CPT1C

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0006631 fatty acid metabolic process	IBA GO_REF:0000033	REMOVE	Summary: IBA annotation based on phylogenetic inference from CPT1 family. However, CPT1C has evolved a distinct function from its paralogs CPT1A and CPT1B. Recent reviews emphasize that CPT1C has markedly reduced canonical CPT1 enzymatic activity and functions primarily as a malonyl-CoA/nutrient sensor rather than a fatty acid metabolic enzyme (CPT1C-deep-research-falcon.md). The negated ISS annotation for this same term correctly reflects that CPT1C is NOT involved in fatty acid metabolism. Reason: CPT1C has neofunctionalized as a palmitoyl thioesterase rather than a fatty acid metabolic enzyme. While phylogenetically related to CPT1A/B which function in fatty acid metabolism, experimental evidence demonstrates CPT1C lacks the canonical CPT1 transferase activity. The IBA annotation incorrectly propagates ancestral function that CPT1C does not retain. Note: The negated ISS annotation for this term states the opposite (NOT fatty acid metabolic process) and is ACCEPTED. Supporting Evidence: PMID:30135643 CPT1C effect on AMPARs is likely due to changes in the palmitoylation state of GluA1
GO:0009437 carnitine metabolic process	IBA GO_REF:0000033	REMOVE	Summary: IBA annotation based on phylogenetic inference. However, CPT1C does not function in carnitine metabolism. Recent literature emphasizes CPT1C has poor canonical CPT1 catalysis and functions as a malonyl-CoA sensor rather than in carnitine-dependent metabolism (CPT1C-deep-research-falcon.md). The negated ISS annotation for this same term correctly reflects that CPT1C is NOT involved in carnitine metabolism. Reason: CPT1C has lost the carnitine-dependent transferase activity of the ancestral CPT1. It functions instead as a palmitoyl thioesterase. The IBA incorrectly infers carnitine involvement based on family membership, but functional studies demonstrate CPT1C is not involved in carnitine-dependent acyl transfer. Note: The negated ISS annotation for this term states the opposite (NOT carnitine metabolic process) and is ACCEPTED. Supporting Evidence: PMID:30135643 CPT1C acts on AMPAR through an enzymatic activity (dependent on a catalytic histidine) and not due to a mere structural interaction
GO:0005789 endoplasmic reticulum membrane	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation for ER membrane localization is correct and supported by experimental evidence. PMID:30135643 demonstrates CPT1C functions at the ER level and PMID:25751282 shows CPT1C localizes to the endoplasmic reticulum. Reason: ER membrane localization is well-supported by multiple lines of evidence including IDA from PMID:30135643. This distinguishes CPT1C from CPT1A/B which localize to mitochondrial outer membrane. Supporting Evidence: PMID:30135643 this data indicates that the depalmitoylating effect of CPT1C on AMPARs is clearly CPT1C specific and possibly happens at ER level
GO:0098734 macromolecule depalmitoylation	IEA GO_REF:0000108	ACCEPT	Summary: IEA annotation based on logical inference. This accurately reflects CPT1C's experimentally demonstrated function as a depalmitoylating enzyme. PMID:30135643 demonstrates the catalytic triad responsible for palmitoyl thioesterase activity. Reason: This annotation correctly captures the core molecular function of CPT1C. The depalmitoylation of GRIA1 to regulate AMPAR trafficking is the primary demonstrated function of CPT1C. Supporting Evidence: PMID:30135643 our experiments prove the involvement of a depalmitoylation process in the CPT1C-mediated increase of surface AMPARs
GO:0003824 catalytic activity	IEA GO_REF:0000117	ACCEPT	Summary: Very general term indicating catalytic activity. CPT1C does have catalytic activity as a palmitoyl thioesterase (EC 3.1.2.22). However, this term is too general to be informative - the specific activity GO:0008474 palmitoyl-(protein) hydrolase activity is more appropriate. Reason: While correct that CPT1C has catalytic activity, this is a root-level term that provides minimal information. Acceptable as IEA but the more specific palmitoyl-(protein) hydrolase activity annotation is the informative one. Supporting Evidence: PMID:30135643 CPT1C acts on AMPAR through an enzymatic activity (dependent on a catalytic histidine)
GO:0005789 endoplasmic reticulum membrane	IEA GO_REF:0000120	ACCEPT	Summary: Duplicate IEA annotation for ER membrane. Correctly supported by experimental evidence from PMID:30135643 and PMID:25751282. CPT1C localizes to ER, not mitochondria like CPT1A/B. Reason: Correct localization, supported by experimental data. Duplicate with IBA and ISS annotations for same term. Supporting Evidence: PMID:30135643 this data indicates that the depalmitoylating effect of CPT1C on AMPARs is clearly CPT1C specific and possibly happens at ER level PMID:25751282 CPT1C, which localizes to the endoplasmic reticulum, is expressed in motor neurons
GO:0006629 lipid metabolic process	IEA GO_REF:0000043	KEEP AS NON CORE	Summary: IEA based on UniProt keyword mapping. CPT1C is involved in lipid metabolism in a limited sense - it depalmitoylates protein substrates (removing palmitate, a lipid). However, this term implies involvement in general lipid metabolism pathways, which is misleading given CPT1C's specific role in protein depalmitoylation rather than lipid biosynthesis/degradation. Reason: While CPT1C does act on palmitate (a fatty acid/lipid), its function is protein depalmitoylation for receptor trafficking regulation, not classical lipid metabolism. The term is not wrong but may be over-interpretation. Supporting Evidence: PMID:30135643 CPT1C effect on AMPARs is likely due to changes in the palmitoylation state of GluA1
GO:0008474 palmitoyl-(protein) hydrolase activity	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation that correctly matches the experimentally demonstrated function of CPT1C. This is also supported by IDA evidence from PMID:30135643. UniProt now classifies CPT1C as "Palmitoyl thioesterase CPT1C" with EC 3.1.2.22. Reason: This is the correct molecular function for CPT1C. Supported by direct experimental evidence demonstrating palmitoyl thioesterase activity with characterized catalytic triad. Supporting Evidence: PMID:30135643 Ser 252, His 470 and Asp 474 are predicted to be the catalytic triad responsible for CPT1C palmitoyl thioesterase (PTE) activity
GO:0016740 transferase activity	IEA GO_REF:0000043	REMOVE	Summary: IEA based on keyword mapping from the carnitine palmitoyltransferase family annotation. However, CPT1C does NOT have transferase activity. Recent reviews emphasize CPT1C has markedly reduced canonical CPT1 enzymatic activity and is often described as a pseudoenzyme with limited transferase activity (CPT1C-deep-research-falcon.md). Reason: This annotation is INCORRECT. CPT1C is a hydrolase (thioesterase), not a transferase. The annotation is a computational error based on family membership. CPT1C has evolved away from the ancestral transferase function. Supporting Evidence: PMID:30135643 Ser 252, His 470 and Asp 474 are predicted to be the catalytic triad responsible for CPT1C palmitoyl thioesterase (PTE) activity
GO:0016746 acyltransferase activity	IEA GO_REF:0000120	REMOVE	Summary: IEA annotation incorrectly attributing acyltransferase activity to CPT1C. This conflicts with experimental evidence showing CPT1C functions as a thioesterase rather than a transferase. Reason: CPT1C does NOT have acyltransferase activity. It functions as a hydrolase (palmitoyl thioesterase). This annotation is computationally inferred based on family membership but is experimentally contradicted. Supporting Evidence: PMID:30135643 CPT1C acts on AMPAR through an enzymatic activity (dependent on a catalytic histidine) and not due to a mere structural interaction
GO:0016787 hydrolase activity	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation that is correct. CPT1C is a hydrolase - specifically a palmitoyl thioesterase that hydrolyzes thioester bonds to remove palmitate from palmitoylated proteins. Reason: Correct general classification. CPT1C catalyzes hydrolysis of thioester bonds (palmitoyl-protein + H2O = palmitate + protein), consistent with hydrolase activity. Supporting Evidence: PMID:30135643 Ser 252, His 470 and Asp 474 are predicted to be the catalytic triad responsible for CPT1C palmitoyl thioesterase (PTE) activity
GO:0030424 axon	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for axonal localization. Supported by literature showing CPT1C is expressed in motor neurons (PMID:25751282). Reason: Axonal localization is experimentally supported. CPT1C is expressed in neurons and localizes to axons as well as dendrites, consistent with its role in regulating AMPAR trafficking. Supporting Evidence: PMID:25751282 CPT1C, which localizes to the endoplasmic reticulum, is expressed in motor neurons
GO:0030425 dendrite	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for dendritic localization. Supported by PMID:25751282 showing CPT1C expression in motor neurons. Reason: Dendritic localization is experimentally supported. CPT1C functions in neurons to regulate AMPAR trafficking, and dendritic localization is consistent with this synaptic function. Supporting Evidence: PMID:25751282 CPT1C, which localizes to the endoplasmic reticulum, is expressed in motor neurons
GO:0005783 endoplasmic reticulum	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for ER localization. Well supported by multiple experimental studies. PMID:30135643 demonstrates CPT1C functions at the ER level. Reason: ER localization is a key distinguishing feature of CPT1C compared to mitochondrial CPT1A/B. Experimentally validated. Supporting Evidence: PMID:30135643 this data indicates that the depalmitoylating effect of CPT1C on AMPARs is clearly CPT1C specific and possibly happens at ER level
GO:0032281 AMPA glutamate receptor complex	IEA GO_REF:0000107	ACCEPT	Summary: IEA based on ortholog transfer. CPT1C is peripherally associated with the AMPAR complex. PMID:30135643 shows GluA1 and CPT1C coimmunoprecipitate and CPT1C acts on GluA1 to regulate AMPAR trafficking. Reason: CPT1C associates with the AMPAR complex but as a peripheral constituent, not as a core component. The biological relationship is valid - keep annotation but note peripheral nature. Supporting Evidence: PMID:30135643 the interaction between the GluA1 subunit of AMPARs and carnitine palmitoyltransferase 1C (CPT1C)
GO:0098794 postsynapse	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA annotation for postsynaptic localization. CPT1C regulates AMPAR trafficking which affects postsynaptic receptors, but CPT1C itself functions at the ER level rather than at the postsynaptic membrane. Reason: CPT1C functions at the ER to regulate AMPAR trafficking to postsynaptic membranes. Whether CPT1C itself localizes to the postsynapse is less certain - its primary site of action is ER. This annotation may be an over-interpretation based on its functional effects on postsynaptic receptors. Supporting Evidence: PMID:30135643 this data indicates that the depalmitoylating effect of CPT1C on AMPARs is clearly CPT1C specific and possibly happens at ER level
GO:0098978 glutamatergic synapse	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA annotation. CPT1C functionally regulates glutamatergic synaptic transmission through AMPAR trafficking control. Its role affects glutamatergic synapse function though its site of action is ER. Reason: CPT1C affects glutamatergic synapse function through AMPAR regulation, but localizes to ER rather than the synapse itself. The annotation captures functional relevance but not direct localization. Supporting Evidence: PMID:30135643 synaptic transmission in CPT1C knockout (KO) mice is diminished supporting a positive trafficking role for that protein
GO:0099072 regulation of postsynaptic membrane neurotransmitter receptor levels	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation accurately captures CPT1C's biological function. CPT1C modulates AMPAR surface expression through depalmitoylation of GluA1. PMID:30135643 demonstrates CPT1C re-expression increased the surface/intracellular ratio of GluA1. Reason: This is a core function of CPT1C. By depalmitoylating GluA1, CPT1C regulates AMPAR trafficking to the postsynaptic membrane, controlling receptor levels and synaptic transmission. Supporting Evidence: PMID:30135643 the re-expression of CPT1C increased the surface/intracellular ratio of GluA1 while CPT1C(H470A) did not
GO:0004095 carnitine O-palmitoyltransferase activity	ISS NOT GO_REF:0000024	ACCEPT	Summary: Negated (NOT) annotation correctly stating that CPT1C does NOT have carnitine O-palmitoyltransferase activity. This is explicitly supported by experimental and review literature showing CPT1C has markedly reduced canonical CPT1 enzymatic activity (CPT1C-deep-research-falcon.md). Reason: This NOT annotation is critical and MUST be retained. It correctly distinguishes CPT1C from CPT1A/B and prevents incorrect functional inference based on family membership. Experimental evidence supports that CPT1C lacks the canonical CPT1 transferase activity. Supporting Evidence: PMID:30135643 Ser 252, His 470 and Asp 474 are predicted to be the catalytic triad responsible for CPT1C palmitoyl thioesterase (PTE) activity
GO:0005739 mitochondrion	ISS NOT GO_REF:0000024	ACCEPT	Summary: Negated (NOT) annotation correctly stating CPT1C is NOT localized to mitochondria. Unlike CPT1A and CPT1B which are outer mitochondrial membrane proteins, CPT1C localizes to the ER (PMID:25751282, PMID:30135643). Reason: This NOT annotation is critical for distinguishing CPT1C from its paralogs. CPT1C's ER localization rather than mitochondrial is consistent with its distinct thioesterase function rather than fatty acid transport into mitochondria for beta-oxidation. Supporting Evidence: PMID:30135643 this data indicates that the depalmitoylating effect of CPT1C on AMPARs is clearly CPT1C specific and possibly happens at ER level PMID:25751282 CPT1C, which localizes to the endoplasmic reticulum, is expressed in motor neurons
GO:0005783 endoplasmic reticulum	IDA PMID:30135643 Mechanisms of CPT1C-Dependent AMPAR Trafficking Enhancement.	ACCEPT	Summary: High-quality IDA annotation demonstrating ER localization. PMID:30135643 used co-localization with ER markers to show CPT1C localizes to ER in both COS-7 cells and neurons. Reason: Core localization annotation supported by direct experimental assay. ER localization is essential for CPT1C function in regulating AMPAR trafficking at the early secretory pathway level. Supporting Evidence: PMID:30135643 this data indicates that the depalmitoylating effect of CPT1C on AMPARs is clearly CPT1C specific and possibly happens at ER level
GO:0005789 endoplasmic reticulum membrane	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation for ER membrane localization. Supported by experimental data showing CPT1C is a multi-pass membrane protein in the ER. Reason: ER membrane localization is well-supported. CPT1C has two transmembrane helices and is an integral ER membrane protein. Supporting Evidence: PMID:30135643 this data indicates that the depalmitoylating effect of CPT1C on AMPARs is clearly CPT1C specific and possibly happens at ER level
GO:0006631 fatty acid metabolic process	ISS NOT GO_REF:0000024	ACCEPT	Summary: Negated (NOT) annotation correctly stating CPT1C is NOT involved in fatty acid metabolic process. This distinguishes CPT1C from CPT1A/B which function in fatty acid transport into mitochondria for beta-oxidation. Recent reviews confirm CPT1C functions as a malonyl-CoA sensor rather than in fatty acid metabolism (CPT1C-deep-research-falcon.md). Reason: This NOT annotation is important and accurate. CPT1C has evolved a distinct function (protein depalmitoylation) from the ancestral CPT1 function in fatty acid metabolism. Note: The positive IBA annotation for this term is REMOVED as it incorrectly states CPT1C IS involved in fatty acid metabolism. Supporting Evidence: PMID:30135643 CPT1C effect on AMPARs is likely due to changes in the palmitoylation state of GluA1
GO:0008474 palmitoyl-(protein) hydrolase activity	IDA PMID:30135643 Mechanisms of CPT1C-Dependent AMPAR Trafficking Enhancement.	ACCEPT	Summary: Key IDA annotation demonstrating CPT1C's core molecular function as a palmitoyl thioesterase. PMID:30135643 identified the catalytic triad (Ser-252, His-470, Asp-474) and showed mutation of these residues abolishes activity. Reason: This is the PRIMARY molecular function of CPT1C. UniProt now classifies CPT1C as "Palmitoyl thioesterase CPT1C" (EC 3.1.2.22). The enzyme depalmitoylates GRIA1 to regulate AMPAR trafficking. Supporting Evidence: PMID:30135643 Ser 252, His 470 and Asp 474 are predicted to be the catalytic triad responsible for CPT1C palmitoyl thioesterase (PTE) activity PMID:30135643 the histidine residue (His 470) of CPT1C is crucial for the increase in GluA1 surface expression in neurons
GO:0009437 carnitine metabolic process	ISS NOT GO_REF:0000024	ACCEPT	Summary: Negated (NOT) annotation correctly stating CPT1C is NOT involved in carnitine metabolic process. CPT1C binds malonyl-CoA and palmitoyl-CoA but does not catalyze carnitine-dependent acyl transfer. Reason: This NOT annotation is accurate and important. CPT1C lacks the carnitine palmitoyltransferase activity that would involve it in carnitine metabolism. It functions as a thioesterase independent of carnitine. Note: The positive IBA annotation for this term is REMOVED as it incorrectly states CPT1C IS involved in carnitine metabolism. Supporting Evidence: PMID:30135643 Ser 252, His 470 and Asp 474 are predicted to be the catalytic triad responsible for CPT1C palmitoyl thioesterase (PTE) activity
GO:0005515 protein binding	IPI PMID:25751282 Mutation in CPT1C Associated With Pure Autosomal Dominant Sp...	KEEP AS NON CORE	Summary: IPI annotation for protein binding based on interaction with ATL1 (atlastin-1). PMID:25751282 demonstrated CPT1C interacts with atlastin-1, an endoplasmic reticulum protein encoded by the ATL1 gene. Reason: While the protein interaction is valid, GO:0005515 "protein binding" is too general to be informative. CPT1C interacts with ATL1 (PMID:25751282) and with GRIA1 substrate (PMID:30135643). The annotation is not wrong but provides minimal functional insight. Supporting Evidence: PMID:25751282 CPT1C, which localizes to the endoplasmic reticulum, is expressed in motor neurons and interacts with atlastin-1 PMID:30135643 the interaction between the GluA1 subunit of AMPARs and carnitine palmitoyltransferase 1C (CPT1C)
GO:0030424 axon	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation for axonal localization. Supported by PMID:25751282 showing CPT1C expression in motor neurons. Reason: Duplicate of IEA annotation for same term. Axonal localization is experimentally supported. Supporting Evidence: PMID:25751282 CPT1C, which localizes to the endoplasmic reticulum, is expressed in motor neurons
GO:0030425 dendrite	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation for dendritic localization. Supported by PMID:25751282. Reason: Dendritic localization supported by experimental evidence. Supporting Evidence: PMID:25751282 CPT1C, which localizes to the endoplasmic reticulum, is expressed in motor neurons
GO:0005783 endoplasmic reticulum	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation for ER localization. Multiple supporting evidence sources. Reason: ER localization is well-established for CPT1C. Supporting Evidence: PMID:30135643 this data indicates that the depalmitoylating effect of CPT1C on AMPARs is clearly CPT1C specific and possibly happens at ER level
GO:0002084 protein depalmitoylation	IDA PMID:30135643 Mechanisms of CPT1C-Dependent AMPAR Trafficking Enhancement.	NEW	Summary: NEW annotation suggestion. CPT1C depalmitoylates GRIA1, which is the mechanism by which it regulates AMPAR trafficking. This biological process annotation captures the core function of CPT1C. Reason: This process annotation directly describes CPT1C's demonstrated biological activity - removing palmitate from GRIA1 protein. The GO:0098734 "macromolecule depalmitoylation" is present as IEA, but GO:0002084 "protein depalmitoylation" is more specific and should have IDA support from PMID:30135643. Supporting Evidence: PMID:30135643 our experiments prove the involvement of a depalmitoylation process in the CPT1C-mediated increase of surface AMPARs PMID:30135643 the depalmitoylating effect of CPT1C on AMPARs is clearly CPT1C specific
GO:1904719 positive regulation of AMPA glutamate receptor clustering	IDA PMID:30135643 Mechanisms of CPT1C-Dependent AMPAR Trafficking Enhancement.	NEW	Summary: NEW annotation suggestion. CPT1C positively regulates AMPAR surface expression and clustering. Knockout of CPT1C reduces AMPAR surface levels as shown in PMID:30135643. Reason: CPT1C increases AMPAR surface expression through depalmitoylation of GluA1. This represents positive regulation of AMPAR clustering at the plasma membrane. Supporting Evidence: PMID:30135643 synaptic transmission in CPT1C knockout (KO) mice is diminished supporting a positive trafficking role for that protein PMID:30135643 the re-expression of CPT1C increased the surface/intracellular ratio of GluA1 while CPT1C(H470A) did not

Gene Description

Existing Annotations Review

Core Functions

Primary molecular function. CPT1C is a palmitoyl thioesterase (EC 3.1.2.22) with catalytic triad Ser-252, His-470, Asp-474. Demonstrated by mutagenesis studies in PMID:30135643.

References

Deep Research

Falcon

📚 Additional Documentation

Notes

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