FASN encodes fatty acid synthase, the cytosolic type I fatty acid synthase of mammals: a large multifunctional homodimeric "megasynthase" (~273 kDa per protomer) that carries out the complete cycle of de novo long-chain saturated fatty acid biosynthesis, producing mainly palmitate (C16:0) from acetyl-CoA and malonyl-CoA using NADPH as reductant. Each subunit contains seven catalytic activities and an acyl-carrier-protein (ACP) domain bearing a 4'-phosphopantetheine prosthetic group. Using an acetyl-CoA primer, the enzyme iteratively condenses malonyl-CoA-derived two-carbon units and reduces the growing chain through a repeating condensation/reduction/dehydration/reduction cycle, releasing palmitate via its C-terminal thioesterase. The catalytic components are: the bifunctional malonyl/acetyl transferase (MAT; [ACP] S-acetyltransferase and S-malonyltransferase), the beta-ketoacyl (condensing) synthase (KS), beta-ketoacyl reductase (KR), beta-hydroxyacyl dehydratase (DH), enoyl reductase (ER), and thioesterase (TE), organized into a condensing region and a modifying region joined by a flexible neck, with catalytically dead pseudo-KR and pseudo-methyltransferase domains. The tethered ACP shuttles intermediates between the active sites. FASN is the primary enzyme of de novo lipogenesis, supplying fatty acids for membrane phospholipids, energy storage, protein acylation (e.g. palmitoylation) and lipid signaling. It is expressed ubiquitously with prominent expression in liver, adipose tissue, brain, lung and mammary gland, is transcriptionally induced by SREBP and ChREBP in response to nutrients/insulin, and is frequently overexpressed in cancers.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: FASN is a cytosolic enzyme; the phylogenetic (IBA) inference that it is active in the cytoplasm is correct. Cytosol (GO:0005829) is the more precise term captured by experimental annotations, but cytoplasm is not wrong. |
| GO:0004312 fatty acid synthase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Core molecular function. FASN is the fatty acid synthase; the IBA inference across the family is correct and is directly confirmed experimentally in human FASN. |
| GO:0006633 fatty acid biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: Core biological process. FASN performs de novo fatty acid biosynthesis; the IBA inference is correct. |
| GO:0004312 fatty acid synthase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Core molecular function, IEA duplicate of the experimentally supported fatty acid synthase activity (EC 2.3.1.85). Correct; kept as core rather than flagged as a redundant IEA. |
| GO:0004313 [acyl-carrier-protein] S-acetyltransferase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Genuine partial activity of the bifunctional MAT domain (EC 2.3.1.38), directly demonstrated experimentally in human FASN (also annotated EXP/IDA below). Correct. |
| GO:0004314 [acyl-carrier-protein] S-malonyltransferase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Genuine partial activity of the bifunctional MAT domain (EC 2.3.1.39). UniProt lists EC 2.3.1.39 with ECO:0000269 experimental support from PubMed:7567999, 8962082 and 9356448. Correct component activity. |
| GO:0004315 3-oxoacyl-[acyl-carrier-protein] synthase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Genuine condensing (beta-ketoacyl synthase / KS) partial activity (EC 2.3.1.41), directly demonstrated in human FASN (also EXP below). Correct. |
| GO:0004316 3-oxoacyl-[acyl-carrier-protein] reductase (NADPH) activity | IEA GO_REF:0000120 | ACCEPT | Summary: Genuine beta-ketoacyl reductase (KR) partial activity (EC 1.1.1.100), directly demonstrated in human FASN (also IDA below). Correct. |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: Correct cytoplasmic localization (IEA duplicate). Cytosol (GO:0005829) is the more precise experimentally supported location. |
| GO:0006631 fatty acid metabolic process | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Correct but a general parent of the more specific fatty acid biosynthetic process (GO:0006633) that is the core BP for FASN. Kept as accurate but non-core. |
| GO:0006633 fatty acid biosynthetic process | IEA GO_REF:0000120 | ACCEPT | Summary: Core biological process (IEA duplicate of the IBA annotation). Correct. |
| GO:0008610 lipid biosynthetic process | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Correct but a broad parent of fatty acid biosynthetic process. Kept as accurate but non-core given the more specific term is annotated. |
| GO:0016297 fatty acyl-[ACP] hydrolase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Genuine thioesterase (TE) partial activity of FASN (EC 3.1.2.14) that releases the finished palmitate; directly demonstrated in human FASN (UniProt ECO:0000269 from PubMed:15507492, 7567999, 8962082, 9356448). Correct component activity. |
| GO:0016491 oxidoreductase activity | IEA GO_REF:0000120 | MARK AS OVER ANNOTATED | Summary: Root-level parent term covering the KR and ER reductase activities of FASN. Correct in the broadest sense but uninformative; the specific reductase terms (GO:0004316, GO:0141148) are the informative annotations. |
| GO:0016740 transferase activity | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: Very general parent (covers the MAT and KS acyltransferase activities). Uninformative; the specific transferase terms are already annotated. |
| GO:0016746 acyltransferase activity | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: General parent of the MAT ([ACP] S-acetyl/S-malonyltransferase) and KS acyltransferase activities. Correct but subsumed by the more specific terms; over-annotated at this level. |
| GO:0019171 (3R)-hydroxyacyl-[acyl-carrier-protein] dehydratase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Genuine beta-hydroxyacyl dehydratase (DH) partial activity of FASN (EC 4.2.1.59), directly demonstrated in human FASN (also IDA/EXP below). Correct. |
| GO:0031177 phosphopantetheine binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: The ACP domain of FASN carries a covalently attached 4'-phosphopantetheine prosthetic group (attachment at Ser-2156/Ser-2156 region), so phosphopantetheine binding is a real cofactor-associated feature of the enzyme. Kept as a real but ancillary (non-core) molecular feature supporting the ACP carrier function. |
| GO:0042470 melanosome | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: FASN was detected by mass spectrometry in melanosome fractions (UniProt SUBCELLULAR LOCATION note; PMID:17081065), which is the basis of this SubCell-derived IEA. FASN is a cytosolic enzyme, so this is a secondary/co-purifying localization; kept non-core. |
| GO:0141148 enoyl-[acyl-carrier-protein] reductase (NADPH) activity | IEA GO_REF:0000120 | ACCEPT | Summary: Genuine enoyl reductase (ER) partial activity of FASN (EC 1.3.1.39), directly demonstrated in human FASN (also EXP below). Correct component activity. |
| GO:0005515 protein binding | IPI PMID:23427160 Hepatitis C virus replication is modulated by the interactio... | MARK AS OVER ANNOTATED | Summary: IPI interaction with HCV nonstructural protein NS5B (Q99IB8 chain), modulating HCV replication. A real virus-host interaction but "protein binding" is uninformative as a molecular function. Kept per policy (experimental IPI) but flagged as over-annotated. |
| GO:0005515 protein binding | IPI PMID:25959826 Quantitative interaction proteomics of neurodegenerative dis... | MARK AS OVER ANNOTATED | Summary: IPI interaction with HTT (P42858) from interaction proteomics. Generic "protein binding"; uninformative as a molecular function. Kept (IPI) but over-annotated. |
| GO:0005515 protein binding | IPI PMID:27478939 C13orf31 (FAMIN) is a central regulator of immunometabolic f... | MARK AS OVER ANNOTATED | Summary: IPI interaction with FAMIN/LACC1 (Q8IV20); FAMIN forms a complex with FASN on peroxisomes and promotes de novo lipogenesis. A biologically meaningful interaction, but the bare "protein binding" term is uninformative. Kept (IPI) but over-annotated. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: IPI interaction with ADIPOQ (Q15848) from a binary interactome map. Generic "protein binding"; uninformative. Kept (IPI) but over-annotated. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: IPI interaction with LNX1 (Q8TBB1) from a binary interactome map. Generic "protein binding"; uninformative. Kept (IPI) but over-annotated. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MARK AS OVER ANNOTATED | Summary: IPI interaction with HTT (P42858) from a neurodegenerative-disease interactome map. Generic "protein binding"; uninformative. Kept (IPI) but over-annotated. |
| GO:0005515 protein binding | IPI PMID:36604718 Targeting fatty acid synthase modulates sensitivity of hepat... | MARK AS OVER ANNOTATED | Summary: IPI interaction with GPX4 (Q16665) in a hepatocellular-carcinoma ferroptosis context. Generic "protein binding"; uninformative as a molecular function. Kept (IPI) but over-annotated. |
| GO:0006084 acetyl-CoA metabolic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: FASN consumes acetyl-CoA (primer) and malonyl-CoA (derived from acetyl-CoA via ACC) as substrates, so participation in acetyl-CoA metabolism is defensible. Orthology-based (Ensembl) transfer; kept as accurate but peripheral to the core biosynthetic role. |
| GO:0007584 response to nutrient | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: FASN expression/activity is strongly regulated by nutritional state (SREBP/ChREBP, insulin, feeding), consistent with a response-to-nutrient role by orthology transfer. Regulatory/physiological context; kept non-core. |
| GO:0031667 response to nutrient levels | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: As with response to nutrient, FASN is induced by high-nutrient/lipogenic states. A regulatory/physiological context term; kept non-core. |
| GO:0042802 identical protein binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: FASN is an obligate homodimer arranged head-to-tail; identical protein binding (self-association) is a genuine molecular property confirmed structurally (PMID:37308485, PMID:39979457) and in the UniProt SUBUNIT record. Kept as accurate but non-core relative to the catalytic function. |
| GO:0046949 fatty-acyl-CoA biosynthetic process | TAS Reactome:R-HSA-75105 | KEEP AS NON CORE | Summary: Reactome pathway ("Fatty acyl-CoA biosynthesis") placing FASN in fatty acid/acyl-CoA biosynthesis. FASN produces free palmitate (released by its thioesterase), which is subsequently activated to acyl-CoA by other enzymes; the term is pathway-context accurate. Kept non-core (the direct product term is fatty acid biosynthetic process). |
| GO:0004312 fatty acid synthase activity | EXP PMID:18455495 Differential activation of recombinant human acetyl-CoA carb... | ACCEPT | Summary: Reactome-assigned EXP annotation of the core fatty acid synthase activity. The linked PMID cached abstract is about acetyl-CoA carboxylase activation by citrate (the enzyme upstream of FASN) and does not itself demonstrate FASN catalysis; the citation is a poor match. The activity itself is correct and strongly supported elsewhere (PMID:8962082, PMID:26851298), so per policy the experimental annotation is retained rather than removed, but its supporting reference is flagged (see reference_review for PMID:18455495). |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Core localization. FASN is a soluble cytosolic enzyme; immunofluorescence (HPA IDA) correctly places it in the cytosol. |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | MARK AS OVER ANNOTATED | Summary: Immunofluorescence (HPA) plasma-membrane signal. FASN is a cytosolic soluble enzyme with no membrane-anchoring features; this likely reflects peripheral/cortical staining or a minor pool. Kept per policy (IDA) but treated as a non-core, secondary localization. |
| GO:0005829 cytosol | IDA PMID:37308485 Atomic model for core modifying region of human fatty acid s... | ACCEPT | Summary: Core localization, supported by ComplexPortal IDA from the cryoEM study of the human FASN modifying region. Correct. |
| GO:0005835 fatty acid synthase complex | IPI PMID:39979457 Snapshots of acyl carrier protein shuttling in human fatty a... | ACCEPT | Summary: Core assembly. FASN is the sole component of the homodimeric fatty acid synthase complex (ComplexPortal CPX-26624); the cryoEM study confirms a stable homodimer. Correct cellular-component/complex annotation. |
| GO:0046949 fatty-acyl-CoA biosynthetic process | NAS PMID:39979457 Snapshots of acyl carrier protein shuttling in human fatty a... | KEEP AS NON CORE | Summary: NAS annotation placing FASN in fatty-acyl-CoA/palmitate biosynthesis, consistent with its role as the primary de novo lipogenesis enzyme. Pathway-context accurate; kept non-core relative to fatty acid biosynthetic process (its direct product is free palmitate). |
| GO:0004316 3-oxoacyl-[acyl-carrier-protein] reductase (NADPH) activity | IDA PMID:26851298 S-nitrosylation of fatty acid synthase regulates its activit... | ACCEPT | Summary: Directly assayed beta-ketoacyl reductase (KR) partial activity of human FASN. Genuine component activity of the megasynthase. Correct. |
| GO:0005737 cytoplasm | IDA PMID:17081065 Proteomic and bioinformatic characterization of the biogenes... | ACCEPT | Summary: IDA (large-scale) that FASN is active in the cytoplasm; consistent with its cytosolic localization and function. Correct, though cytosol (GO:0005829) is more precise. |
| GO:0006631 fatty acid metabolic process | IDA PMID:26851298 S-nitrosylation of fatty acid synthase regulates its activit... | KEEP AS NON CORE | Summary: IDA that FASN participates in fatty acid metabolism, from the S-nitrosylation/activity study. Correct but a general parent of the core fatty acid biosynthetic process (GO:0006633). Kept as accurate but non-core. |
| GO:0019171 (3R)-hydroxyacyl-[acyl-carrier-protein] dehydratase activity | IDA PMID:8962082 Cloning and expression of the multifunctional human fatty ac... | ACCEPT | Summary: Directly assayed beta-hydroxyacyl dehydratase (DH) partial activity in recombinant human FASN domain I. Genuine component activity. Correct. |
| GO:0004312 fatty acid synthase activity | EXP PMID:26851298 S-nitrosylation of fatty acid synthase regulates its activit... | ACCEPT | Summary: Core molecular function, experimentally supported: this study directly measures human FASN enzymatic activity (and its regulation by S-nitrosylation). Correct. |
| GO:0004313 [acyl-carrier-protein] S-acetyltransferase activity | EXP PMID:26851298 S-nitrosylation of fatty acid synthase regulates its activit... | ACCEPT | Summary: Experimentally supported [ACP] S-acetyltransferase (MAT) partial activity of human FASN. Genuine component activity. Correct. |
| GO:0004315 3-oxoacyl-[acyl-carrier-protein] synthase activity | EXP PMID:26851298 S-nitrosylation of fatty acid synthase regulates its activit... | ACCEPT | Summary: Experimentally supported condensing (KS / beta-ketoacyl synthase) partial activity of human FASN. Genuine component activity. Correct. |
| GO:0019171 (3R)-hydroxyacyl-[acyl-carrier-protein] dehydratase activity | EXP PMID:26851298 S-nitrosylation of fatty acid synthase regulates its activit... | ACCEPT | Summary: Experimentally supported beta-hydroxyacyl dehydratase (DH) partial activity of human FASN (duplicate of the IDA from PMID:8962082). Genuine component activity. Correct. |
| GO:0141148 enoyl-[acyl-carrier-protein] reductase (NADPH) activity | EXP PMID:26851298 S-nitrosylation of fatty acid synthase regulates its activit... | ACCEPT | Summary: Experimentally supported enoyl reductase (ER) partial activity of human FASN. Genuine component activity. Correct. |
| GO:0004313 [acyl-carrier-protein] S-acetyltransferase activity | IDA PMID:8962082 Cloning and expression of the multifunctional human fatty ac... | ACCEPT | Summary: Directly assayed [ACP] S-acetyltransferase (MAT) partial activity in recombinant human FASN domain I. Genuine component activity. Correct. |
| GO:0044788 host-mediated perturbation of viral process | IDA PMID:34320401 Inhibitors of VPS34 and fatty-acid metabolism suppress SARS-... | KEEP AS NON CORE | Summary: FASN activity/de novo fatty acid synthesis is required for SARS-CoV-2 replication; FASN knockout impairs replication and is rescued by fatty acids. This is the UniProt "microbial infection" FUNCTION. A genuine host-pathogen context role but not a core cellular function of the enzyme; kept non-core. |
| GO:0045296 cadherin binding | HDA PMID:25468996 E-cadherin interactome complexity and robustness resolved by... | MARK AS OVER ANNOTATED | Summary: From a high-throughput E-cadherin proximity-interactome dataset in which FASN is one of hundreds of proximal proteins. Reflects proximity/abundance rather than a dedicated cadherin-binding molecular function. Over-annotation. |
| GO:0001649 osteoblast differentiation | HDA PMID:16210410 Differential expression profiling of membrane proteins by qu... | KEEP AS NON CORE | Summary: Derived from a differential membrane-proteomics dataset during osteoblast differentiation; FASN abundance changes correlatively. No direct evidence that FASN functions in osteoblast differentiation. Correlative high-throughput association; kept non-core. |
| GO:0016020 membrane | HDA PMID:16210410 Differential expression profiling of membrane proteins by qu... | MARK AS OVER ANNOTATED | Summary: Detection in a membrane-enriched proteomic fraction. FASN is a soluble cytosolic enzyme with no membrane-anchoring features; a high-throughput co-fractionation signal. Over-annotation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-163733 | ACCEPT | Summary: Reactome TAS placing FASN in the cytosol. Correct core localization. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-163756 | ACCEPT | Summary: Reactome TAS (FAS dimer formation) placing FASN in the cytosol. Correct core localization. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-199202 | ACCEPT | Summary: Reactome TAS (phosphopantetheine conjugation of the ACP domain) placing FASN in the cytosol. Correct core localization. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-75872 | ACCEPT | Summary: Reactome TAS (conversion of malonyl-CoA and acetyl-CoA to palmitate) placing FASN in the cytosol. Correct core localization. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9948053 | ACCEPT | Summary: Reactome TAS placing FASN in the cytosol. Correct core localization. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1655843 | ACCEPT | Summary: Reactome TAS (expression of FASN) placing FASN in the cytosol. Correct core localization. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9605063 | ACCEPT | Summary: Reactome TAS placing FASN in the cytosol. Correct core localization. |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | MARK AS OVER ANNOTATED | Summary: Detection of FASN in exosome proteomics. A high-throughput co-purifying signal for an abundant cytosolic enzyme; not a functional extracellular localization. Over-annotation. |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | MARK AS OVER ANNOTATED | Summary: Detection in an NK-cell membrane-proteome survey. FASN is a soluble cytosolic enzyme; a high-throughput membrane co-fractionation signal. Over-annotation. |
| GO:0003723 RNA binding | HDA PMID:22658674 Insights into RNA biology from an atlas of mammalian mRNA-bi... | MARK AS OVER ANNOTATED | Summary: From a system-wide mRNA-interactome capture study. There is no evidence for a dedicated RNA-binding function of FASN; the crosslink likely reflects the enzyme's abundance and nucleotide-cofactor (NADPH/acyl-CoA) chemistry. Over-annotation. |
| GO:0003723 RNA binding | HDA PMID:22681889 The mRNA-bound proteome and its global occupancy profile on ... | MARK AS OVER ANNOTATED | Summary: Second mRNA-interactome capture dataset; same caveat as PMID:22658674. No evidence for a functional RNA-binding role. Over-annotation. |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | MARK AS OVER ANNOTATED | Summary: Detection in urinary exosome proteomics; high-throughput co-purifying signal. Over-annotation of a cytosolic enzyme. |
| GO:0070062 extracellular exosome | HDA PMID:20458337 MHC class II-associated proteins in B-cell exosomes and pote... | MARK AS OVER ANNOTATED | Summary: Detection in B-cell exosome proteomics; high-throughput co-purifying signal. Over-annotation of a cytosolic enzyme. |
| GO:0005515 protein binding | IPI PMID:18022563 Mechanism and substrate recognition of human holo ACP syntha... | MARK AS OVER ANNOTATED | Summary: IPI interaction with AASDHPPT (Q9NRN7), the human holo-ACP synthase / phosphopantetheinyl transferase that installs the 4'-phosphopantetheine on the FASN ACP domain (co-crystal structure). This is a functionally important, mechanistically specific interaction, but the bare "protein binding" term is uninformative. Kept (IPI) but flagged as over-annotated. |
| GO:0006631 fatty acid metabolic process | TAS PMID:7835891 Isolation and chromosomal mapping of genomic clones encoding... | KEEP AS NON CORE | Summary: TAS from the human FASN genomic cloning paper. Correct but a general parent of the core fatty acid biosynthetic process (GO:0006633). Kept as accurate but non-core. |
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