ACLY

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005829 cytosol	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) inference that ACLY is active in the cytosol. This matches the experimentally established primary localization of this cytosolic acetyl-CoA-generating enzyme. Correct core localization. Supporting Evidence: PMID:9116495 ATP:citrate lyase (ACL) is a major generator of cytosolic acetyl-coenzymeA
GO:0006633 fatty acid biosynthetic process	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic inference that ACLY is involved in fatty acid biosynthesis. ACLY supplies the acetyl-CoA that is the committed carbon source for de novo fatty acid synthesis; this is a central physiological role of the gene. Consistent with experimental IDA evidence. Supporting Evidence: file:human/ACLY/ACLY-uniprot.txt the latter serving as common substrate in multiple biochemical reactions in protein, carbohydrate and lipid metabolism
GO:0003878 ATP citrate synthase activity	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic inference of the gene's own core molecular function, ATP citrate synthase activity (EC 2.3.3.8). Strongly supported by multiple experimental IDA instances and by the UniProt curated function/catalytic activity. Redundant with the experimental annotations but correct; retain. Supporting Evidence: file:human/ACLY/ACLY-uniprot.txt Catalyzes the cleavage of citrate into oxaloacetate and acetyl-CoA
GO:0006085 acetyl-CoA biosynthetic process	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic inference that ACLY is involved in acetyl-CoA biosynthesis. Acetyl-CoA is a direct product of the ACLY reaction, making this a core biological process. Well supported. Supporting Evidence: PMID:31873304 ATP-citrate lyase (ACLY) is the predominant source of nucleocytosolic acetyl-CoA
GO:0003824 catalytic activity	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	Summary: Uninformative root-level catalytic activity term applied electronically from an InterPro domain (succinyl-CoA ligase C-terminal). ACLY's catalytic activity is captured precisely by GO:0003878 (ATP citrate synthase activity), so this generic parent is an over-annotation.
GO:0003878 ATP citrate synthase activity	IEA GO_REF:0000120	ACCEPT	Summary: Electronic annotation of the gene's own core molecular function via ARBA/Ensembl/InterPro/ Rhea/EC mapping. This is the correct enzymatic activity of ACLY and matches multiple experimental IDA annotations; retain as core despite being redundant IEA. Supporting Evidence: file:human/ACLY/ACLY-uniprot.txt Catalyzes the cleavage of citrate into oxaloacetate and acetyl-CoA
GO:0005829 cytosol	IEA GO_REF:0000044	ACCEPT	Summary: Electronic localization annotation derived from the UniProt Subcellular Location keyword (cytosol). Matches the experimentally established primary location. Correct core CC. Supporting Evidence: file:human/ACLY/ACLY-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:0006085 acetyl-CoA biosynthetic process	IEA GO_REF:0000002	ACCEPT	Summary: InterPro2GO electronic annotation to acetyl-CoA biosynthetic process from the ATP-citrate synthase InterPro signature. Acetyl-CoA is a direct product of the reaction; correct core BP, redundant with experimental IDA/IMP. Supporting Evidence: PMID:31873304 ATP-citrate lyase (ACLY) is the predominant source of nucleocytosolic acetyl-CoA
GO:0006101 citrate metabolic process	IEA GO_REF:0000002	ACCEPT	Summary: InterPro2GO electronic annotation to citrate metabolic process. Citrate is the substrate consumed by ACLY; correct core BP, redundant with the experimental IDA (PMID:1371749). Supporting Evidence: PMID:39881208 In the cytosol, ATP citrate lyase (ACLY) converts citrate into oxaloacetate and acetyl-CoA
GO:0006637 acyl-CoA metabolic process	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: ARBA electronic annotation to the broad parent acyl-CoA metabolic process. ACLY produces acetyl-CoA (an acyl-CoA), so this is not wrong, but it is a less informative generalization of the acetyl-CoA-specific processes already annotated. Keep as non-core.
GO:0046912 acyltransferase activity, acyl groups converted into alkyl on transfer	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	Summary: InterPro2GO electronic MF annotation from the generic citrate synthase InterPro signatures. This decarboxylating acyltransferase term does not accurately describe the ATP-citrate lyase reaction, which is fully captured by GO:0003878 (ATP citrate synthase activity). Imprecise electronic over-annotation.
GO:0015936 coenzyme A metabolic process	IDA PMID:31873304 Molecular basis for acetyl-CoA production by ATP-citrate lya...	ACCEPT	Summary: ComplexPortal IDA annotation (from the cryo-EM mechanistic study) to coenzyme A metabolic process. CoA is a substrate consumed to form acetyl-CoA in the ACLY reaction; correct BP. Retained, though acetyl-CoA biosynthetic process is the more informative core term. Supporting Evidence: PMID:31873304 Together these domains use glycolytically-derived citrate with Mg-ATP and Coenzyme-A (CoA) cosubstrates to produce the acetyl-CoA and oxaloacetate (OAA) coproducts
GO:0140615 ATP-dependent citrate lyase complex	IPI PMID:31873304 Molecular basis for acetyl-CoA production by ATP-citrate lya...	ACCEPT	Summary: ComplexPortal annotation that ACLY is part of the ATP-dependent citrate lyase complex. In human this complex is the ACLY homotetramer resolved by cryo-EM. Correct core CC/complex annotation. Supporting Evidence: PMID:31873304 ACLY forms a homotetramer with a rigid
GO:0005829 cytosol	IDA GO_REF:0000052	ACCEPT	Summary: Immunofluorescence-based (HPA) IDA localization to cytosol. Consistent with the established primary location of ACLY. Correct core CC. Supporting Evidence: file:human/ACLY/ACLY-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:0006085 acetyl-CoA biosynthetic process	IMP PMID:39881208 SLC25A1 and ACLY maintain cytosolic acetyl-CoA and regulate ...	ACCEPT	Summary: IMP annotation to acetyl-CoA biosynthetic process based on ACLY knockdown/inhibition experiments showing loss of cytosolic acetyl-CoA production. Directly supports ACLY's core role in generating acetyl-CoA from citrate. Supporting Evidence: PMID:39881208 In the cytosol, ATP citrate lyase (ACLY) converts citrate into oxaloacetate and acetyl-CoA
GO:0110076 negative regulation of ferroptosis	IMP PMID:39881208 SLC25A1 and ACLY maintain cytosolic acetyl-CoA and regulate ...	KEEP AS NON CORE	Summary: IMP annotation: ACLY knockdown/inhibition sensitizes cancer cells to ferroptosis, so ACLY normally suppresses it. This is a genuine but downstream, context-specific consequence of ACLY supplying acetyl-CoA that sustains FSP1 acetylation and stability, not a direct core function of the enzyme. Keep as a non-core physiological role. Supporting Evidence: PMID:39881208 ACLY knockdown heightened cell susceptibility to RSL3- and erastin-induced ferroptosis
GO:0006633 fatty acid biosynthetic process	IDA PMID:10653665 Phosphorylation of recombinant human ATP:citrate lyase by cA...	ACCEPT	Summary: Experimental (IDA) annotation linking ACLY to fatty acid biosynthesis. ACLY generates the acetyl-CoA that is the building block for de novo fatty acid synthesis; this is a central physiological function. Accept. Supporting Evidence: PMID:19286649 The ACL-dependent synthesis of acetyl-CoA is thought to be an essential step for the de novo synthesis of fatty acids and cholesterol
GO:0006633 fatty acid biosynthetic process	IDA PMID:19286649 A novel direct homogeneous assay for ATP citrate lyase.	ACCEPT	Summary: Experimental (IDA) annotation to fatty acid biosynthetic process from the direct ACL activity assay study, which frames acetyl-CoA production by ACLY as the essential step for de novo fatty acid and cholesterol synthesis. Correct core physiological role. Supporting Evidence: PMID:19286649 The ACL-dependent synthesis of acetyl-CoA is thought to be an essential step for the de novo synthesis of fatty acids and cholesterol
GO:0003878 ATP citrate synthase activity	IDA PMID:10653665 Phosphorylation of recombinant human ATP:citrate lyase by cA...	ACCEPT	Summary: Direct experimental demonstration of ATP citrate synthase activity: recombinant human ACLY was purified and its kinetics (citrate/CoA/ATP dependence) characterized before and after phosphorylation. This is the core molecular function. Accept. Supporting Evidence: PMID:10653665 Recombinantly expressed human ATP:citrate lyase was purified from E. coli, and its kinetic behavior was characterized before and after phosphorylation
GO:0003878 ATP citrate synthase activity	IDA PMID:19286649 A novel direct homogeneous assay for ATP citrate lyase.	ACCEPT	Summary: Direct experimental measurement of ACL enzyme activity (a novel direct homogeneous assay detecting acetyl-CoA produced from citrate, CoA, ATP and Mg2+). Confirms the core molecular function. Accept. Supporting Evidence: PMID:19286649 ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes the synthesis of acetyl-CoA and oxaloacetate using citrate, CoA, and ATP as substrates
GO:0003878 ATP citrate synthase activity	IDA PMID:9116495 Variant cDNA sequences of human ATP:citrate lyase: cloning, ...	ACCEPT	Summary: Direct experimental annotation: recombinant human ACL was purified to homogeneity as an active tetramer and its enzymology characterized. Core molecular function. Accept. Supporting Evidence: PMID:9116495 Expression of the hACL cDNA in Spodoptera frugiperda 9 insect cells resulted in the production of high levels of soluble, active enzyme
GO:0005829 cytosol	IDA PMID:9116495 Variant cDNA sequences of human ATP:citrate lyase: cloning, ...	ACCEPT	Summary: Experimental annotation of cytosolic localization. ACLY is described and purified as a cytosolic enzyme; the established primary location. Correct core CC. Supporting Evidence: PMID:9116495 ATP:citrate lyase (ACL) is a major generator of cytosolic acetyl-coenzymeA
GO:0015936 coenzyme A metabolic process	TAS PMID:1371749 Cloning and expression of a human ATP-citrate lyase cDNA.	ACCEPT	Summary: TAS annotation to coenzyme A metabolic process (BHF-UCL) from the human ACLY cloning study. CoA is a substrate of the ACLY reaction; correct BP, though acetyl-CoA biosynthetic process is more informative. Retain. Supporting Evidence: PMID:1371749 Further sequence analysis identified the His765 catalytic phosphorylation site, the ATP-binding site, as well as the CoA binding site
GO:0005576 extracellular region	TAS Reactome:R-HSA-6798751	MARK AS OVER ANNOTATED	Summary: Reactome (neutrophil-degranulation "Exocytosis of azurophil granule lumen proteins") localization to extracellular region. This reflects capture of an abundant cytosolic enzyme in a secretory/degranulation pathway rather than a site where ACLY performs its function. Not a functional location; over-annotation.
GO:0005576 extracellular region	TAS Reactome:R-HSA-6800434	MARK AS OVER ANNOTATED	Summary: Reactome (neutrophil-degranulation "Exocytosis of ficolin-rich granule lumen proteins") localization to extracellular region. As above, this is a degranulation-pathway capture of a cytosolic enzyme, not a functional location. Over-annotation.
GO:0035578 azurophil granule lumen	TAS Reactome:R-HSA-6798751	MARK AS OVER ANNOTATED	Summary: Reactome neutrophil-degranulation annotation placing ACLY in the azurophil granule lumen. ACLY is a cytosolic enzyme; its appearance in granule/degranulation proteomics does not indicate function in this compartment. Over-annotation.
GO:1904813 ficolin-1-rich granule lumen	TAS Reactome:R-HSA-6800434	MARK AS OVER ANNOTATED	Summary: Reactome neutrophil-degranulation annotation placing ACLY in the ficolin-1-rich granule lumen. Same rationale as the azurophil granule annotation: a degranulation-pathway capture of a cytosolic enzyme, not a functional location. Over-annotation.
GO:0003878 ATP citrate synthase activity	IDA PMID:1371749 Cloning and expression of a human ATP-citrate lyase cDNA.	ACCEPT	Summary: Experimental (IDA, BHF-UCL) annotation of the core molecular function. The human ACLY cDNA was expressed to yield an enzymatically active protein, and mutating the catalytic His diminished activity, directly demonstrating ATP citrate synthase activity. Accept. Supporting Evidence: PMID:1371749 Site-specific mutagenesis of His765----Ala diminishes the catalytic activity of the expressed ATP-citrate lyase protein
GO:0005524 ATP binding	TAS PMID:1371749 Cloning and expression of a human ATP-citrate lyase cDNA.	ACCEPT	Summary: TAS annotation for ATP binding. ATP is a co-substrate of ACLY and the enzyme contains an ATP-grasp domain with multiple mapped ATP-binding residues; the cloning study explicitly identified the ATP-binding site. Genuine molecular function. Accept. Supporting Evidence: PMID:1371749 Further sequence analysis identified the His765 catalytic phosphorylation site, the ATP-binding site, as well as the CoA binding site
GO:0006085 acetyl-CoA biosynthetic process	IDA PMID:1371749 Cloning and expression of a human ATP-citrate lyase cDNA.	ACCEPT	Summary: Experimental (IDA, BHF-UCL) annotation to acetyl-CoA biosynthetic process. Acetyl-CoA is the product of the demonstrated ACLY reaction; a core biological process for this gene. Accept. Supporting Evidence: PMID:31873304 ATP-citrate lyase (ACLY) is the predominant source of nucleocytosolic acetyl-CoA
GO:0006101 citrate metabolic process	IDA PMID:1371749 Cloning and expression of a human ATP-citrate lyase cDNA.	ACCEPT	Summary: Experimental (IDA, BHF-UCL) annotation to citrate metabolic process. Citrate is the substrate cleaved by ACLY; core BP. Accept. Supporting Evidence: PMID:39881208 In the cytosol, ATP citrate lyase (ACLY) converts citrate into oxaloacetate and acetyl-CoA
GO:0006107 oxaloacetate metabolic process	IDA PMID:1371749 Cloning and expression of a human ATP-citrate lyase cDNA.	ACCEPT	Summary: Experimental (IDA, BHF-UCL) annotation to oxaloacetate metabolic process. Oxaloacetate is a direct co-product of the ACLY reaction; core BP. Accept. Supporting Evidence: PMID:39881208 In the cytosol, ATP citrate lyase (ACLY) converts citrate into oxaloacetate and acetyl-CoA
GO:0006695 cholesterol biosynthetic process	TAS PMID:1371749 Cloning and expression of a human ATP-citrate lyase cDNA.	ACCEPT	Summary: TAS annotation to cholesterol biosynthetic process. ACLY-derived acetyl-CoA is the carbon source for cholesterol/isoprenoid synthesis, and ACLY inhibition (e.g. bempedoic acid) lowers cholesterol. A central physiological role of the gene. Accept. Supporting Evidence: PMID:9116495 which is required for both fatty acid and cholesterol biosynthesis
GO:0070062 extracellular exosome	HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres...	KEEP AS NON CORE	Summary: Detected in an extracellular-vesicle proteome. The protein is plausible EV content, but this is not where it functions. Reason: Cytosolic ATP-citrate lyase. Cytosolic protein (UniProt); cytosolic proteins, including abundant enzymes and cytoskeletal proteins, are expected and often promiscuous EV contents (MISEV2018 (PMID:30637094) category 2b). True, but not its core location. (Manual re-review for OMICS_EVIDENCE, 2026-10-10; previous action: MARK_AS_OVER_ANNOTATED.)
GO:0016020 membrane	HDA PMID:19946888 Defining the membrane proteome of NK cells.	MARK AS OVER ANNOTATED	Summary: High-throughput proteomics (HDA) detection of ACLY in an NK-cell membrane proteome. ACLY is a soluble cytosolic enzyme with no transmembrane domain; membrane co-purification does not indicate a functional membrane localization. Over-annotation.
GO:0070062 extracellular exosome	HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos...	KEEP AS NON CORE	Summary: Detected in an extracellular-vesicle proteome. The protein is plausible EV content, but this is not where it functions. Reason: Cytosolic ATP-citrate lyase. Cytosolic protein (UniProt); cytosolic proteins, including abundant enzymes and cytoskeletal proteins, are expected and often promiscuous EV contents (MISEV2018 (PMID:30637094) category 2b). True, but not its core location. (Manual re-review for OMICS_EVIDENCE, 2026-10-10; previous action: MARK_AS_OVER_ANNOTATED.)
GO:0003878 ATP citrate synthase activity	TAS PMID:23932781 Acetylation stabilizes ATP-citrate lyase to promote lipid bi...	ACCEPT	Summary: TAS annotation of the core molecular function from the ACLY acetylation/stability study, which treats ACLY as the ATP-citrate lyase that drives fatty acid synthesis. Correct core MF. Supporting Evidence: PMID:23932781 ATP-citrate lyase (ACLY) is upregulated or activated in several types of cancer, and inhibition of ACLY arrests proliferation of cancer cells
GO:0005515 protein binding	IPI PMID:23932781 Acetylation stabilizes ATP-citrate lyase to promote lipid bi...	MARK AS OVER ANNOTATED	Summary: Bare protein binding IPI (interactor UniProtKB:Q5T4S7). Per curation guidelines, "protein binding" is uninformative about ACLY's actual function; the biologically meaningful interactions (with the ubiquitination/acetylation machinery that regulates ACLY stability) are captured through PTM annotations instead. Marked as over-annotated rather than removed (experimental IPI).
GO:0008610 lipid biosynthetic process	IDA PMID:23932781 Acetylation stabilizes ATP-citrate lyase to promote lipid bi...	KEEP AS NON CORE	Summary: Experimental (IDA) annotation to the broad parent lipid biosynthetic process, from the study showing acetylation-stabilized ACLY promotes de novo lipid synthesis. Genuine, but the more specific children (fatty acid and cholesterol biosynthetic process) are already annotated; keep this general parent as non-core. Supporting Evidence: PMID:23932781 Substitution of 3K abolishes ACLY ubiquitylation and promotes de novo lipid synthesis, cell proliferation, and tumor growth
GO:0070062 extracellular exosome	HDA PMID:20458337 MHC class II-associated proteins in B-cell exosomes and pote...	KEEP AS NON CORE	Summary: Detected in an extracellular-vesicle proteome. The protein is plausible EV content, but this is not where it functions. Reason: Cytosolic ATP-citrate lyase. Cytosolic protein (UniProt); cytosolic proteins, including abundant enzymes and cytoskeletal proteins, are expected and often promiscuous EV contents (MISEV2018 (PMID:30637094) category 2b). True, but not its core location. (Manual re-review for OMICS_EVIDENCE, 2026-10-10; previous action: MARK_AS_OVER_ANNOTATED.)
GO:0005829 cytosol	TAS Reactome:R-HSA-163770	ACCEPT	Summary: Reactome TAS localization to cytosol (transcriptional-activation pathway context). Consistent with the established primary location of ACLY. Correct core CC. Supporting Evidence: file:human/ACLY/ACLY-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:0005829 cytosol	TAS Reactome:R-HSA-75848	ACCEPT	Summary: Reactome TAS localization to cytosol ("ACLY tetramer transforms CIT to Ac-CoA"). This is the compartment in which ACLY performs its catalytic function. Correct core CC. Supporting Evidence: file:human/ACLY/ACLY-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:0005829 cytosol	TAS Reactome:R-HSA-9734540	ACCEPT	Summary: Reactome TAS localization to cytosol ("ACLY tetramer binds ETC-1002-CoA", the bempedoic acid active metabolite). Correct primary location of ACLY. Accept. Supporting Evidence: file:human/ACLY/ACLY-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol

Gene Description

Existing Annotations Review

Core Functions

ATP binding: ATP is a co-substrate hydrolyzed during citrate cleavage; ACLY contains an ATP-grasp module in its ASH superdomain with multiple ATP-coordinating residues.

References

📚 Additional Documentation

Notes

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