches are used to compare wild-type and mutant cells and to identify metabolic vulnerabilities.
Chromatin and histone acylation assays
Chromatin immunoprecipitation and histone acylation assays can measure how acyl-CoA levels affect histone acetylation and other acylations [1,6]. Metabolic regulation of histone acetyltransferases by endogenous acyl-CoA cofactors can be studied by manipulating acyl-CoA supply.
CRISPR screening and functional genomics
CRISPR library screening can identify acyl-CoA metabolic genes required for cell growth, survival or drug resistance [1,4]. Combined with metabolomics and transcriptomics, these screens provide causal insights into acyl-CoA metabolism in disease [1,4].
How CRISPR Can Be Used to Study GO:0006637 acyl-CoA metabolic process
Knockout
CRISPR knockout of acyl-CoA metabolic genes such as ACSL4, ACSS2 or CPT1A can reveal their roles in acyl-CoA pools, lipid composition and cell growth [1,4]. Knockout models are used to test whether a gene is required for beta-oxidation, lipid synthesis or histone acetylation [4,6].
Point Mutation
Point-mutation knock-in can model disease-associated variants in acyl-CoA enzymes and test their effects on substrate specificity, catalytic activity and cellular metabolism. These models are valuable for understanding inherited fatty acid oxidation disorders.
Knock-in
Knock-in of tagged or reporter constructs allows visualisation and affinity purification of acyl-CoA enzymes, enabling subcellular localisation and interaction studies [1,2]. Knock-in of wild-type or mutant cDNA can rescue or exacerbate phenotypes in knockout backgrounds.
Overexpression
Overexpression of acyl-CoA synthetases or thioesterases can increase or decrease acyl-CoA levels and test downstream effects on histone acetylation, lipid synthesis and cell proliferation. Overexpression models are useful for gain-of-function studies and drug target validation [1,6].
How EDITGENE Supports acyl-CoA metabolic process Research
Researchers studying acyl-CoA metabolic process-related genes often need to determine whether a candidate gene is causally involved in metabolic, chromatin or disease phenotypes. EDITGENE provides CRISPR-based cell model services that enable precise knockout, point-mutation, knock-in and overexpression of acyl-CoA metabolic genes, combined with library screening and bioinformatics to accelerate functional discovery [1,4].
Contact EDITGENE today to design your custom CRISPR model for acyl-CoA metabolic process research.
Frequently Asked Questions About acyl-CoA metabolic process
What is acyl-CoA metabolic process?
Acyl-CoA metabolic process (GO:0006637) is the set of chemical reactions and pathways involving acyl-CoA, any derivative of coenzyme A in which the sulfhydryl group is in thiolester linkage with an acyl group.
What genes are involved in acyl-CoA metabolic process?
Key genes include acyl-CoA synthetases such as ACSL1, ACSL3, ACSL4, ACSL6, SLC27A1, SLC27A2, SLC27A4, ACSS1 and ACSS2, as well as thioesterases, carnitine acyltransferases and acyl-CoA dehydrogenases [3,4,8].
Why is acyl-CoA metabolism important for chromatin?
Short-chain acyl-CoAs such as acetyl-CoA and propionyl-CoA are substrates for histone acetyltransferases and other lysine acyltransferases, linking acyl-CoA metabolism to chromatin regulation [1,6].
How is acyl-CoA metabolism compartmentalised?
Acyl-CoA metabolism occurs in cytosol, mitochondria, peroxisomes, endoplasmic reticulum and nucleus, with distinct pools that can be regulated independently [1,2].
What diseases are linked to acyl-CoA metabolism?
Acyl-CoA metabolism has been linked to cancer, neurodegeneration, peroxisomal disorders, inherited fatty acid oxidation disorders and ischemia-reperfusion injury [1,2,3,4,7,8].
How can I study acyl-CoA metabolic process in the lab?
Common methods include LC-MS metabolomics, subcellular fractionation, lipidomics, histone acylation assays, CRISPR knockout screening and RNA-seq [1,2,4,6].
What is the role of acyl-CoA synthetases?
Acyl-CoA synthetases activate fatty acids to acyl-CoA, controlling substrate availability for beta-oxidation, lipid synthesis and phospholipid acyl-chain diversity [3,4,8].
How does ischemia affect acyl-CoA metabolism?
Ischemia promotes acyl-CoA dephosphorylation and propionyl-CoA accumulation, which can affect mitochondrial and chromatin function.
Can CRISPR be used to study acyl-CoA metabolism?
Yes, CRISPR knockout, point-mutation, knock-in and overexpression models are widely used to dissect causal roles of acyl-CoA metabolic genes [1,4].
What is the GO ID for acyl-CoA metabolic process?
The GO ID for acyl-CoA metabolic process is GO:0006637.
Conclusion
GO:0006637 acyl-CoA metabolic process is a central biological process that connects fatty acid metabolism, energy production, lipid synthesis and protein acylation. Its compartmentalised nature and regulation by nutrient and stress signals make it a rich area for mechanistic and translational research [1,2,4,7]. CRISPR-based cell models, combined with metabolomics, lipidomics and chromatin assays, provide powerful tools to dissect the causal roles of acyl-CoA metabolic genes in health and disease [1,4,6]. EDITGENE offers comprehensive services to support these studies, from knockout and knock-in models to library screening and bioinformatics.
References
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- 2. Trefely S et al.. 2022. Quantitative subcellular acyl-CoA analysis reveals distinct nuclear metabolism and isoleucine-dependent histone propionylation.. Mol Cell 82(2):447-462.e6 PMID: 34856123
- 3. Watkins PA et al.. 2012. Peroxisomal acyl-CoA synthetases.. Biochim Biophys Acta 1822(9):1411-20 PMID: 22366061
- 4. Grevengoed TJ et al.. 2014. Acyl-CoA metabolism and partitioning.. Annu Rev Nutr 34:1-30 PMID: 24819326
- 5. Ellis JM et al.. 2015. Metabolic and tissue-specific regulation of acyl-CoA metabolism.. PLoS One 10(3):e0116587 PMID: 25760036
- 6. Montgomery DC et al.. 2015. Metabolic Regulation of Histone Acetyltransferases by Endogenous Acyl-CoA Cofactors.. Chem Biol 22(8):1030-1039 PMID: 26190825
- 7. He W et al.. 2023. Ischemia promotes acyl-CoAs dephosphorylation and propionyl-CoA accumulation.. Metabolomics 19(2):12 PMID: 36750484
- 8. Fernandez RF et al.. 2020. Acyl-CoA synthetases as regulators of brain phospholipid acyl-chain diversity.. Prostaglandins Leukot Essent Fatty Acids 161:102175 PMID: 33031993
