GO:0005835 fatty acid synthase complex: Components, Assembly and Research Methods, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0005835 (fatty acid synthase complex) is a cellular_component term describing a multienzyme complex that catalyses fatty acid synthesis from acetyl-CoA [1,3].
• The complex is a cytosolic nanofactory composed of multiple catalytic domains that perform iterative cycles of condensation, reduction, dehydration, and reduction.
• Fatty acid synthase (FASN) is the central enzyme; its overexpression is linked to cancer, metabolic disorders, and nonalcoholic fatty liver disease [1,2].
• The complex is regulated by hormones, nutrients, and protein degradation pathways such as TRIM56-mediated ubiquitination [2,5].
• Studying GO:0005835 requires integrated approaches including CRISPR knockout, point mutation, knock-in, overexpression, and proteomics [6,7,8].
• Dysregulation of the fatty acid synthase complex is a therapeutic target in oncology and metabolic diseases [1,5,6].
Description
The fatty acid synthase complex (GO:0005835) is a large multienzyme assembly that catalyses the de novo synthesis of fatty acids from acetyl-CoA and malonyl-CoA [1,3]. This complex is essential for cellular lipid homeostasis and is highly conserved from bacteria to humans. In humans, the cytosolic type I fatty acid synthase (FASN) is a single polypeptide with multiple catalytic domains, while in plants and bacteria, the type II system consists of separate enzymes [3,7]. The complex is a key node in lipogenesis and is often upregulated in cancer and metabolic diseases [1,2]. Understanding its structure, regulation, and function is critical for developing targeted therapies [1,5,6]. This article provides a comprehensive overview of GO:0005835, integrating authoritative QuickGO data with real PubMed literature to guide researchers in experimental design and therapeutic targeting.
fatty acid synthase complex At A Glance
| GO ID | GO:0005835 |
|---|---|
| GO term | fatty acid synthase complex |
| Ontology | cellular_component |
| Synonym | cytosolic FAS complex, cytosolic fatty acid synthase complex, cytosolic type I FAS complex, cytosolic type I fatty acid synthase complex, FAS complex, fatty acid synthetase complex, holo-[acyl-carrier-protein] synthase complex |
| Major function | Catalysis of fatty acid synthesis from acetyl-CoA |
| Location | Cytosol |
| Substrates | Acetyl-CoA, malonyl-CoA, NADPH |
| Products | Palmitate, CoA, NADP+ |
What Is GO:0005835?
GO:0005835, fatty acid synthase complex, is defined as a multienzyme complex that catalyses the synthesis of fatty acids from acetyl CoA [1,3]. It is a cellular component located in the cytosol and is synonymous with cytosolic FAS complex, type I FAS complex, and fatty acid synthetase complex. The complex performs iterative cycles of condensation, reduction, dehydration, and reduction to elongate the acyl chain, using NADPH as a reducing agent.
Why Is fatty acid synthase complex Important in Cell Biology?
The fatty acid synthase complex is a central regulator of lipid metabolism and energy homeostasis [1,3]. Its dysregulation is implicated in a wide range of human diseases, including cancer, obesity, type 2 diabetes, and nonalcoholic fatty liver disease [1,2,5]. In cancer, FASN overexpression supports the lipogenic phenotype required for rapid membrane synthesis and energy production. Therefore, the complex is a promising therapeutic target, and understanding its structure and regulation is essential for drug development [5,6].
• Drives de novo lipogenesis, providing fatty acids for membrane biogenesis and energy storage [1,3].
• Overexpressed in many cancers, including breast, prostate, and colon cancer, correlating with poor prognosis [1,5].
• Involved in metabolic disorders such as nonalcoholic fatty liver disease (NAFLD) and insulin resistance.
• Target of anticancer agents like anastrozole and myrianthic acid [5,6].
• Regulated by ubiquitin-proteasome pathways, e.g., TRIM56-mediated degradation.
• Essential for embryonic development; knockout is lethal in mice.
• Provides a model for studying multienzyme complex assembly and catalysis.
• Plant FAS complexes are targets for herbicide development [7,8].
• Serves as a biomarker for lipogenic phenotype in tumors.
• Enables CRISPR screening to identify synthetic lethal interactions in cancer.
Structure and Composition of fatty acid synthase complex
Overall Architecture
In simple terms: The fatty acid synthase complex is like a molecular assembly line where each station performs a specific chemical reaction.
The type I fatty acid synthase (FASN) is a large homodimer, with each monomer containing seven catalytic domains: beta-ketoacyl synthase (KS), acetyltransferase (AT), malonyl/acetyltransferase (MAT), dehydratase (DH), enoyl reductase (ER), beta-ketoacyl reductase (KR), and acyl carrier protein (ACP). The domains are arranged in a linear sequence and function iteratively. In plants, the complex is dissociated into separate enzymes (type II), as seen in sunflower [7,8].
Catalytic Domains and Their Roles
In simple terms: Each domain acts as a specialized tool that modifies the growing fatty acid chain.
The KS domain catalyzes the condensation of acetyl-CoA and malonyl-CoA, while KR, DH, and ER sequentially reduce the beta-keto group to a saturated acyl chain. The ACP shuttles the growing chain between domains. The MAT domain loads acetyl-CoA and malonyl-CoA onto ACP. These domains work in a coordinated cycle to elongate the fatty acid by two carbons per cycle.
Assembly and Stoichiometry
In simple terms: The complex is built from two identical protein chains that pair up to form the active enzyme.
FASN functions as a homodimer, with each monomer contributing to the active site of the partner, a phenomenon known as half-of-sites reactivity. The dimerization is essential for catalytic activity. In rat liver, the fatty acid synthesizing complex was isolated as a high-molecular-weight multienzyme complex. The complex is localized in the cytosol and is associated with the cytoskeleton in some cell types.
Post-translational Modifications and Interactors
In simple terms: The complex can be modified by other proteins that control its stability and activity.
FASN undergoes ubiquitination and degradation mediated by E3 ligases such as TRIM56, which targets it for proteasomal degradation in NAFLD. Additionally, FASN interacts with other proteins, including the terpenoid myrianthic acid, which binds to the complex and inhibits its activity. These interactions modulate the complex's function in response to cellular signals.
Key Genes Involved in GO:0005835 fatty acid synthase complex
The following genes and proteins are key components or regulators of the fatty acid synthase complex (GO:0005835).
| Gene | Major Role | Research Relevance |
|---|---|---|
| FASN | Core enzyme of the complex; catalyzes all steps of fatty acid synthesis | Target in cancer and metabolic diseases; knockout reduces lipogenesis [1,5] |
| ACACA | Acetyl-CoA carboxylase; produces malonyl-CoA for FASN | Regulates substrate supply; knockout impairs fatty acid synthesis |
| ACACB | Acetyl-CoA carboxylase 2; controls fatty acid oxidation | Potential target for obesity and diabetes |
| TRIM56 | E3 ubiquitin ligase; promotes FASN degradation | Protects against NAFLD; overexpression reduces FASN levels |
| SREBF1 | Transcription factor; upregulates FASN expression | Master regulator of lipogenesis; knockout decreases FASN |
| MLXIPL | Transcription factor; activates lipogenic genes including FASN | Linked to insulin sensitivity and fatty liver |
| NR1H3 | Liver X receptor; regulates FASN transcription | Modulates cholesterol and fatty acid metabolism |
| PPARG | Nuclear receptor; controls adipocyte differentiation and lipogenesis | Target for diabetes drugs; affects FASN expression |
| INS | Insulin; induces FASN expression via SREBP-1c | Hormonal regulation of lipogenesis |
| PRKAA1 | AMPK catalytic subunit; phosphorylates and inhibits ACC | Energy sensor; activation reduces lipogenesis |
| KAT2A | Histone acetyltransferase; may regulate FASN transcription | Epigenetic regulation of lipogenic genes |
| HDAC3 | Histone deacetylase; represses lipogenic genes | Influences FASN expression via chromatin remodeling |
| USP7 | Deubiquitinase; stabilizes FASN | Potential target to modulate FASN levels |
| FBXW7 | E3 ligase; targets FASN for degradation | Tumor suppressor; loss increases FASN |
| CUL3 | Cullin-RING ligase component; may regulate FASN stability | Ubiquitin-proteasome pathway |
| BTRC | F-box protein; part of SCF complex targeting FASN | Regulates FASN turnover |
| KEAP1 | E3 ligase; may interact with FASN under oxidative stress | Links oxidative stress to lipogenesis |
| NFE2L2 | Transcription factor; regulates antioxidant and lipogenic genes | Modulates FASN under stress |
How Is fatty acid synthase complex Regulated?
The fatty acid synthase complex is regulated at multiple levels: transcriptionally by SREBP-1c, ChREBP, and LXR in response to insulin and glucose [1,5]; post-translationally by ubiquitination and degradation via TRIM56, FBXW7, and other E3 ligases; and allosterically by metabolites such as malonyl-CoA and NADPH. Hormonal signals like insulin and glucagon reciprocally control FASN expression. Additionally, AMPK phosphorylates acetyl-CoA carboxylase, reducing malonyl-CoA supply and indirectly inhibiting FASN activity.
fatty acid synthase complex and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| FASN | Breast cancer, prostate cancer, NAFLD | CRISPR knockout in MCF-7 and HepG2 cells; xenograft models [1,2,5] |
| TRIM56 | NAFLD | Liver-specific knockout mice; overexpression in hepatocytes |
| SREBF1 | Metabolic syndrome, cancer | Knockout in mouse liver; CRISPR activation |
| ACACA | Obesity, diabetes | Point mutation in ACC phosphorylation sites; knock-in mice |
| MLXIPL | Fatty liver disease | Knockout in HepG2 cells; overexpression |
Cancer
FASN is overexpressed in many cancers, including breast, prostate, and colon, where it supports the lipogenic phenotype necessary for rapid proliferation. Inhibition of FASN induces apoptosis and reduces tumor growth in preclinical models [1,5]. Anastrozole, an aromatase inhibitor, downregulates FASN in breast cancer, linking estrogen signaling to lipogenesis. Myrianthic acid, a terpenoid, directly interacts with FASN and shows anticancer activity.
Nonalcoholic Fatty Liver Disease (NAFLD)
TRIM56 promotes the degradation of FASN, protecting against NAFLD. Reduced TRIM56 levels lead to FASN accumulation, hepatic steatosis, and insulin resistance. Targeting the TRIM56-FASN axis may offer therapeutic benefits for NAFLD.
Metabolic Disorders
Dysregulation of FASN is associated with obesity, type 2 diabetes, and insulin resistance [1,3]. Elevated FASN activity contributes to ectopic lipid accumulation in liver and muscle, impairing insulin signaling. Pharmacological inhibition of FASN improves insulin sensitivity in animal models.
From fatty acid synthase complex-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does FASN knockout reduce tumor growth? | CRISPR knockout in cancer cell lines and mouse xenografts |
| How does TRIM56 regulate FASN stability? | Knockout of TRIM56 in hepatocytes; proteasome inhibitor treatment |
| What is the effect of FASN point mutations on catalysis? | CRISPR point mutation of catalytic residues in FASN |
| Can FASN be tagged for live-cell imaging? | Knock-in of fluorescent tag (e.g., GFP) at FASN locus |
| Does FASN overexpression drive lipogenesis? | CRISPR overexpression via SAM or cDNA transduction |
| What genes are synthetic lethal with FASN inhibition? | Genome-wide CRISPR library screening |
How to Study the fatty acid synthase complex Process
| Method | What It Measures | Typical Application |
|---|---|---|
| CRISPR knockout | Loss-of-function phenotype | Identify essentiality of FASN in cancer cells |
| CRISPR point mutation | Effect of specific amino acid changes | Study catalytic residues in FASN |
| Knock-in tagging | Protein localization and interactions | Live-cell imaging of FASN |
| Overexpression | Gain-of-function effects | Drive lipogenesis in metabolic models |
| Proteomics | Protein interactions and modifications | Identify FASN regulators |
| Metabolic flux analysis | Pathway activity | Quantify fatty acid synthesis |
| CRISPR library screening | Synthetic lethal interactions | Find combination targets with FASN inhibitors |
| RNA-seq | Transcriptional changes | Measure FASN and lipogenic gene expression |
Proteomics and Interactomics
Mass spectrometry-based proteomics can identify FASN interactors and post-translational modifications. Affinity purification coupled to MS reveals binding partners like myrianthic acid. These methods help map the complex's composition and regulation.
CRISPR Screening
Genome-wide CRISPR knockout screens can identify genes that are synthetic lethal with FASN inhibition, revealing vulnerabilities in cancer cells. This approach is powerful for target discovery and drug combination strategies.
Metabolic Flux Analysis
Isotope tracing with 13C-labeled substrates measures flux through the fatty acid synthesis pathway. This quantifies the contribution of FASN to lipogenesis in different conditions.
Imaging and Localization
Fluorescence microscopy of tagged FASN (e.g., GFP knock-in) visualizes the complex's subcellular localization and dynamics. Live-cell imaging can track its assembly and interactions.
How CRISPR Can Be Used to Study GO:0005835 fatty acid synthase complex
Knockout
CRISPR knockout of FASN in cancer cell lines reduces proliferation and induces apoptosis, validating its role in lipogenesis. Knockout of TRIM56 in hepatocytes increases FASN levels, mimicking NAFLD. These models are essential for target validation.
Point Mutation
Introducing point mutations in catalytic residues of FASN (e.g., KS or KR domains) via CRISPR can dissect the enzymatic mechanism. Such models help determine which domains are essential for fatty acid synthesis.
Knock-in
Knock-in of a fluorescent tag (e.g., GFP) at the endogenous FASN locus allows real-time visualization of the complex's localization and dynamics. This is valuable for studying its assembly and interactions in live cells.
Overexpression
CRISPR activation (CRISPRa) or cDNA overexpression of FASN increases lipogenesis and can drive tumor growth in xenograft models. Overexpression models are useful for studying the consequences of FASN upregulation in metabolic diseases.
How EDITGENE Supports fatty acid synthase complex Research
Researchers studying fatty acid synthase complex-related genes often need to determine whether a candidate gene is causally involved in lipogenesis, cancer, or metabolic disease. EDITGENE provides a comprehensive suite of CRISPR services to accelerate this discovery.
Contact EDITGENE today to design your custom CRISPR model for fatty acid synthase complex research.
Frequently Asked Questions About fatty acid synthase complex
What is the fatty acid synthase complex?
The fatty acid synthase complex (GO:0005835) is a multienzyme complex that catalyses the synthesis of fatty acids from acetyl-CoA [1,3].
What genes are involved in the fatty acid synthase complex?
Key genes include FASN, ACACA, SREBF1, TRIM56, and MLXIPL, among others [1,2,3].
Where is the fatty acid synthase complex located?
It is located in the cytosol.
What is the function of FASN?
FASN is the core enzyme that catalyzes all steps of fatty acid synthesis, producing palmitate [1,3].
How is the fatty acid synthase complex regulated?
It is regulated transcriptionally by SREBP-1c and ChREBP, and post-translationally by ubiquitination via TRIM56 [1,2].
What diseases are associated with the fatty acid synthase complex?
Cancer, nonalcoholic fatty liver disease, obesity, and type 2 diabetes [1,2,5].
Can CRISPR be used to study the fatty acid synthase complex?
Yes, CRISPR knockout, point mutation, knock-in, and overexpression models are widely used [1,3,6].
What are the subunits of the fatty acid synthase complex?
In type I FAS, a single polypeptide contains seven catalytic domains; in type II, separate enzymes form the complex [3,7].
How is FASN degraded?
FASN is ubiquitinated by E3 ligases such as TRIM56 and targeted for proteasomal degradation.
What is the role of FASN in cancer?
FASN supports the lipogenic phenotype of cancer cells, and its inhibition reduces tumor growth [1,5].
Conclusion
The fatty acid synthase complex (GO:0005835) is a central metabolic machine with profound implications for cancer, metabolic diseases, and basic cell biology. Its structure, regulation, and interactions are active areas of research, and CRISPR-based models are indispensable for dissecting its functions. EDITGENE provides end-to-end CRISPR solutions to accelerate discoveries targeting this complex.
References
- 1. Menendez JA et al.. 2007. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis.. Nat Rev Cancer 7(10):763-77 PMID: 17882277
- 2. Xu S et al.. 2024. TRIM56 protects against nonalcoholic fatty liver disease by promoting the degradation of fatty acid synthase.. J Clin Invest 134(5) PMID: 38206764
- 3. Paiva P et al.. 2021. Animal Fatty Acid Synthase: A Chemical Nanofactory.. Chem Rev 121(15):9502-9553 PMID: 34156235
- 4. Gillevet PM et al.. 1982. Rat-liver fatty-acid-synthesizing complex.. Biosci Rep 2(10):841-8 PMID: 6129006
- 5. Cairns J et al.. 2022. Anastrozole Regulates Fatty Acid Synthase in Breast Cancer.. Mol Cancer Ther 21(1):206-216 PMID: 34667110
- 6. Capuano A et al.. 2024. Fatty Acid Synthase as Interacting Anticancer Target of the Terpenoid Myrianthic Acid Disclosed by MS-Based Proteomics Approaches.. Int J Mol Sci 25(11) PMID: 38892106
- 7. González-Thuillier I et al.. 2021. Sunflower (Helianthus annuus) fatty acid synthase complex: β-Ketoacyl-[acyl carrier protein] reductase genes.. Plant Physiol Biochem 166:689-699 PMID: 34214779
- 8. González-Thuillier I et al.. 2016. Sunflower (Helianthus annuus) fatty acid synthase complex: β-hydroxyacyl-[acyl carrier protein] dehydratase genes.. Planta 243(2):397-410 PMID: 26433735
