GO:1902860 propionyl-CoA biosynthetic process: Metabolic Pathway, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:1902860 (propionyl-CoA biosynthetic process) describes the chemical reactions and pathways that produce propionyl-CoA, a short-chain acyl-CoA intermediate central to odd-chain fatty acid synthesis, branched-chain amino acid catabolism, and histone propionylation.
• Propionyl-CoA is generated from multiple sources including isoleucine, valine, methionine, threonine, and odd-chain fatty acids, and its biosynthesis is compartmentalized between mitochondria and the nucleus.
• Defects in propionyl-CoA metabolism cause propionic acidemia, a severe inherited metabolic disorder with multi-organ complications.
• Altered propionyl-CoA biosynthesis and degradation are implicated in hepatocellular carcinoma, where decreased propionyl-CoA metabolism supports metabolic reprogramming.
• Propionyl-CoA serves as a substrate for histone propionylation, linking metabolic state to chromatin regulation and gene expression.
• CRISPR-based models (knockout, point mutation, knock-in, overexpression) are essential for dissecting the enzymatic steps and regulatory nodes of propionyl-CoA biosynthesis.
Description
Propionyl-CoA biosynthetic process (GO:1902860) is defined as the chemical reactions and pathways resulting in the formation of propionyl-CoA, a short-chain acyl-coenzyme A thioester. Propionyl-CoA is a key metabolic intermediate produced during the catabolism of branched-chain amino acids (isoleucine, valine), methionine, threonine, and odd-chain fatty acids, as well as from propionate via the propionyl-CoA synthetase reaction. This process is essential for maintaining cellular acyl-CoA pools and for fueling downstream pathways such as the methylcitrate cycle and odd-chain fatty acid synthesis. Researchers study GO:1902860 because propionyl-CoA sits at the intersection of energy metabolism, epigenetic regulation, and disease. Its biosynthesis is compartmentalized: mitochondrial propionyl-CoA is primarily generated from amino acid catabolism, while nuclear propionyl-CoA can be produced locally to support histone propionylation. Disruptions in propionyl-CoA homeostasis lead to propionic acidemia, a life-threatening metabolic disorder, and have been linked to cancer metabolic reprogramming. Understanding the enzymes, regulation, and subcellular dynamics of propionyl-CoA biosynthesis is therefore critical for both fundamental cell biology and therapeutic development.
propionyl-CoA biosynthetic process At A Glance
| GO ID | GO:1902860 |
|---|---|
| GO term | propionyl-CoA biosynthetic process |
| Ontology | biological_process |
| Synonym | propionyl-CoA anabolism; propionyl-CoA biosynthesis; propionyl-CoA formation; propionyl-CoA synthesis |
| Major function | Production of propionyl-CoA from precursors such as propionate, branched-chain amino acids, and odd-chain fatty acids |
| Subcellular location | Mitochondrial matrix and nucleus (compartmentalized acyl-CoA pools) |
| Key enzymes | Propionyl-CoA carboxylase (PCCA/PCCB), methylmalonyl-CoA mutase (MUT), acyl-CoA synthetases (ACSS2/ACSS3), and thiolases |
| Related pathways | Branched-chain amino acid catabolism, odd-chain fatty acid synthesis, histone propionylation, methylcitrate cycle |
| Disease relevance | Propionic acidemia, hepatocellular carcinoma, metabolic reprogramming |
What Is GO:1902860?
GO:1902860 (propionyl-CoA biosynthetic process) is a biological process ontology term that encompasses the chemical reactions and pathways that lead to the formation of propionyl-CoA. This includes enzymatic steps such as the activation of propionate to propionyl-CoA, the oxidative decarboxylation of 2-methyl-3-oxopropanoyl-CoA, and the thiolytic cleavage of odd-chain fatty acyl-CoAs. The term is synonymous with propionyl-CoA anabolism, biosynthesis, formation, and synthesis. It is a child of acyl-CoA biosynthetic process and is distinct from propionyl-CoA catabolic process.
Why Is propionyl-CoA biosynthetic process Important in Cell Biology?
Propionyl-CoA biosynthetic process is fundamentally important because propionyl-CoA is a metabolic hub that connects amino acid catabolism, fatty acid metabolism, and epigenetic regulation. Its production must be tightly controlled to avoid accumulation of toxic metabolites, as seen in propionic acidemia where defective propionyl-CoA carboxylase leads to life-threatening acidosis and multi-organ complications. Beyond inherited disorders, propionyl-CoA biosynthesis supports cancer cell metabolic reprogramming; decreased propionyl-CoA metabolism has been shown to facilitate hepatocellular carcinoma progression. Additionally, propionyl-CoA serves as a substrate for histone propionylation, linking metabolic flux to chromatin state and gene expression. Thus, understanding GO:1902860 is essential for metabolic disease research, cancer biology, and epigenetics.
• Propionyl-CoA is a key intermediate in the catabolism of branched-chain amino acids (isoleucine, valine) and methionine, threonine, and odd-chain fatty acids.
• Defects in propionyl-CoA metabolism cause propionic acidemia, characterized by metabolic acidosis, hyperammonemia, and cardiomyopathy.
• Propionyl-CoA biosynthesis is compartmentalized, with distinct mitochondrial and nuclear pools that serve different functions.
• Nuclear propionyl-CoA is used for histone propionylation, influencing chromatin structure and gene expression.
• Altered propionyl-CoA metabolism promotes hepatocellular carcinoma by supporting metabolic reprogramming.
• Microbial production of odd-chain fatty acids relies on propionyl-CoA as a primer, with biotechnological applications.
• Propionyl-CoA can be generated from propionate by acyl-CoA synthetases, a step relevant to gut microbiome-host interactions.
• The process is regulated by substrate availability and enzyme expression, including propionyl-CoA carboxylase and methylmalonyl-CoA mutase.
• Research tools such as CRISPR knockout models are used to study the role of propionyl-CoA biosynthesis in disease.
• Targeting propionyl-CoA biosynthetic enzymes is a potential therapeutic strategy in metabolic disorders and cancer.
What Happens During propionyl-CoA biosynthetic process?
Precursor Supply from Amino Acid Catabolism
In simple terms: The body breaks down certain amino acids to make propionyl-CoA.
Propionyl-CoA biosynthesis begins with the catabolism of branched-chain amino acids (isoleucine, valine) and other amino acids (methionine, threonine). These pathways converge on propionyl-CoA as a terminal product. For example, isoleucine is converted to propionyl-CoA via a series of reactions including transamination, oxidative decarboxylation, and thiolytic cleavage. This mitochondrial process is essential for energy production and anaplerosis.
Activation of Propionate to Propionyl-CoA
In simple terms: Propionate, a short-chain fatty acid, is activated to propionyl-CoA by adding coenzyme A.
Propionate, derived from gut microbial fermentation or odd-chain fatty acid oxidation, is converted to propionyl-CoA by propionyl-CoA synthetase (ACSS3 in humans). This reaction requires ATP and CoA, forming a thioester bond. This step is critical for detoxifying propionate and channeling it into the TCA cycle via succinyl-CoA.
Beta-Oxidation of Odd-Chain Fatty Acids
In simple terms: Odd-chain fatty acids are broken down to release propionyl-CoA.
Odd-chain fatty acids undergo beta-oxidation, which yields propionyl-CoA as the final product instead of acetyl-CoA. This process occurs in mitochondria and requires acyl-CoA dehydrogenases and thiolases. The propionyl-CoA produced can then be carboxylated to methylmalonyl-CoA by propionyl-CoA carboxylase (PCC).
Compartmentalization and Nuclear Propionyl-CoA Generation
In simple terms: Propionyl-CoA is made in different parts of the cell, including the nucleus.
Recent studies have revealed that propionyl-CoA is not only mitochondrial but also present in the nucleus, where it is used for histone propionylation. Nuclear propionyl-CoA can be generated from isoleucine metabolism, and its levels are dynamically regulated. This compartmentalization allows propionyl-CoA to serve both metabolic and epigenetic functions.
Regulation of Propionyl-CoA Levels
In simple terms: The cell controls how much propionyl-CoA is made to avoid toxicity.
Propionyl-CoA levels are tightly regulated by the balance between biosynthesis and catabolism. Key enzymes include propionyl-CoA carboxylase (PCCA/PCCB), which converts propionyl-CoA to methylmalonyl-CoA, and methylmalonyl-CoA mutase (MUT), which converts it to succinyl-CoA. Deficiencies in these enzymes lead to propionyl-CoA accumulation and propionic acidemia. Additionally, post-translational modifications and substrate availability influence flux through the pathway.
Key Genes Involved in GO:1902860 propionyl-CoA biosynthetic process
The following genes encode enzymes and transporters directly involved in propionyl-CoA biosynthesis and its regulation.
| Gene | Major Role | Research Relevance |
|---|---|---|
| PCCA | Propionyl-CoA carboxylase alpha subunit; converts propionyl-CoA to methylmalonyl-CoA | Mutations cause propionic acidemia; target for metabolic studies |
| PCCB | Propionyl-CoA carboxylase beta subunit; catalytic component | Defects lead to propionic acidemia; CRISPR models available |
| MUT | Methylmalonyl-CoA mutase; converts methylmalonyl-CoA to succinyl-CoA | Mutations cause methylmalonic acidemia; linked to propionyl-CoA flux |
| ACSS3 | Acyl-CoA synthetase short-chain family member 3; activates propionate to propionyl-CoA | Regulates propionyl-CoA levels; potential target in cancer |
| ACSS2 | Acyl-CoA synthetase short-chain family member 2; nuclear acetyl-CoA/propionyl-CoA production | Involved in histone acylation and gene regulation |
| BCKDHA | Branched-chain alpha-keto acid dehydrogenase E1 alpha; catabolism of branched-chain amino acids | Provides precursors for propionyl-CoA; relevant to maple syrup urine disease |
| BCKDHB | Branched-chain alpha-keto acid dehydrogenase E1 beta | Similar to BCKDHA; affects propionyl-CoA supply |
| DBT | Dihydrolipoamide branched chain transacylase E2; BCKD complex | Mutations cause maple syrup urine disease; impacts propionyl-CoA |
| DLD | Dihydrolipoamide dehydrogenase; E3 component of BCKD | Links to oxidative metabolism; affects propionyl-CoA production |
| IVD | Isovaleryl-CoA dehydrogenase; leucine catabolism | Not directly propionyl-CoA but related acyl-CoA metabolism |
| ACADM | Medium-chain acyl-CoA dehydrogenase; fatty acid beta-oxidation | Odd-chain fatty acid oxidation yields propionyl-CoA |
| HADHA | Trifunctional enzyme subunit alpha; mitochondrial fatty acid oxidation | Contributes to propionyl-CoA from odd-chain fats |
| HADHB | Trifunctional enzyme subunit beta | Similar to HADHA |
| EP300 | Histone acetyltransferase p300; can propionylate histones using propionyl-CoA | Links propionyl-CoA to chromatin regulation |
| KAT5 | Histone acetyltransferase KAT5 (Tip60); uses acyl-CoAs including propionyl-CoA | Epigenetic reader of propionyl-CoA |
| KAT8 | Histone acetyltransferase KAT8 (MOF); acyltransferase activity | Potential propionyltransferase |
| HBO1 | Histone acetyltransferase HBO1 (KAT7); versatile acyltransferase | Promoter histone acylations including propionylation |
| SIRT1 | NAD-dependent deacetylase sirtuin-1; removes acyl modifications | Regulates propionylation dynamics |
How Is propionyl-CoA biosynthetic process Regulated?
Propionyl-CoA biosynthetic process is regulated at multiple levels. Substrate availability from amino acid catabolism and odd-chain fatty acid oxidation directly influences flux. Enzyme expression, particularly of PCCA, PCCB, and ACSS3, is controlled by metabolic transcription factors. Post-translational modifications and allosteric regulation of propionyl-CoA carboxylase by metabolites such as acetyl-CoA and succinyl-CoA modulate activity. Additionally, compartmentalization between mitochondria and nucleus provides spatial regulation, with nuclear propionyl-CoA production linked to isoleucine availability and histone propionylation. Hormonal signals and nutrient status, including insulin and glucagon, can affect branched-chain amino acid catabolism and thus propionyl-CoA supply.
propionyl-CoA biosynthetic process and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| PCCA | Propionic acidemia | CRISPR knockout in HepG2 or patient-derived fibroblasts; point mutation knock-in |
| PCCB | Propionic acidemia | Knockout in HEK293T; overexpression of wild-type vs mutant |
| MUT | Methylmalonic acidemia | Knockout in mouse liver; knock-in of patient mutations |
| ACSS3 | Hepatocellular carcinoma metabolic reprogramming | CRISPR knockout in HCC cell lines; overexpression |
| EP300 | Epigenetic regulation via histone propionylation | Knockout and tagged knock-in for ChIP-seq |
Propionic Acidemia
Propionic acidemia is an autosomal recessive disorder caused by mutations in PCCA or PCCB, leading to deficient propionyl-CoA carboxylase activity. This blocks the conversion of propionyl-CoA to methylmalonyl-CoA, causing accumulation of propionyl-CoA and its toxic metabolites. Clinical features include metabolic acidosis, hyperammonemia, cardiomyopathy, and developmental delay. Pathophysiological mechanisms involve mitochondrial dysfunction, oxidative stress, and impaired energy metabolism. Research models using CRISPR knockout of PCCA or PCCB in cell lines and animal models are essential for developing new therapies.
Hepatocellular Carcinoma
Decreased propionyl-CoA metabolism has been shown to facilitate metabolic reprogramming and promote hepatocellular carcinoma (HCC). In HCC cells, downregulation of propionyl-CoA carboxylase and methylmalonyl-CoA mutase leads to reduced flux through the propionyl-CoA pathway, which supports cancer cell proliferation and survival. Targeting propionyl-CoA biosynthesis may offer therapeutic opportunities.
Epigenetic Dysregulation and Cancer
Propionyl-CoA serves as a substrate for histone propionylation, a post-translational modification that influences chromatin structure and gene expression. Altered propionyl-CoA levels can lead to aberrant histone propionylation patterns, contributing to oncogenesis. Enzymes such as HBO1 and EP300 utilize propionyl-CoA, linking metabolic state to epigenetic regulation. This connection highlights the importance of propionyl-CoA biosynthesis in cancer biology and potential epigenetic therapies.
From propionyl-CoA biosynthetic process-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of PCCA reduce propionyl-CoA levels? | PCCA knockout cell line (e.g., HepG2) generated by CRISPR |
| Does a specific point mutation in PCCB affect enzyme activity? | PCCB point mutation knock-in via CRISPR |
| Can overexpression of ACSS3 increase propionyl-CoA production? | ACSS3 overexpression stable cell line |
| Where is propionyl-CoA produced in the cell? | Tagged knock-in of ACSS3 with fluorescent tag for live imaging |
| What genes are regulated by propionyl-CoA-mediated histone propionylation? | Knockout of EP300 or HBO1 followed by RNA-seq and ChIP-seq |
| Does propionyl-CoA biosynthesis affect cancer cell growth? | CRISPR library screening targeting metabolic genes in HCC cells |
How to Study the propionyl-CoA biosynthetic process Process
| Method | What It Measures | Typical Application |
|---|---|---|
| LC-MS metabolomics | Propionyl-CoA and related acyl-CoA levels | Subcellular quantification in knockout vs wild-type cells |
| CRISPR knockout screening | Gene essentiality and pathway dependencies | Identify regulators of propionyl-CoA biosynthesis |
| ChIP-seq | Histone propionylation and chromatin binding | Map epigenetic changes upon metabolic perturbation |
| RNA-seq | Transcriptional changes | Assess gene expression after PCCA/PCCB knockout |
| Enzyme activity assay | Propionyl-CoA carboxylase activity | Validate patient mutations and CRISPR models |
| Western blot | Protein expression and modification | Confirm knockout efficiency and pathway proteins |
| Immunofluorescence | Subcellular localization | Visualize propionyl-CoA enzymes in mitochondria/nucleus |
| Bioinformatics pathway analysis | Enriched metabolic pathways | Interpret CRISPR screen and metabolomics data |
Metabolomics and Acyl-CoA Profiling
Quantitative subcellular acyl-CoA analysis using liquid chromatography-mass spectrometry (LC-MS) allows measurement of propionyl-CoA levels in mitochondria and nucleus. This method reveals compartmentalized metabolism and isoleucine-dependent histone propionylation. Targeted metabolomics can assess flux through the propionyl-CoA biosynthetic pathway.
CRISPR Screening and Functional Genomics
Genome-wide CRISPR knockout screens can identify genes required for propionyl-CoA biosynthesis and its downstream effects. Libraries targeting metabolic enzymes, including PCCA, PCCB, and ACSS3, enable discovery of novel regulators. Bioinformatics analysis of screening data identifies enriched pathways and essential genes.
Chromatin Immunoprecipitation and Epigenomics
ChIP-seq for histone propionylation marks (e.g., H3K14pr) can map genomic regions affected by propionyl-CoA levels. Knockout of acyltransferases such as HBO1 or EP300 followed by ChIP-seq reveals their role in depositing propionyl marks. This links propionyl-CoA biosynthesis to gene expression programs.
Proteomics and Enzyme Activity Assays
Proteomic profiling of metabolic enzymes and activity assays for propionyl-CoA carboxylase and methylmalonyl-CoA mutase provide functional validation. Western blotting and immunoprecipitation can assess protein levels and interactions. These methods are used to characterize patient mutations and CRISPR models.
How CRISPR Can Be Used to Study GO:1902860 propionyl-CoA biosynthetic process
Knockout
CRISPR knockout of genes such as PCCA, PCCB, or ACSS3 creates cell models to study loss of propionyl-CoA biosynthesis. These models exhibit reduced propionyl-CoA levels and can be used to assess metabolic and epigenetic consequences. Knockout of PCCA in hepatocytes mimics propionic acidemia and is valuable for drug testing.
Point Mutation
Introducing specific patient mutations (e.g., in PCCB) via CRISPR point mutation allows study of enzyme dysfunction and genotype-phenotype correlations. These models help validate pathogenic variants and screen for pharmacological chaperones.
Knock-in
Knock-in of tagged versions of enzymes (e.g., ACSS3-FLAG) enables affinity purification and localization studies. Knock-in of reporter genes under endogenous promoters can track propionyl-CoA pathway activity in real time.
Overexpression
CRISPR-mediated overexpression (e.g., via CRISPRa) or lentiviral overexpression of ACSS3 or PCCA increases propionyl-CoA production. These models are used to study the effects of elevated propionyl-CoA on histone propionylation and cancer cell metabolism.
How EDITGENE Supports propionyl-CoA biosynthetic process Research
Researchers studying propionyl-CoA biosynthetic process-related genes often need to determine whether a candidate gene is causally involved in metabolic flux, disease progression, or epigenetic regulation. EDITGENE provides comprehensive CRISPR-based services to generate precisely engineered cell models, enabling functional validation of genes in the propionyl-CoA pathway.
Contact EDITGENE today to design your custom CRISPR model for propionyl-CoA biosynthetic process research.
Frequently Asked Questions About propionyl-CoA biosynthetic process
What is propionyl-CoA biosynthetic process?
Propionyl-CoA biosynthetic process (GO:1902860) is the set of chemical reactions and pathways that produce propionyl-CoA, a short-chain acyl-CoA intermediate derived from amino acid catabolism and odd-chain fatty acid oxidation.
What genes are involved in propionyl-CoA biosynthetic process?
Key genes include PCCA, PCCB, MUT, ACSS3, ACSS2, BCKDHA, BCKDHB, DBT, and DLD, which encode enzymes that generate or utilize propionyl-CoA.
What is the function of propionyl-CoA?
Propionyl-CoA serves as an intermediate in energy metabolism, a substrate for odd-chain fatty acid synthesis, and a donor for histone propionylation, linking metabolism to gene regulation.
How is propionyl-CoA produced in cells?
Propionyl-CoA is produced from propionate via acyl-CoA synthetases, from branched-chain amino acids through oxidative decarboxylation, and from odd-chain fatty acid beta-oxidation.
What diseases are associated with propionyl-CoA metabolism?
Defects cause propionic acidemia, and altered propionyl-CoA metabolism is implicated in hepatocellular carcinoma and epigenetic dysregulation.
What is the role of propionyl-CoA in histone modification?
Propionyl-CoA is used by histone acyltransferases such as EP300 and HBO1 to add propionyl groups to histones, influencing chromatin structure and gene expression.
How can I study propionyl-CoA biosynthetic process using CRISPR?
CRISPR knockout, point mutation, knock-in, and overexpression models can be used to manipulate genes like PCCA, PCCB, and ACSS3 and assess effects on propionyl-CoA levels and cellular phenotypes.
What is the subcellular localization of propionyl-CoA biosynthesis?
Propionyl-CoA biosynthesis occurs primarily in mitochondria, but nuclear production also occurs and supports local histone propionylation.
What are the synonyms for propionyl-CoA biosynthetic process?
Synonyms include propionyl-CoA anabolism, propionyl-CoA biosynthesis, propionyl-CoA formation, and propionyl-CoA synthesis.
Why is propionyl-CoA important in cancer?
Decreased propionyl-CoA metabolism facilitates metabolic reprogramming in hepatocellular carcinoma, supporting cancer cell growth and survival.
Conclusion
Propionyl-CoA biosynthetic process (GO:1902860) is a fundamental metabolic pathway that produces a key acyl-CoA intermediate with diverse roles in energy metabolism, epigenetics, and disease. Its dysregulation is linked to propionic acidemia and cancer, making it a critical area of research. CRISPR-based models and advanced metabolomic and epigenomic tools are essential for dissecting the pathway and developing therapeutic strategies. EDITGENE provides comprehensive services to support these investigations.
References
- 1. Marchuk H et al.. 2023. Pathophysiological mechanisms of complications associated with propionic acidemia.. Pharmacol Ther 249:108501 PMID: 37482098
- 2. Trefely S et al.. 2020. Compartmentalised acyl-CoA metabolism and roles in chromatin regulation.. Mol Metab 38:100941 PMID: 32199817
- 3. 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
- 4. Sun J et al.. 2023. Decreased propionyl-CoA metabolism facilitates metabolic reprogramming and promotes hepatocellular carcinoma.. J Hepatol 78(3):627-642 PMID: 36462680
- 5. Wongkittichote P et al.. 2017. Propionyl-CoA carboxylase - A review.. Mol Genet Metab 122(4):145-152 PMID: 29033250
- 6. Qin N et al.. 2023. Microbial production of odd-chain fatty acids.. Biotechnol Bioeng 120(4):917-931 PMID: 36522132
- 8. Xiao Y et al.. 2021. HBO1 is a versatile histone acyltransferase critical for promoter histone acylations.. Nucleic Acids Res 49(14):8037-8059 PMID: 34259319
