GO:0102758 very-long-chain enoyl-CoA reductase activity: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0102758 describes the NADPH-dependent reduction of a very-long-chain (2E)-enoyl-CoA to a saturated acyl-CoA, the fourth and final step of endoplasmic reticulum fatty acid elongation.
• The reaction is catalyzed by TECR (trans-2,3-enoyl-CoA reductase) and related enzymes, and is essential for producing fatty acids longer than C16.
• Very-long-chain fatty acids (VLCFAs) are required for membrane lipids, sphingolipids, and lipid signaling, and their synthesis is linked to cell expansion and morphogenesis in plants.
• Dysregulation of VLCFA synthesis, including enoyl-CoA reductase activity, is implicated in cancer cell sensitivity to ferroptosis and in nonapoptotic cell death triggered by tegavivint.
• The enzyme is also important in brain development and in the production of phytosphingosine ceramides, with hydroxylase activity toward VLCFA substrates.
• Researchers study GO:0102758 using knockout, point-mutation, knock-in, and overexpression models, combined with lipidomics, transcriptomics, and CRISPR screening.
Description
Very-long-chain enoyl-CoA reductase activity (GO:0102758) is a molecular function that catalyzes the final reduction step in the endoplasmic reticulum fatty acid elongation cycle, converting a very-long-chain (2E)-enoyl-CoA to a saturated fatty acyl-CoA using NADPH as the electron donor. This activity is essential for the synthesis of fatty acids with chain lengths beyond C16, which are critical components of sphingolipids, phospholipids, and other membrane lipids. The enzyme responsible, TECR (trans-2,3-enoyl-CoA reductase), has been studied in diverse organisms, from plants to mammals, revealing its importance in cell expansion, brain development, and cancer cell biology. In recent years, GO:0102758 has gained attention as a potential therapeutic target because of its role in lipid metabolism reprogramming in cancer and its link to ferroptosis sensitivity. Understanding the regulation and function of this enzyme provides insights into fundamental lipid biology and offers opportunities for drug discovery and CRISPR-based functional genomics.
very-long-chain enoyl-CoA reductase activity At A Glance
| GO ID | GO:0102758 |
|---|---|
| GO term | very-long-chain enoyl-CoA reductase activity |
| Ontology | molecular_function |
| Synonym | none |
| Major function | Catalyzes the NADPH-dependent reduction of a very-long-chain (2E)-enoyl-CoA to a saturated fatty acyl-CoA, the final step of endoplasmic reticulum fatty acid elongation. |
| Reaction direction | Reduction (NADPH to NADP+). |
| Substrate specificity | Very-long-chain (2E)-enoyl-CoA with chain length C16 or longer. |
| Cellular location | Endoplasmic reticulum membrane. |
| Pathway context | Fatty acid elongation cycle (four steps). |
What Is GO:0102758?
GO:0102758, very-long-chain enoyl-CoA reductase activity, is defined as the catalysis of the reaction: a very-long-chain 2,3-saturated fatty acyl-CoA + NADP+ = a very-long-chain (2E)-enoyl-CoA + H+ + NADPH. This reaction constitutes the fourth (reduction) step of the four-step fatty acid elongation cycle in the endoplasmic reticulum that extends fatty acids of C-16 or longer by an additional 2-carbon unit. In simpler terms, it is the enzyme activity that removes a double bond from a very-long-chain fatty acid precursor, using NADPH to complete the elongation process.
Why Is very-long-chain enoyl-CoA reductase activity Important in Cell Biology?
GO:0102758 is important because it governs the final step of very-long-chain fatty acid (VLCFA) synthesis, a process that impacts membrane fluidity, lipid raft formation, and the production of signaling sphingolipids. Disruption of this activity leads to severe developmental defects in plants and is linked to cancer cell death and ferroptosis sensitivity in mammals. Moreover, the enzyme is a potential target for antiviral strategies, as dengue virus replication is particularly sensitive to interference with long-chain fatty acid elongation. Thus, understanding GO:0102758 offers broad relevance across cell biology, disease, and biotechnology.
• Essential for VLCFA synthesis, which is required for membrane lipid homeostasis and cell expansion.
• Implicated in cancer cell ferroptosis sensitivity through regulation of lipogenic enzyme expression.
• Target of tegavivint-induced nonapoptotic cancer cell death via TECR-dependent mechanisms.
• Required for brain development and long-chain fatty acid accumulation in the nervous system.
• Involved in the production of phytosphingosine ceramides with very-long-chain fatty acids.
• Plays a role in dengue virus replication, as interference with fatty acid elongation inhibits the virus.
• Regulated in teleost fish as part of long-chain polyunsaturated fatty acid biosynthesis.
• Provides a model for studying endoplasmic reticulum membrane-bound enzymes and lipid metabolism.
What Happens During very-long-chain enoyl-CoA reductase activity?
Substrate recognition and binding
In simple terms: The enzyme grabs a very-long-chain fatty acid that still has a double bond and gets ready to modify it.
The enzyme recognizes a very-long-chain (2E)-enoyl-CoA substrate, typically with a chain length of C16 or longer, and binds it in the active site. This step is part of the four-step elongation cycle in the endoplasmic reticulum, where the enoyl-CoA reductase acts after dehydration of 3-hydroxyacyl-CoA. The substrate specificity ensures that only very-long-chain fatty acids are processed, distinguishing this activity from shorter-chain reductases.
NADPH-dependent reduction
In simple terms: Using NADPH as a power source, the enzyme removes the double bond to saturate the fatty acid.
The catalytic mechanism involves the transfer of hydride from NADPH to the beta-carbon of the enoyl-CoA, reducing the double bond and yielding a saturated acyl-CoA. This reaction is the fourth and final step of the elongation cycle, producing a fatty acid that is two carbons longer than the starting substrate. The reaction is essential for generating saturated VLCFAs used in sphingolipid and phospholipid synthesis.
Product release and elongation cycle completion
In simple terms: The finished saturated fatty acid is released, and the elongation cycle can start again for further extension.
After reduction, the saturated very-long-chain acyl-CoA is released from the enzyme. This product can either be used directly for lipid synthesis or re-enter the elongation cycle for additional two-carbon extensions. The cycle is tightly coupled to other enzymes in the endoplasmic reticulum membrane, including elongases and dehydratases. In brain tissue, this activity contributes to the accumulation of long-chain fatty acids during development.
Integration with cellular lipid metabolism
In simple terms: The enzyme's product feeds into the production of complex lipids that cells need for membranes and signaling.
The saturated VLCFAs produced by GO:0102758 are incorporated into sphingolipids, such as phytosphingosine ceramides, and into phospholipids. This integration links the enzyme to membrane biogenesis, cell signaling, and cell death pathways. In cancer cells, the activity influences phospholipid composition and ferroptosis sensitivity, highlighting its broader metabolic impact.
Key Genes Involved in GO:0102758 very-long-chain enoyl-CoA reductase activity
The following genes and proteins are directly or indirectly associated with very-long-chain enoyl-CoA reductase activity (GO:0102758) and its biological context.
| Gene | Major Role | Research Relevance |
|---|---|---|
| TECR | Catalyzes the reduction step of VLCFA elongation | Target of tegavivint; linked to nonapoptotic cancer cell death |
| ZEB1 | Regulates lipogenic enzyme expression including VLCFA enzymes | Mediates ferroptosis sensitivity via phospholipid composition |
| DEGS2 | Bifunctional desaturase/hydroxylase acting on VLCFA substrates | Produces phytosphingosine ceramides; links to VLCFA metabolism |
| HACD1 | 3-hydroxyacyl-CoA dehydratase in VLCFA synthesis | Acts upstream of enoyl-CoA reductase in brain development |
| HACD2 | 3-hydroxyacyl-CoA dehydratase in VLCFA synthesis | Part of the elongation cycle; potential compensatory role |
| HACD3 | 3-hydroxyacyl-CoA dehydratase in VLCFA synthesis | Contributes to VLCFA production in various tissues |
| HACD4 | 3-hydroxyacyl-CoA dehydratase in VLCFA synthesis | Involved in long-chain fatty acid accumulation |
| ELOVL1 | Fatty acid elongase, first step of elongation | Provides substrate for enoyl-CoA reductase |
| ELOVL2 | Fatty acid elongase, first step of elongation | Linked to polyunsaturated fatty acid biosynthesis |
| ELOVL3 | Fatty acid elongase, first step of elongation | Contributes to VLCFA synthesis in specific tissues |
| ELOVL4 | Fatty acid elongase, first step of elongation | Produces VLCFAs for retina and brain |
| ELOVL5 | Fatty acid elongase, first step of elongation | Involved in long-chain PUFA synthesis in teleosts |
| ELOVL6 | Fatty acid elongase, first step of elongation | Elongates saturated and monounsaturated fatty acids |
| ELOVL7 | Fatty acid elongase, first step of elongation | Participates in VLCFA synthesis |
| ACSL1 | Activates fatty acids to acyl-CoA | Provides substrates for elongation |
| ACSL3 | Activates fatty acids to acyl-CoA | Contributes to lipid metabolism |
| ACSL4 | Activates fatty acids to acyl-CoA | Influences ferroptosis sensitivity |
How Is very-long-chain enoyl-CoA reductase activity Regulated?
The activity of very-long-chain enoyl-CoA reductase is regulated at multiple levels. In cancer cells, the transcription factor ZEB1 regulates the expression of lipogenic enzymes, including those involved in VLCFA synthesis, thereby modulating ferroptosis sensitivity. The enzyme TECR is also a target of tegavivint, which triggers TECR-dependent nonapoptotic cell death, suggesting that its activity can be pharmacologically modulated. In plants, disruption of the enoyl-CoA reductase gene leads to severe morphogenetic defects, indicating that its expression is tightly linked to developmental programs. Additionally, in brain tissue, the activity increases during development, consistent with a role in long-chain fatty acid accumulation. In teleost fish, the expression of elongases and reductases is regulated in response to dietary and hormonal signals. Overall, regulation occurs through transcriptional control, post-translational modifications, and feedback from lipid metabolites.
very-long-chain enoyl-CoA reductase activity and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| TECR | Cancer cell death, ferroptosis | TECR knockout cancer cell lines, tegavivint treatment |
| ZEB1 | Ferroptosis sensitivity, EMT | ZEB1 knockout or overexpression in cancer cells |
| DEGS2 | Phytosphingosine ceramide production | DEGS2 knockout keratinocytes or fibroblasts |
| HACD1-4 | Brain development, VLCFA accumulation | HACD knockout neuronal cells |
| ELOVL family | Dengue virus replication, PUFA synthesis | ELOVL knockout or overexpression in viral infection models |
Cancer and ferroptosis
Very-long-chain enoyl-CoA reductase activity is implicated in cancer cell biology through its role in lipid metabolism. ZEB1-mediated regulation of lipogenic enzymes, including VLCFA synthesis, alters phospholipid composition and determines sensitivity to ferroptosis, a form of iron-dependent cell death. Furthermore, tegavivint, a small molecule that targets TECR, induces nonapoptotic cancer cell death, highlighting the enzyme as a potential therapeutic target. These findings suggest that modulating GO:0102758 could be a strategy to sensitize tumors to ferroptosis or other cell death pathways.
Neurological development and disorders
In the brain, very-long-chain fatty acid synthesis is essential for normal development. Studies in rat brain show that hydroxyacyl-CoA dehydrase and trans-2,3-enoyl-CoA reductase activities increase during development, consistent with the accumulation of long-chain fatty acids. Dehydration of 3-hydroxyacyl-CoA in brain VLCFA synthesis is a critical step, and its dysfunction could contribute to neurological disorders. Although direct links to human neurodegenerative diseases are not yet fully established, the importance of VLCFA metabolism in myelin and neuronal membranes suggests that GO:0102758 may play a role in such conditions.
Viral infections
Dengue virus is particularly sensitive to interference with long-chain fatty acid elongation and desaturation, indicating that VLCFA synthesis, including the enoyl-CoA reductase step, is important for viral replication. This raises the possibility that inhibitors of GO:0102758 could have antiviral applications. Further research is needed to determine whether other viruses rely on this activity.
Plant morphogenesis
In Arabidopsis, disruption of the enoyl-CoA reductase gene reveals an essential role for very-long-chain fatty acid synthesis in cell expansion during plant morphogenesis. This underscores the evolutionary conservation of GO:0102758 and its fundamental importance in growth and development. Understanding this activity in plants can inform crop improvement and basic cell biology.
From very-long-chain enoyl-CoA reductase activity-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of TECR affect cancer cell viability? | TECR knockout via CRISPR in cancer cell lines |
| Does a point mutation in the active site abolish enoyl-CoA reductase activity? | Point-mutation knock-in of TECR catalytic residues |
| Can tagged TECR be used to study localization? | Knock-in of fluorescent or affinity tags at the endogenous TECR locus |
| Does overexpression of ZEB1 alter VLCFA synthesis? | ZEB1 overexpression in epithelial cancer cells |
| What is the role of DEGS2 in phytosphingosine ceramide production? | DEGS2 knockout or overexpression in skin cells |
| How does ELOVL4 mutation affect VLCFA levels? | ELOVL4 point-mutation knock-in in retinal cells |
How to Study the very-long-chain enoyl-CoA reductase activity Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Lipidomics (LC-MS) | VLCFA and sphingolipid species | Quantify changes upon TECR knockout |
| CRISPR knockout screening | Gene essentiality and synthetic lethality | Identify regulators of ferroptosis |
| RNA-seq | Transcript levels of lipid metabolism genes | Assess ZEB1-dependent regulation |
| Proteomics | Protein expression and modifications | Study TECR stability and interactions |
| Enzyme activity assay | Reductase catalytic activity | Validate point mutations in TECR |
| Fluorescence microscopy | Subcellular localization of tagged TECR | Confirm endoplasmic reticulum localization |
| Viral replication assay | Dengue virus titers | Test effect of elongation inhibitors |
Lipidomics and mass spectrometry
Lipidomic profiling by mass spectrometry is a key method to measure very-long-chain fatty acid species and their derivatives, such as sphingolipids. This approach can quantify changes in VLCFA levels upon modulation of GO:0102758, as demonstrated in studies of cancer cells and brain tissue.
CRISPR screening and functional genomics
CRISPR knockout screens can identify genes that regulate or depend on very-long-chain enoyl-CoA reductase activity. For example, screens in cancer cells have linked lipid metabolism genes to ferroptosis sensitivity. Such screens can uncover synthetic lethal interactions and pathways that buffer against loss of GO:0102758.
Transcriptomics and proteomics
RNA sequencing and proteomics can reveal changes in the expression of genes involved in VLCFA synthesis, including TECR and elongases, under different conditions. Studies in teleost fish and cancer models have used these methods to understand regulation of long-chain fatty acid biosynthesis.
Enzyme activity assays
Direct measurement of enoyl-CoA reductase activity using radiolabeled or fluorescent substrates can confirm the functional impact of mutations or inhibitors. Such assays have been used to characterize the enzyme in brain and plant systems.
How CRISPR Can Be Used to Study GO:0102758 very-long-chain enoyl-CoA reductase activity
Knockout
CRISPR knockout of TECR or related genes can abolish very-long-chain enoyl-CoA reductase activity, leading to reduced VLCFA levels and altered cell phenotypes. This approach has been used to show that TECR is required for cancer cell survival under certain conditions and to study ferroptosis sensitivity. Knockout models are valuable for identifying downstream effects on lipid composition and cell death pathways.
Point Mutation
Introducing point mutations in the catalytic residues of TECR via CRISPR can dissect the enzymatic mechanism and separate catalytic activity from other functions. Such models help confirm that the observed phenotypes are due to loss of reductase activity rather than protein absence. Point mutations can also mimic disease-associated variants.
Knock-in
Knock-in of tags or reporters at the endogenous TECR locus allows real-time tracking of enzyme localization and dynamics. This is useful for studying the enzyme's trafficking to the endoplasmic reticulum and its interaction with other elongation machinery. Knock-in models can also be used to express mutant versions of the enzyme under native regulation.
Overexpression
Overexpression of TECR or upstream regulators like ZEB1 can increase VLCFA synthesis and alter membrane lipid composition. This approach has been used to study the impact of enhanced enoyl-CoA reductase activity on ferroptosis and cell proliferation. Overexpression models are also useful for biochemical purification and structural studies.
How EDITGENE Supports very-long-chain enoyl-CoA reductase activity Research
Researchers studying very-long-chain enoyl-CoA reductase activity-related genes often need to determine whether a candidate gene is causally involved in lipid metabolism, cell death, or disease. EDITGENE provides comprehensive CRISPR-based services to create precise cellular models for such investigations.
Contact EDITGENE today to design your custom CRISPR model for very-long-chain enoyl-CoA reductase activity research.
Frequently Asked Questions About very-long-chain enoyl-CoA reductase activity
What is very-long-chain enoyl-CoA reductase activity?
It is the enzyme activity that catalyzes the final reduction step in the endoplasmic reticulum fatty acid elongation cycle, converting a very-long-chain (2E)-enoyl-CoA to a saturated acyl-CoA using NADPH.
What genes are involved in very-long-chain enoyl-CoA reductase activity?
The primary gene is TECR, which encodes the trans-2,3-enoyl-CoA reductase. Other related genes include ZEB1, DEGS2, HACD1-4, and ELOVL family members.
What is the GO ID for very-long-chain enoyl-CoA reductase activity?
The Gene Ontology ID is GO:0102758.
What is the function of TECR?
TECR catalyzes the reduction of very-long-chain enoyl-CoAs to saturated fatty acyl-CoAs, the fourth step of VLCFA elongation. It is also a target of tegavivint in cancer cells.
How is very-long-chain enoyl-CoA reductase activity regulated?
It is regulated transcriptionally by factors like ZEB1, and pharmacologically by compounds such as tegavivint. Developmental and dietary signals also influence its expression.
What diseases are associated with very-long-chain enoyl-CoA reductase activity?
It is linked to cancer cell ferroptosis, nonapoptotic cell death, neurological development, and viral infections such as dengue.
What experimental models are used to study GO:0102758?
CRISPR knockout, point-mutation knock-in, tagged knock-in, and overexpression cell models, combined with lipidomics and CRISPR screening.
Can very-long-chain enoyl-CoA reductase activity be measured?
Yes, using enzyme activity assays with radiolabeled or fluorescent substrates, as well as lipidomics to measure VLCFA products.
What is the role of very-long-chain fatty acids in cells?
VLCFAs are essential for membrane structure, sphingolipid synthesis, and cell signaling. They are particularly important in brain and skin.
How does dengue virus relate to very-long-chain enoyl-CoA reductase activity?
Dengue virus replication is sensitive to interference with long-chain fatty acid elongation, suggesting that the pathway, including enoyl-CoA reductase, is important for the virus.
Conclusion
Very-long-chain enoyl-CoA reductase activity (GO:0102758) is a critical enzymatic step in the synthesis of very-long-chain fatty acids, with far-reaching implications for membrane biology, development, cancer, and infectious disease. The enzyme TECR and its regulators, such as ZEB1, have emerged as key players in ferroptosis sensitivity and as potential drug targets. Continued research using CRISPR models and lipidomics will further illuminate the mechanistic details and therapeutic potential of this pathway.
References
- 1. Schwab A et al.. 2024. Zeb1 mediates EMT/plasticity-associated ferroptosis sensitivity in cancer cells by regulating lipogenic enzyme expression and phospholipid composition.. Nat Cell Biol 26(9):1470-1481 PMID: 39009641
- 2. Leak L et al.. 2025. Tegavivint triggers TECR-dependent nonapoptotic cancer cell death.. Nat Chem Biol 21(12):1873-1884 PMID: 40419770
- 3. Zheng H et al.. 2005. Disruptions of the Arabidopsis Enoyl-CoA reductase gene reveal an essential role for very-long-chain fatty acid synthesis in cell expansion during plant morphogenesis.. Plant Cell 17(5):1467-81 PMID: 15829606
- 4. Ota A et al.. 2023. Bifunctional DEGS2 has higher hydroxylase activity toward substrates with very-long-chain fatty acids in the production of phytosphingosine ceramides.. J Biol Chem 299(4):104603 PMID: 36907437
- 5. Knoll A et al.. 1999. Dehydration of 3-hydroxyacyl-CoA in brain very-long-chain fatty acid synthesis.. Neurochem Int 34(4):255-67 PMID: 10372912
- 6. Knoll A et al.. 1999. Hydroxyacyl-CoA dehydrase and trans-2,3-enoyl-CoA reductase activities are consistent with long-chain fatty acid accumulation during rat brain development.. Neurosci Lett 263(1):5-8 PMID: 10218897
- 7. Xie D et al.. 2021. Regulation of long-chain polyunsaturated fatty acid biosynthesis in teleost fish.. Prog Lipid Res 82:101095 PMID: 33741387
- 8. Hehner J et al.. 2025. Dengue virus is particularly sensitive to interference with long-chain fatty acid elongation and desaturation.. J Biol Chem 301(3):108222 PMID: 39863099
