Palmitoyl thioesterase (EC 3.1.2.22) specifically expressed in the endoplasmic reticulum of neurons. Unlike its paralogs CPT1A and CPT1B, CPT1C does NOT have carnitine O-palmitoyltransferase activity (EC 2.3.1.21) and is not involved in fatty acid beta-oxidation. CPT1C functions as a depalmitoylating enzyme that modulates AMPA receptor (AMPAR) trafficking to the plasma membrane through depalmitoylation of GRIA1. The catalytic activity depends on the Ser-252, His-470, Asp-474 triad. Also regulates AMPAR trafficking through regulation of SACM1L phosphatidylinositol-3-phosphatase activity. Mutations cause SPG73 spastic paraplegia.
| 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
|
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template_variables:
organism: human
gene_id: CPT1C
gene_symbol: CPT1C
uniprot_accession: Q8TCG5
protein_description: 'RecName: Full=Palmitoyl thioesterase CPT1C {ECO:0000305};
EC=3.1.2.22 {ECO:0000269|PubMed:30135643}; AltName: Full=Carnitine O-palmitoyltransferase
1, brain isoform; Short=CPTI-B; AltName: Full=Carnitine palmitoyltransferase 1C;
AltName: Full=Carnitine palmitoyltransferase I {ECO:0000303|PubMed:12376098};
Short=CPT I-C {ECO:0000303|PubMed:12376098};'
gene_info: Name=CPT1C {ECO:0000312|HGNC:HGNC:18540}; Synonyms=CATL1;
organism_full: Homo sapiens (Human).
protein_family: Belongs to the carnitine/choline acetyltransferase family.
protein_domains: Carn_acyl_trans. (IPR000542); CAT-like_dom_sf. (IPR023213); Cho/carn_acyl_trans.
(IPR039551); Cho/carn_acyl_trans_2. (IPR042231); CPT_N. (IPR032476)
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BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.
DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'CPT1C' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information
Please provide a comprehensive research report on the gene CPT1C (gene ID: CPT1C, UniProt: Q8TCG5) in human.
The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
We are interested in where in or outside the cell the gene product carries out its function.
We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.
Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.
Question: You are an expert researcher providing comprehensive, well-cited information.
Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies
Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.
BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.
DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'CPT1C' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information
Please provide a comprehensive research report on the gene CPT1C (gene ID: CPT1C, UniProt: Q8TCG5) in human.
The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
We are interested in where in or outside the cell the gene product carries out its function.
We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.
Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.
Plan
- Verified identity and nomenclature: CPT1C (human; UniProt Q8TCG5), a CPT1-family member that is neuron-enriched and ER-localized, mitigating symbol ambiguity and ensuring correct mapping of evidence (completed).
- Retrieved and synthesized recent (2023–2024) literature on function, localization, malonyl-CoA sensing, and disease relevance; emphasized authoritative reviews and primary studies (completed via sources below).
- Extracted precise evidence on pathways (AMPK–ACC–malonyl-CoA), neuronal roles, and cancer relevance (completed).
- Created a compact artifact table summarizing key claims, sources, and URLs to support rapid verification (completed).
- Synthesized the comprehensive research report with citations, URLs, and publication years; prioritized 2023–2024 sources (completed).
Artifact summary
| Topic | Key claim | Source (year) | Journal | URL |
|---|---|---:|---|---|
| Identity / Localization | Human CPT1C is a brain-enriched neuronal CPT1 isoform, localized to the endoplasmic reticulum (ER) and encoded at 19q13.33 (UniProt Q8TCG5). (duan2024theroleof pages 4-5) | 2024 | Biology | https://doi.org/10.3390/biology13110892 |
| Family / Malonyl-CoA sensitivity | Member of the CPT1/carnitine acyltransferase family; retains malonyl-CoA binding motifs and can bind malonyl-CoA, supporting a malonyl-CoA sensing role. (duan2024theroleof pages 4-5, schlaepfer2020cpt1amediatedfatoxidation pages 5-6) | 2024; 2020 | Biology; Endocrinology | https://doi.org/10.3390/biology13110892; https://doi.org/10.1210/endocr/bqz046 |
| Catalytic activity vs pseudoenzyme | CPT1C displays markedly reduced/"suboptimal" canonical CPT1 enzymatic activity vs CPT1A/B and is often described as a pseudoenzyme (limited transferase activity reported; enzymatic role remains ambiguous). (fado2023tobeor pages 1-2, muley2023cpt1cdownregulationcauses pages 1-2, duan2024theroleof pages 9-11) | 2023; 2023; 2024 | Cell Death & Disease; Int J Mol Sci; Biology | https://doi.org/10.1038/s41419-023-05599-1; https://doi.org/10.3390/ijms24020946; https://doi.org/10.3390/biology13110892 |
| Primary biochemical function | Acts primarily as a nutrient / malonyl-CoA sensor that regulates lipid metabolism, autophagy and adaptation to energy/hypoxic stress rather than serving as a main mitochondrial long‑chain acyl‑carnitine transferase. (fado2023tobeor pages 1-2, duan2024theroleof pages 9-11) | 2023; 2024 | Cell Death & Disease; Biology | https://doi.org/10.1038/s41419-023-05599-1; https://doi.org/10.3390/biology13110892 |
| Neuronal roles & subcellular functions | ER-resident in neurons; implicated in hypothalamic control of brown adipose thermogenesis and in regulating lysosome/secretory pathway, vesicle trafficking and dendritic spine maturation. (schlaepfer2020cpt1amediatedfatoxidation pages 5-6, fado2023tobeor pages 1-2) | 2020; 2023 | Endocrinology; Cell Death & Disease | https://doi.org/10.1210/endocr/bqz046; https://doi.org/10.1038/s41419-023-05599-1 |
| AMPK–ACC–malonyl‑CoA pathway links | CPT1C expression/activity is regulated by cellular energy signals (AMPK-sensitive 5'UTR / translational control) and tied to the ACC–malonyl-CoA axis, consistent with a malonyl‑CoA sensing mechanism. (duan2024theroleof pages 4-5, fado2023tobeor pages 1-2) | 2024; 2023 | Biology; Cell Death & Disease | https://doi.org/10.3390/biology13110892; https://doi.org/10.1038/s41419-023-05599-1 |
| Cancer relevance (hypoxia/nutrient stress, APC/C regulation, chemo resistance, CAFs) | CPT1C is frequently upregulated in tumors enabling adaptation to hypoxia/nutrient stress; CPT1C levels are cell-cycle regulated (APC/C substrate) and influence tumor growth, chemoresistance (anthracycline uptake/response) and stromal/CAF-driven immunosuppression. (fado2023tobeor pages 1-2, muley2023cpt1cdownregulationcauses pages 1-2, duan2024theroleof pages 9-11) | 2023; 2023; 2024 | Cell Death & Disease; Int J Mol Sci; Biology | https://doi.org/10.1038/s41419-023-05599-1; https://doi.org/10.3390/ijms24020946; https://doi.org/10.3390/biology13110892 |
| Comparison to CPT1A/B | CPT1A/B are mitochondrial, catalytically active long‑chain acyl‑CoA→acyl‑carnitine transferases (robust FAO drivers and malonyl‑CoA sensitive); by contrast CPT1C is ER-localized, less catalytically active, and functions mainly in sensing/regulation rather than canonical mitochondrial FA import. (schlaepfer2020cpt1amediatedfatoxidation pages 5-6, fado2023tobeor pages 1-2) | 2020; 2023 | Endocrinology; Cell Death & Disease | https://doi.org/10.1210/endocr/bqz046; https://doi.org/10.1038/s41419-023-05599-1 |
Table: Compact table summarizing key evidence about human CPT1C (UniProt Q8TCG5): identity, localization, enzymatic activity debates, regulatory links, neuronal roles, cancer relevance, and comparison to CPT1A/B, with sources (context IDs) and DOIs for verification.
Comprehensive research report: Human CPT1C (UniProt Q8TCG5)
Verification of target identity and scope
- Gene/protein identity: The target is human CPT1C (UniProt Q8TCG5), a member of the CPT1 family distinct from CPT1A/B; it is predominantly neuronal and localizes to the endoplasmic reticulum (ER), not mitochondria (https://doi.org/10.3390/biology13110892, Nov 2024; https://doi.org/10.1210/endocr/bqz046, 2020). These recent sources confirm nomenclature, organism, and subcellular localization consistent with the UniProt description, avoiding confusion with CPT1A/B (duan2024theroleof pages 4-5, schlaepfer2020cpt1amediatedfatoxidation pages 5-6).
1) Key concepts and definitions (current understanding)
- Family/definition: CPT1C is the brain-enriched isoform of the carnitine palmitoyltransferase 1 (CPT1) family. Unlike CPT1A/B, which reside in mitochondria and catalyze acyl‑CoA→acyl‑carnitine transfer to drive fatty acid β‑oxidation, CPT1C is ER-resident in neurons and exhibits markedly reduced canonical CPT1 catalytic activity (https://doi.org/10.1038/s41419-023-05599-1, Jan 2023; https://doi.org/10.1210/endocr/bqz046, 2020) (fado2023tobeor pages 1-2, schlaepfer2020cpt1amediatedfatoxidation pages 5-6).
- Malonyl‑CoA sensing concept: CPT1C retains motifs to bind malonyl‑CoA and is proposed to act primarily as a nutrient/malonyl‑CoA sensor that regulates other lipid and trafficking proteins, rather than serving as a major mitochondrial fatty‑acid transporter (https://doi.org/10.3390/biology13110892, 2024; https://doi.org/10.1038/s41419-023-05599-1, 2023) (duan2024theroleof pages 4-5, fado2023tobeor pages 1-2).
- Cellular localization: Multiple studies place CPT1C at the ER in neurons and cancer cells, highlighting a distinct cellular role from the mitochondrial CPT1A/B isoforms (https://doi.org/10.1210/endocr/bqz046, 2020; https://doi.org/10.1038/s41419-023-05599-1, 2023) (schlaepfer2020cpt1amediatedfatoxidation pages 5-6, fado2023tobeor pages 1-2).
2) Molecular function, catalytic activity, and substrate specificity
- Catalytic activity: Contemporary reviews and primary studies emphasize that CPT1C has “inefficient” or “suboptimal” canonical CPT1 transferase activity compared to CPT1A/B and is frequently described as a pseudoenzyme. Evidence supports binding to malonyl‑CoA and regulatory roles, but not robust long‑chain acyl‑CoA→acyl‑carnitine transfer in mitochondria (https://doi.org/10.1038/s41419-023-05599-1, 2023; https://doi.org/10.3390/ijms24020946, 2023; https://doi.org/10.3390/biology13110892, 2024) (fado2023tobeor pages 1-2, muley2023cpt1cdownregulationcauses pages 1-2, duan2024theroleof pages 9-11).
- Primary biochemical function: The predominant model is that CPT1C functions as a nutrient/malonyl‑CoA sensor that modulates lipid metabolism, autophagy, vesicle/lysosome dynamics, and secretory pathway components to support cellular adaptation to nutrient deprivation and hypoxia, especially in neurons and cancer cells (https://doi.org/10.1038/s41419-023-05599-1, 2023; https://doi.org/10.3390/biology13110892, 2024) (fado2023tobeor pages 1-2, duan2024theroleof pages 9-11).
- Comparison with CPT1A/B: CPT1A/B are mitochondrial long‑chain acyltransferases that are robustly inhibited by malonyl‑CoA (especially CPT1B), serving as gatekeepers of mitochondrial fatty‑acid entry; CPT1C is ER‑localized and less catalytically active, aligning with a sensing/regulatory role (https://doi.org/10.1210/endocr/bqz046, 2020; https://doi.org/10.1038/s41419-023-05599-1, 2023) (schlaepfer2020cpt1amediatedfatoxidation pages 5-6, fado2023tobeor pages 1-2).
3) Cellular localization and tissue expression
- Neuron-enriched, ER-resident: Modern sources consistently localize CPT1C to the ER in neurons, contrasting with mitochondrial CPT1A/B. Reviews place CPT1C on human chromosome 19q13.33 and indicate predominant expression in brain (and some reports of expression in testis) (https://doi.org/10.3390/biology13110892, 2024; https://doi.org/10.1210/endocr/bqz046, 2020) (duan2024theroleof pages 4-5, schlaepfer2020cpt1amediatedfatoxidation pages 5-6).
4) Pathways and mechanism-of-action
- AMPK–ACC–malonyl‑CoA axis: CPT1C expression is tuned by cellular energy availability. Mechanisms include AMPK-sensitive regulation and translational control via its 5′UTR, consistent with a role in malonyl‑CoA sensing and lipid‑metabolism signaling (https://doi.org/10.3390/biology13110892, 2024; https://doi.org/10.1038/s41419-023-05599-1, 2023) (duan2024theroleof pages 4-5, fado2023tobeor pages 1-2).
- Neuronal metabolic control: CPT1C has been associated with hypothalamic regulation of brown adipose tissue thermogenesis and broader neuronal energy homeostasis, emphasizing a signaling/regulatory role rather than direct mitochondrial FA transport (https://doi.org/10.1210/endocr/bqz046, 2020) (schlaepfer2020cpt1amediatedfatoxidation pages 5-6).
5) Neuronal biology: trafficking and synaptic functions
- Regulatory interactions in neurons: Neuroscience data summarized in recent reviews indicate CPT1C interacts with proteins involved in lipid metabolism and transport, lysosome motility, and the secretory pathway, affecting neuronal plasticity and adaptation to stress (https://doi.org/10.1038/s41419-023-05599-1, 2023) (fado2023tobeor pages 1-2).
6) Disease relevance and real‑world implementations
- Cancer biology: 2023–2024 evidence synthesizes a consistent picture in which CPT1C expression supports cancer cell adaptation to metabolic stress (hypoxia, nutrient limitation), suppresses senescence, and promotes tumor growth. Mechanistically, CPT1C depletion impairs mitochondrial function (membrane potential, respiration), reduces ATP, elevates ROS, and remodels cellular lipidomes; these changes limit proliferation/migration/invasion and decrease in vivo tumor growth (https://doi.org/10.1038/s41419-023-05599-1, 2023) (fado2023tobeor pages 3-5).
- Chemotherapy resistance: In breast cancer cells, CPT1C downregulation remodels plasma-membrane lipids (increased phospholipid saturation and rigidity), reduces doxorubicin uptake, and increases survival under anthracycline treatment; clinical correlation suggests lower CPT1C associates with poorer anthracycline response, nominating CPT1C as a predictive biomarker (https://doi.org/10.3390/ijms24020946, 2023) (muley2023cpt1cdownregulationcauses pages 1-2).
- Cell-cycle and regulatory networks: Reviews consolidate evidence that CPT1C is integrated into cell-cycle and transcriptional networks, including regulation by APC/C motifs and miRNAs (e.g., miR‑377‑3p), linking lipid‑metabolism cues to proliferation and stress tolerance, though mechanistic details remain under active investigation (https://doi.org/10.3390/biology13110892, 2024) (duan2024theroleof pages 9-11).
7) Expert opinions and analysis (authoritative sources)
- Fadó et al. (2023) argue the main function of CPT1C is not to “burn fat” but to serve as a malonyl‑CoA/nutrient sensor coordinating lipid metabolic remodeling and trafficking to enable survival under stress; this synthesis reconciles ER localization, poor catalytic activity, and robust phenotypes upon CPT1C perturbation in neurons and tumors (https://doi.org/10.1038/s41419-023-05599-1, 2023) (fado2023tobeor pages 1-2, fado2023tobeor pages 3-5).
- Schlaepfer & Joshi (2020) provide comparative CPT1 family context: CPT1A/B are mitochondrial, catalytically active, and malonyl‑CoA‑regulated; CPT1C is ER‑localized with lower catalytic activity and ties to neuronal thermogenesis control (https://doi.org/10.1210/endocr/bqz046, 2020) (schlaepfer2020cpt1amediatedfatoxidation pages 5-6).
8) Relevant statistics and data from recent studies
- Phenotypic impacts of CPT1C loss in cancer models include marked mitochondrial dysfunction and lipidome remodeling, with downstream decreases in proliferation/migration/invasion and tumor growth in vivo; CPT1C overexpression counters senescence, while silencing promotes it (qualitative summary from a 2023 peer‑reviewed synthesis) (https://doi.org/10.1038/s41419-023-05599-1, 2023) (fado2023tobeor pages 3-5).
- In breast cancer cells, CPT1C silencing increases plasma‑membrane phospholipid saturation (indicative of higher membrane rigidity), reduces doxorubicin uptake, and increases survival during anthracycline exposure; patient‑level analyses correlate lower CPT1C with poorer anthracycline response, suggesting utility as a biomarker (https://doi.org/10.3390/ijms24020946, 2023) (muley2023cpt1cdownregulationcauses pages 1-2).
9) Ambiguities and open questions
- Enzymatic classification and EC assignment: While historical annotations sometimes list enzymatic activities for CPT1C, contemporary mechanistic work emphasizes poor canonical CPT1 catalysis, ER localization, and sensor/regulatory roles. Robust substrate specificity for a physiologically meaningful transferase or thioesterase activity in human CPT1C remains to be conclusively established in vivo; the weight of 2023–2024 expert synthesis supports its role as a malonyl‑CoA/nutrient sensor rather than a primary acyltransferase (https://doi.org/10.1038/s41419-023-05599-1, 2023) (fado2023tobeor pages 1-2).
Summary and implications
CPT1C (Q8TCG5) is a human, neuron‑enriched CPT1‑family protein that localizes to the ER and functions primarily as a malonyl‑CoA/nutrient sensor modulating lipid metabolism and trafficking processes, distinct from the mitochondrial, catalytically active CPT1A/B. In neurons, CPT1C contributes to energy‑balance circuits and thermogenic regulation; in cancer, it facilitates adaptation to metabolic stress, influences mitochondrial function and lipidomes, and modulates chemotherapy response—suggesting roles as both a mechanistic node and a potential biomarker/therapeutic target. The most authoritative 2023–2024 sources converge on a regulatory/sensor view of CPT1C with limited canonical enzymatic activity, aligning molecular localization with function (fado2023tobeor pages 1-2, fado2023tobeor pages 3-5, schlaepfer2020cpt1amediatedfatoxidation pages 5-6, muley2023cpt1cdownregulationcauses pages 1-2, duan2024theroleof pages 4-5, duan2024theroleof pages 9-11).
References
(duan2024theroleof pages 4-5): Yanxia Duan, Jiaxin Liu, Ailin Li, Chang Liu, Guang Shu, and Gang Yin. The role of the cpt family in cancer: searching for new therapeutic strategies. Biology, 13:892, Nov 2024. URL: https://doi.org/10.3390/biology13110892, doi:10.3390/biology13110892. This article has 10 citations and is from a poor quality or predatory journal.
(schlaepfer2020cpt1amediatedfatoxidation pages 5-6): Isabel R Schlaepfer and Molishree Joshi. Cpt1a-mediated fat oxidation, mechanisms and therapeutic potential. Endocrinology, Jan 2020. URL: https://doi.org/10.1210/endocr/bqz046, doi:10.1210/endocr/bqz046. This article has 704 citations and is from a domain leading peer-reviewed journal.
(fado2023tobeor pages 1-2): Rut Fadó, Sebastian Zagmutt, Laura Herrero, Helena Muley, Rosalía Rodríguez-Rodríguez, Huichang Bi, Dolors Serra, and Núria Casals. To be or not to be a fat burner, that is the question for cpt1c in cancer cells. Cell Death & Disease, Jan 2023. URL: https://doi.org/10.1038/s41419-023-05599-1, doi:10.1038/s41419-023-05599-1. This article has 20 citations and is from a peer-reviewed journal.
(muley2023cpt1cdownregulationcauses pages 1-2): Helena Muley, Karmele Valencia, Josefina Casas, Bea Moreno, Luis Botella, Fernando Lecanda, Rut Fadó, and Núria Casals. Cpt1c downregulation causes plasma membrane remodelling and anthracycline resistance in breast cancer. International Journal of Molecular Sciences, 24:946, Jan 2023. URL: https://doi.org/10.3390/ijms24020946, doi:10.3390/ijms24020946. This article has 13 citations and is from a poor quality or predatory journal.
(duan2024theroleof pages 9-11): Yanxia Duan, Jiaxin Liu, Ailin Li, Chang Liu, Guang Shu, and Gang Yin. The role of the cpt family in cancer: searching for new therapeutic strategies. Biology, 13:892, Nov 2024. URL: https://doi.org/10.3390/biology13110892, doi:10.3390/biology13110892. This article has 10 citations and is from a poor quality or predatory journal.
(fado2023tobeor pages 3-5): Rut Fadó, Sebastian Zagmutt, Laura Herrero, Helena Muley, Rosalía Rodríguez-Rodríguez, Huichang Bi, Dolors Serra, and Núria Casals. To be or not to be a fat burner, that is the question for cpt1c in cancer cells. Cell Death & Disease, Jan 2023. URL: https://doi.org/10.1038/s41419-023-05599-1, doi:10.1038/s41419-023-05599-1. This article has 20 citations and is from a peer-reviewed journal.
CPT1C was identified during analysis of human Recon3D metabolic model as having an EC number discrepancy (CLASS_CHANGE type). This prompted a full GO annotation review.
Finding: CPT1C (gene ID 126129) is annotated in Recon3D with carnitine O-palmitoyltransferase activity (EC 2.3.1.21), but experimental evidence demonstrates it actually functions as a palmitoyl thioesterase (EC 3.1.2.22).
| Source | EC Number | Enzyme Class | Function |
|---|---|---|---|
| Recon3D | 2.3.1.21 | Transferase | Carnitine O-palmitoyltransferase |
| UniProt (correct) | 3.1.2.22 | Hydrolase | Palmitoyl thioesterase |
Impact: This is a CLASS_CHANGE error - the enzyme class is completely different:
- Recon3D assumes CPT1C transfers acyl groups to carnitine for mitochondrial fatty acid import
- CPT1C actually hydrolyzes thioester bonds to depalmitoylate proteins in the ER
This would affect:
1. Any metabolic model simulations involving fatty acid beta-oxidation
2. Predictions for CPT1C knockout phenotypes (would incorrectly predict fatty acid metabolism defects)
3. Drug target modeling (thioesterase vs transferase active sites are structurally different)
Root cause: CPT1C was named based on sequence homology to CPT1A and CPT1B, which are bona fide carnitine palmitoyltransferases. However, CPT1C has evolved a distinct function and is now classified as a pseudoenzyme with respect to the canonical CPT1 activity.
Four IEA/IBA annotations incorrectly attribute ancestral CPT1 functions to CPT1C:
| GO Term | Annotation | Problem |
|---|---|---|
| GO:0016740 | transferase activity | WRONG - CPT1C is a hydrolase |
| GO:0016746 | acyltransferase activity | WRONG - CPT1C lacks this activity |
| GO:0006631 | fatty acid metabolic process (IBA) | WRONG - CPT1C not involved |
| GO:0009437 | carnitine metabolic process (IBA) | WRONG - CPT1C not involved |
Notably, the correct NOT annotations already exist:
- NOT GO:0004095 (carnitine O-palmitoyltransferase activity)
- NOT GO:0005739 (mitochondrion)
- NOT GO:0006631 (fatty acid metabolic process)
- NOT GO:0009437 (carnitine metabolic process)
The conflict between positive IBA/IEA and negative ISS annotations reflects the tension between sequence-based inference and experimental evidence.
Mutations in CPT1C cause Spastic Paraplegia 73 (SPG73) [MIM:616282]:
- Autosomal dominant
- Pure spastic paraplegia phenotype
- R37C mutation affects N-terminal regulatory domain
- Mechanism involves altered lipid droplet formation and ATL1 interaction
CPT1C is relevant to AD through:
1. AMPAR regulation - CPT1C controls AMPAR trafficking; glutamatergic dysfunction is a feature of AD
2. Brain-specific expression - Only CPT1 isoform expressed predominantly in neurons
3. Energy sensing - Malonyl-CoA binding couples nutrient status to synaptic function
4. Lipid metabolism - Though not classical fatty acid metabolism, CPT1C affects lipid handling
The Recon3D error would incorrectly model CPT1C in fatty acid oxidation pathways rather than its actual role in synaptic receptor regulation.
CPT1C represents a striking example of enzyme neofunctionalization:
CPT1A/CPT1B (mitochondrial)
- Carnitine O-palmitoyltransferase (EC 2.3.1.21)
- Fatty acid import into mitochondria
Ancestral CPT1 ----{
CPT1C (ER)
- Palmitoyl thioesterase (EC 3.1.2.22)
- Protein depalmitoylation for AMPAR trafficking
Despite retaining the carnitine palmitoyltransferase family fold and name, CPT1C has evolved:
- Different cellular localization (ER vs mitochondria)
- Different enzymatic mechanism (hydrolysis vs transfer)
- Different substrate (palmitoylated proteins vs acyl-CoA + carnitine)
- Different biological role (synaptic regulation vs energy metabolism)
id: Q8TCG5
gene_symbol: CPT1C
product_type: PROTEIN
status: COMPLETE
taxon:
id: NCBITaxon:9606
label: Homo sapiens
description: >-
Palmitoyl thioesterase (EC 3.1.2.22) specifically expressed in the endoplasmic reticulum
of neurons. Unlike its paralogs CPT1A and CPT1B, CPT1C does NOT have carnitine
O-palmitoyltransferase activity (EC 2.3.1.21) and is not involved in fatty acid beta-oxidation.
CPT1C functions as a depalmitoylating enzyme that modulates AMPA receptor (AMPAR)
trafficking to the plasma membrane through depalmitoylation of GRIA1. The catalytic
activity depends on the Ser-252, His-470, Asp-474 triad. Also regulates AMPAR
trafficking through regulation of SACM1L phosphatidylinositol-3-phosphatase activity.
Mutations cause SPG73 spastic paraplegia.
alternative_products:
- name: '1'
id: Q8TCG5-1
- name: '2'
id: Q8TCG5-2
sequence_note: VSP_010677
- name: '3'
id: Q8TCG5-3
sequence_note: VSP_012457
existing_annotations:
# IBA annotations from phylogenetic inference
- term:
id: GO:0006631
label: fatty acid metabolic process
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
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.
action: REMOVE
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.
supported_by:
- reference_id: PMID:30135643
supporting_text: "CPT1C effect on AMPARs is likely due to changes in the palmitoylation state of GluA1"
- term:
id: GO:0009437
label: carnitine metabolic process
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
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.
action: REMOVE
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.
supported_by:
- reference_id: PMID:30135643
supporting_text: "CPT1C acts on AMPAR through an enzymatic activity (dependent on a catalytic histidine) and not due to a mere structural interaction"
- term:
id: GO:0005789
label: endoplasmic reticulum membrane
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
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.
action: ACCEPT
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.
supported_by:
- reference_id: PMID:30135643
supporting_text: "this data indicates that the depalmitoylating effect of CPT1C on AMPARs is clearly CPT1C specific and possibly happens at ER level"
# IEA annotations
- term:
id: GO:0098734
label: macromolecule depalmitoylation
evidence_type: IEA
original_reference_id: GO_REF:0000108
review:
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.
action: ACCEPT
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.
supported_by:
- reference_id: PMID:30135643
supporting_text: "our experiments prove the involvement of a depalmitoylation process in the CPT1C-mediated increase of surface AMPARs"
- term:
id: GO:0003824
label: catalytic activity
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
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.
action: ACCEPT
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.
supported_by:
- reference_id: PMID:30135643
supporting_text: "CPT1C acts on AMPAR through an enzymatic activity (dependent on a catalytic histidine)"
- term:
id: GO:0005789
label: endoplasmic reticulum membrane
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
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.
action: ACCEPT
reason: >-
Correct localization, supported by experimental data. Duplicate with IBA and
ISS annotations for same term.
supported_by:
- reference_id: PMID:30135643
supporting_text: "this data indicates that the depalmitoylating effect of CPT1C on AMPARs is clearly CPT1C specific and possibly happens at ER level"
- reference_id: PMID:25751282
supporting_text: "CPT1C, which localizes to the endoplasmic reticulum, is expressed in motor neurons"
- term:
id: GO:0006629
label: lipid metabolic process
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
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.
action: KEEP_AS_NON_CORE
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.
supported_by:
- reference_id: PMID:30135643
supporting_text: "CPT1C effect on AMPARs is likely due to changes in the palmitoylation state of GluA1"
- term:
id: GO:0008474
label: palmitoyl-(protein) hydrolase activity
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
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.
action: ACCEPT
reason: >-
This is the correct molecular function for CPT1C. Supported by direct
experimental evidence demonstrating palmitoyl thioesterase activity with
characterized catalytic triad.
supported_by:
- reference_id: PMID:30135643
supporting_text: "Ser 252, His 470 and Asp 474 are predicted to be the catalytic triad responsible for CPT1C palmitoyl thioesterase (PTE) activity"
- term:
id: GO:0016740
label: transferase activity
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
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).
action: REMOVE
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.
supported_by:
- reference_id: PMID:30135643
supporting_text: "Ser 252, His 470 and Asp 474 are predicted to be the catalytic triad responsible for CPT1C palmitoyl thioesterase (PTE) activity"
- term:
id: GO:0016746
label: acyltransferase activity
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: >-
IEA annotation incorrectly attributing acyltransferase activity to CPT1C.
This conflicts with experimental evidence showing CPT1C functions as a
thioesterase rather than a transferase.
action: REMOVE
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.
supported_by:
- reference_id: PMID:30135643
supporting_text: "CPT1C acts on AMPAR through an enzymatic activity (dependent on a catalytic histidine) and not due to a mere structural interaction"
- term:
id: GO:0016787
label: hydrolase activity
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: >-
IEA annotation that is correct. CPT1C is a hydrolase - specifically a
palmitoyl thioesterase that hydrolyzes thioester bonds to remove palmitate
from palmitoylated proteins.
action: ACCEPT
reason: >-
Correct general classification. CPT1C catalyzes hydrolysis of thioester
bonds (palmitoyl-protein + H2O = palmitate + protein), consistent with
hydrolase activity.
supported_by:
- reference_id: PMID:30135643
supporting_text: "Ser 252, His 470 and Asp 474 are predicted to be the catalytic triad responsible for CPT1C palmitoyl thioesterase (PTE) activity"
- term:
id: GO:0030424
label: axon
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: >-
IEA annotation for axonal localization. Supported by literature showing
CPT1C is expressed in motor neurons (PMID:25751282).
action: ACCEPT
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.
supported_by:
- reference_id: PMID:25751282
supporting_text: "CPT1C, which localizes to the endoplasmic reticulum, is expressed in motor neurons"
- term:
id: GO:0030425
label: dendrite
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: >-
IEA annotation for dendritic localization. Supported by PMID:25751282
showing CPT1C expression in motor neurons.
action: ACCEPT
reason: >-
Dendritic localization is experimentally supported. CPT1C functions in
neurons to regulate AMPAR trafficking, and dendritic localization is
consistent with this synaptic function.
supported_by:
- reference_id: PMID:25751282
supporting_text: "CPT1C, which localizes to the endoplasmic reticulum, is expressed in motor neurons"
- term:
id: GO:0005783
label: endoplasmic reticulum
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: >-
IEA annotation for ER localization. Well supported by multiple experimental
studies. PMID:30135643 demonstrates CPT1C functions at the ER level.
action: ACCEPT
reason: >-
ER localization is a key distinguishing feature of CPT1C compared to
mitochondrial CPT1A/B. Experimentally validated.
supported_by:
- reference_id: PMID:30135643
supporting_text: "this data indicates that the depalmitoylating effect of CPT1C on AMPARs is clearly CPT1C specific and possibly happens at ER level"
- term:
id: GO:0032281
label: AMPA glutamate receptor complex
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
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.
action: ACCEPT
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.
supported_by:
- reference_id: PMID:30135643
supporting_text: "the interaction between the GluA1 subunit of AMPARs and carnitine palmitoyltransferase 1C (CPT1C)"
- term:
id: GO:0098794
label: postsynapse
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
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.
action: KEEP_AS_NON_CORE
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.
supported_by:
- reference_id: PMID:30135643
supporting_text: "this data indicates that the depalmitoylating effect of CPT1C on AMPARs is clearly CPT1C specific and possibly happens at ER level"
- term:
id: GO:0098978
label: glutamatergic synapse
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
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.
action: KEEP_AS_NON_CORE
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.
supported_by:
- reference_id: PMID:30135643
supporting_text: "synaptic transmission in CPT1C knockout (KO) mice is diminished supporting a positive trafficking role for that protein"
- term:
id: GO:0099072
label: regulation of postsynaptic membrane neurotransmitter receptor levels
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
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.
action: ACCEPT
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.
supported_by:
- reference_id: PMID:30135643
supporting_text: "the re-expression of CPT1C increased the surface/intracellular ratio of GluA1 while CPT1C(H470A) did not"
# Negated ISS annotations - these are important and should be retained
- term:
id: GO:0004095
label: carnitine O-palmitoyltransferase activity
evidence_type: ISS
original_reference_id: GO_REF:0000024
negated: true
review:
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).
action: ACCEPT
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.
supported_by:
- reference_id: PMID:30135643
supporting_text: "Ser 252, His 470 and Asp 474 are predicted to be the catalytic triad responsible for CPT1C palmitoyl thioesterase (PTE) activity"
- term:
id: GO:0005739
label: mitochondrion
evidence_type: ISS
original_reference_id: GO_REF:0000024
negated: true
review:
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).
action: ACCEPT
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.
supported_by:
- reference_id: PMID:30135643
supporting_text: "this data indicates that the depalmitoylating effect of CPT1C on AMPARs is clearly CPT1C specific and possibly happens at ER level"
- reference_id: PMID:25751282
supporting_text: "CPT1C, which localizes to the endoplasmic reticulum, is expressed in motor neurons"
# IDA annotations - highest quality experimental evidence
- term:
id: GO:0005783
label: endoplasmic reticulum
evidence_type: IDA
original_reference_id: PMID:30135643
review:
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.
action: ACCEPT
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.
supported_by:
- reference_id: PMID:30135643
supporting_text: "this data indicates that the depalmitoylating effect of CPT1C on AMPARs is clearly CPT1C specific and possibly happens at ER level"
- term:
id: GO:0005789
label: endoplasmic reticulum membrane
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: >-
ISS annotation for ER membrane localization. Supported by experimental
data showing CPT1C is a multi-pass membrane protein in the ER.
action: ACCEPT
reason: >-
ER membrane localization is well-supported. CPT1C has two transmembrane
helices and is an integral ER membrane protein.
supported_by:
- reference_id: PMID:30135643
supporting_text: "this data indicates that the depalmitoylating effect of CPT1C on AMPARs is clearly CPT1C specific and possibly happens at ER level"
- term:
id: GO:0006631
label: fatty acid metabolic process
evidence_type: ISS
original_reference_id: GO_REF:0000024
negated: true
review:
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).
action: ACCEPT
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.
supported_by:
- reference_id: PMID:30135643
supporting_text: "CPT1C effect on AMPARs is likely due to changes in the palmitoylation state of GluA1"
- term:
id: GO:0008474
label: palmitoyl-(protein) hydrolase activity
evidence_type: IDA
original_reference_id: PMID:30135643
review:
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.
action: ACCEPT
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.
supported_by:
- reference_id: PMID:30135643
supporting_text: "Ser 252, His 470 and Asp 474 are predicted to be the catalytic triad responsible for CPT1C palmitoyl thioesterase (PTE) activity"
- reference_id: PMID:30135643
supporting_text: "the histidine residue (His 470) of CPT1C is crucial for the increase in GluA1 surface expression in neurons"
- term:
id: GO:0009437
label: carnitine metabolic process
evidence_type: ISS
original_reference_id: GO_REF:0000024
negated: true
review:
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.
action: ACCEPT
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.
supported_by:
- reference_id: PMID:30135643
supporting_text: "Ser 252, His 470 and Asp 474 are predicted to be the catalytic triad responsible for CPT1C palmitoyl thioesterase (PTE) activity"
# IPI annotation
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:25751282
review:
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.
action: KEEP_AS_NON_CORE
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.
additional_reference_ids:
- PMID:30135643
supported_by:
- reference_id: PMID:25751282
supporting_text: "CPT1C, which localizes to the endoplasmic reticulum, is expressed in motor neurons and interacts with atlastin-1"
- reference_id: PMID:30135643
supporting_text: "the interaction between the GluA1 subunit of AMPARs and carnitine palmitoyltransferase 1C (CPT1C)"
# Additional ISS annotations
- term:
id: GO:0030424
label: axon
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: >-
ISS annotation for axonal localization. Supported by PMID:25751282
showing CPT1C expression in motor neurons.
action: ACCEPT
reason: >-
Duplicate of IEA annotation for same term. Axonal localization is
experimentally supported.
supported_by:
- reference_id: PMID:25751282
supporting_text: "CPT1C, which localizes to the endoplasmic reticulum, is expressed in motor neurons"
- term:
id: GO:0030425
label: dendrite
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: >-
ISS annotation for dendritic localization. Supported by PMID:25751282.
action: ACCEPT
reason: >-
Dendritic localization supported by experimental evidence.
supported_by:
- reference_id: PMID:25751282
supporting_text: "CPT1C, which localizes to the endoplasmic reticulum, is expressed in motor neurons"
- term:
id: GO:0005783
label: endoplasmic reticulum
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: >-
ISS annotation for ER localization. Multiple supporting evidence sources.
action: ACCEPT
reason: >-
ER localization is well-established for CPT1C.
supported_by:
- reference_id: PMID:30135643
supporting_text: "this data indicates that the depalmitoylating effect of CPT1C on AMPARs is clearly CPT1C specific and possibly happens at ER level"
# Suggested new annotations
- term:
id: GO:0002084
label: protein depalmitoylation
evidence_type: IDA
original_reference_id: PMID:30135643
review:
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.
action: NEW
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.
supported_by:
- reference_id: PMID:30135643
supporting_text: "our experiments prove the involvement of a depalmitoylation process in the CPT1C-mediated increase of surface AMPARs"
- reference_id: PMID:30135643
supporting_text: "the depalmitoylating effect of CPT1C on AMPARs is clearly CPT1C specific"
- term:
id: GO:1904719
label: positive regulation of AMPA glutamate receptor clustering
evidence_type: IDA
original_reference_id: PMID:30135643
review:
summary: >-
NEW annotation suggestion. CPT1C positively regulates AMPAR surface
expression and clustering. Knockout of CPT1C reduces AMPAR surface
levels as shown in PMID:30135643.
action: NEW
reason: >-
CPT1C increases AMPAR surface expression through depalmitoylation
of GluA1. This represents positive regulation of AMPAR clustering
at the plasma membrane.
supported_by:
- reference_id: PMID:30135643
supporting_text: "synaptic transmission in CPT1C knockout (KO) mice is diminished supporting a positive trafficking role for that protein"
- reference_id: PMID:30135643
supporting_text: "the re-expression of CPT1C increased the surface/intracellular ratio of GluA1 while CPT1C(H470A) did not"
core_functions:
- molecular_function:
id: GO:0008474
label: palmitoyl-(protein) hydrolase activity
description: >-
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.
locations:
- id: GO:0005789
label: endoplasmic reticulum membrane
directly_involved_in:
- id: GO:0002084
label: protein depalmitoylation
- id: GO:0099072
label: regulation of postsynaptic membrane neurotransmitter receptor levels
references:
- id: GO_REF:0000024
title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
by curator judgment of sequence similarity
findings: []
- id: GO_REF:0000033
title: Annotation inferences using phylogenetic trees
findings: []
- id: GO_REF:0000043
title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
findings: []
- id: GO_REF:0000107
title: Automatic transfer of experimentally verified manual GO annotation data to
orthologs using Ensembl Compara
findings: []
- id: GO_REF:0000108
title: Automatic assignment of GO terms using logical inference, based on on inter-ontology
links
findings: []
- id: GO_REF:0000117
title: Electronic Gene Ontology annotations created by ARBA machine learning models
findings: []
- id: GO_REF:0000120
title: Combined Automated Annotation using Multiple IEA Methods
findings: []
- id: PMID:12376098
title: A novel brain-expressed protein related to carnitine palmitoyltransferase I.
findings:
- statement: CPT1C is specifically expressed in brain and testis
- statement: Does not have or has very low carnitine O-palmitoyltransferase activity
- id: PMID:25751282
title: Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia.
findings:
- statement: R37C mutation causes SPG73 spastic paraplegia
- statement: CPT1C localizes to ER in motor neurons
- statement: CPT1C interacts with ATL1 (atlastin-1)
- statement: Mutation alters protein conformation and lipid droplet formation
- id: PMID:30135643
title: Mechanisms of CPT1C-Dependent AMPAR Trafficking Enhancement.
findings:
- statement: CPT1C has palmitoyl thioesterase activity
- statement: Catalytic triad is Ser-252, His-470, Asp-474
- statement: CPT1C depalmitoylates GRIA1 to promote AMPAR surface expression
- statement: Activity is specific to CPT1C isoform, not CPT1A
- statement: CPT1C functions at ER level
- statement: CPT1C knockout mice have diminished AMPAR surface content