OTC

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005739 mitochondrion	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) assertion that OTC is active in mitochondria. Correct but less specific than the well-supported mitochondrial matrix localization; retained as accurate parent-level localization. Reason: OTC is a mitochondrial-matrix enzyme; the mitochondrion is the correct compartment at this level. The more specific matrix term is captured separately (GO:0005759).
GO:0006526 L-arginine biosynthetic process	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: IBA-transferred role in L-arginine biosynthesis. OTC produces citrulline, which is a precursor for argininosuccinate and thence arginine; the urea cycle is the biosynthetic route to arginine. This is a downstream pathway role rather than OTC's direct biosynthetic product. Reason: OTC's direct product is L-citrulline, not L-arginine; arginine biosynthesis is a downstream consequence of the urea cycle in which OTC participates. Biologically defensible at the pathway level but not the core function of the enzyme.
GO:0019240 L-citrulline biosynthetic process	IBA GO_REF:0000033	ACCEPT	Summary: IBA assertion that OTC is involved in L-citrulline biosynthesis. This is exactly the direct product of the OTC reaction and is strongly supported experimentally and by the UniProt pathway annotation. Reason: L-citrulline is the direct product of the reaction OTC catalyzes; UniProt records "Nitrogen metabolism; urea cycle; L-citrulline from L-ornithine and carbamoyl phosphate: step 1/1." Core biological process. Supporting Evidence: PMID:2556444 An arginine to glutamine mutation in residue 109 of human ornithine transcarbamylase completely abolishes enzymatic activity in Cos1 cells.
GO:0004585 ornithine carbamoyltransferase activity	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) assignment of the diagnostic molecular function. Concordant with experimental IDA/EXP annotations and UniProt catalytic activity. Core function. Reason: This is the defining enzymatic activity of OTC (EC 2.1.3.3), supported by multiple experimental annotations and UniProt.
GO:0004585 ornithine carbamoyltransferase activity	IEA GO_REF:0000120	ACCEPT	Summary: Automated (IEA, multi-method) assignment of the core ornithine carbamoyltransferase activity, backed by EC 2.1.3.3 / RHEA:19513 and ARBA. Consistent with the experimental core. Reason: Correct core molecular function; redundant with the experimental and IBA annotations of the same term.
GO:0005739 mitochondrion	IEA GO_REF:0000117	ACCEPT	Summary: ARBA machine-learning electronic annotation to mitochondrion. Correct compartment at the organelle level. Reason: OTC is a mitochondrial protein; the more specific matrix location is captured by GO:0005759.
GO:0005759 mitochondrial matrix	IEA GO_REF:0000044	ACCEPT	Summary: UniProt SubCell mapping (SL-0170) to mitochondrial matrix, matching the experimentally established localization of the mature enzyme. Reason: Mitochondrial matrix is the correct, experimentally supported location of mature OTC. Supporting Evidence: PMID:6372096 We have deduced the complete primary structure of the precursor of a human mitochondrial matrix enzyme, ornithine transcarbamylase (OTC)
GO:0006520 amino acid metabolic process	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: InterPro2GO electronic annotation to the broad amino acid metabolic process. Correct but very general; the specific urea-cycle and citrulline/arginine biosynthesis terms convey the actual role. Reason: True at a high level (OTC metabolizes ornithine and produces citrulline) but too general to be a core annotation; more specific terms are present.
GO:0016597 amino acid binding	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Electronic annotation for amino acid binding, reflecting OTC's binding of the amino acid substrate L-ornithine within catalysis. Subsumed by the catalytic molecular function. Reason: Ornithine binding is part of the catalytic mechanism captured by GO:0004585; substrate binding is not an independent core function.
GO:0016743 carboxyl- or carbamoyltransferase activity	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: InterPro2GO annotation to the parent carbamoyltransferase activity class. Correct but less specific than the exact GO:0004585. Reason: This is a parent of the precise ornithine carbamoyltransferase activity term already annotated; retained as an accurate but general classification.
GO:0000050 urea cycle	IEA GO_REF:0000120	ACCEPT	Summary: Automated annotation placing OTC in the urea cycle, consistent with the experimental IDA annotation and UniProt pathway. Core process. Reason: OTC catalyzes the citrulline-forming step of the urea cycle; central core process.
GO:0001889 liver development	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Ensembl Compara ortholog-transfer (from rat OTC, P00481) of a liver-development role. OTC is highly expressed in liver but there is no evidence it functions in liver morphogenesis/development; this is an over-annotation conflating tissue of expression with a developmental role. Reason: Tissue-restricted metabolic expression (liver, intestinal mucosa) is not evidence of participation in organ development. Transferred by Ensembl Compara from a paralog/ortholog experiment; not appropriate as a human OTC function.
GO:0005543 phospholipid binding	IEA GO_REF:0000107	REMOVE	Summary: Ensembl Compara ortholog-transfer annotation of phospholipid binding. OTC is a soluble matrix enzyme with no established phospholipid-binding function; not supported by structure or biochemistry. Reason: No evidence that human OTC binds phospholipids; a soluble matrix carbamoyltransferase. Electronic ortholog transfer without biological support.
GO:0005743 mitochondrial inner membrane	IEA GO_REF:0000107	REMOVE	Summary: Ensembl Compara ortholog-transfer localizing OTC to the mitochondrial inner membrane. This is the wrong compartment: mature OTC is a soluble matrix enzyme, not an inner-membrane protein. Reason: UniProt and experimental data place mature OTC in the mitochondrial matrix, not the inner membrane. The inner-membrane assignment is an incorrect electronic transfer. Supporting Evidence: PMID:6372096 We have deduced the complete primary structure of the precursor of a human mitochondrial matrix enzyme, ornithine transcarbamylase (OTC)
GO:0007494 midgut development	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Ensembl Compara ortholog-transfer of a midgut-development role. OTC is expressed in intestinal mucosa but is not known to drive midgut development; over-annotation conflating expression site with development. Reason: Expression in intestinal mucosa does not equate to a role in midgut morphogenesis; transferred electronically without biological support for human OTC.
GO:0009410 response to xenobiotic stimulus	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Ensembl Compara ortholog-transfer (rat) of a "response to xenobiotic" process. Not a described function of human OTC; likely reflects a rat-specific expression-response experiment. Reason: No evidence for human OTC participating in a xenobiotic response as a core or peripheral function; electronic transfer from a rodent stimulus study.
GO:0010043 response to zinc ion	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Ensembl Compara ortholog-transfer of a zinc-response process. Not an established human OTC function; over-annotation from rodent data. Reason: No biological support that human OTC functions in a response to zinc ion; transferred electronically.
GO:0019240 L-citrulline biosynthetic process	IEA GO_REF:0000120	ACCEPT	Summary: Automated (multi-method) annotation of L-citrulline biosynthesis, matching the direct product of OTC and the experimental annotations of the same term. Core process. Reason: Redundant with the experimental IDA and IBA annotations; correctly captures OTC's direct biosynthetic product.
GO:0031667 response to nutrient levels	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Ensembl Compara ortholog-transfer of a "response to nutrient levels" process. While OTC activity is modulated by Lys-88 acetylation in response to nutrient signals (UniProt PTM), this ortholog-transferred process annotation is a peripheral, non-core physiological response rather than a demonstrated human OTC function at this term. Reason: Electronic ortholog transfer; any nutrient-responsive regulation of OTC is an upstream modulation of its activity, not a core process the enzyme executes. Not appropriate as a core annotation.
GO:0032868 response to insulin	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Ensembl Compara ortholog-transfer of an insulin-response process. Not a described function of human OTC; over-annotation from rodent data. Reason: No biological support that human OTC participates in a response to insulin as a gene function; electronic transfer.
GO:0042301 phosphate ion binding	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Ensembl Compara ortholog-transfer of phosphate ion binding. Inorganic phosphate is a product of the OTC reaction, so transient phosphate interaction occurs within catalysis, but as an independent molecular function this is a peripheral, over-annotated activity. Reason: Phosphate handling is part of the catalytic mechanism captured by GO:0004585; standalone "phosphate ion binding" transferred by Ensembl Compara is not a distinct core function.
GO:0042802 identical protein binding	IEA GO_REF:0000107	MODIFY	Summary: Ensembl Compara ortholog-transfer of identical protein binding. This reflects the biologically real fact that active OTC is a homotrimer; "identical protein binding" is an uninformative surrogate for the self-assembly / homotrimerization role. Reason: UniProt records the subunit structure as "Homotrimer"; the annotation should point to the structural/self-association role rather than generic identical protein binding. Non-core relative to catalysis. Proposed replacements: protein-containing complex binding
GO:0055081 monoatomic anion homeostasis	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Ensembl Compara ortholog-transfer of a monoatomic anion homeostasis process. Not an established human OTC function; over-annotation from rodent data. Reason: No biological support that human OTC maintains monoatomic anion homeostasis; electronic ortholog transfer.
GO:0070781 response to biotin	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Ensembl Compara ortholog-transfer of a biotin-response process. Not a described function of human OTC; over-annotation from rodent data. Reason: No biological support that human OTC participates in a response to biotin; electronic transfer.
GO:0005739 mitochondrion	IDA GO_REF:0000052	ACCEPT	Summary: Curated immunofluorescence (HPA) localization of OTC to the mitochondrion. Consistent with the established mitochondrial-matrix localization. Reason: Direct imaging evidence for mitochondrial localization; correct compartment.
GO:0004585 ornithine carbamoyltransferase activity	EXP PMID:6372096 Structure and expression of a complementary DNA for the nucl...	ACCEPT	Summary: Experimental demonstration of OTC enzymatic activity from expression of cloned human OTC cDNA. Core molecular function. Reason: Expression of the cloned cDNA yielded catalytically active OTC, directly demonstrating the ornithine carbamoyltransferase activity. Supporting Evidence: PMID:6372096 enzymatic activity was also detected.
GO:0005759 mitochondrial matrix	EXP PMID:3895227 Arginine in the leader peptide is required for both import a...	ACCEPT	Summary: Experimental study of OTC precursor import establishing OTC as a mitochondrial-matrix enzyme. Core localization. Reason: OTC is imported into and functions in the mitochondrial matrix; the arginine-rich leader peptide directs matrix import and cleavage. Supporting Evidence: PMID:3895227 the human mitochondrial matrix enzyme, ornithine transcarbamoylase
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-9956527	ACCEPT	Summary: Reactome (TAS) localization of OTC to the mitochondrial matrix within a reaction where OTC variants fail to synthesize L-citrulline. Correct compartment. Reason: Matrix localization is well established; the Reactome model correctly places OTC in the matrix.
GO:0005829 cytosol	TAS Reactome:R-HSA-9956513	MARK AS OVER ANNOTATED	Summary: Reactome (TAS) cytosol location arising from a model of OTC leader-sequence variants that are NOT targeted to mitochondria. This is a mistrafficking/precursor context, not the localization of the mature functional enzyme. Reason: The cytosolic location reflects mislocalized targeting-signal variants (Reactome "Leader sequence variants of OTC aren't targeted to the mitochondria"), not the steady-state matrix localization of wild-type OTC. Misleading as a general localization claim.
GO:0005829 cytosol	TAS Reactome:R-HSA-9956502	MARK AS OVER ANNOTATED	Summary: Reactome (TAS) cytosol location from a model of OTC precursor targeting to the mitochondrial matrix. The cytosol appears only as the transient location of the newly synthesized precursor before import, not the mature enzyme's compartment. Reason: Reflects the pre-import precursor stage of the import pathway, not the functional localization of mature OTC (mitochondrial matrix).
GO:0005829 cytosol	TAS Reactome:R-HSA-9959881	MARK AS OVER ANNOTATED	Summary: Reactome (TAS) cytosol location from an "OTC gene expression" reaction. Reflects the biosynthesis/expression step, not the localization of the functional enzyme. Reason: Derived from a gene-expression modeling reaction rather than the mature enzyme's compartment; not the functional localization of OTC.
GO:0005739 mitochondrion	HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an...	ACCEPT	Summary: High-throughput mitochondrial proteomics (MitoCoP) detecting OTC in the high-confidence mitochondrial proteome. Supports mitochondrial localization. Reason: Proteomic evidence corroborating mitochondrial localization; consistent with the matrix assignment. Supporting Evidence: PMID:34800366 mitochondrial high-confidence proteome of >1,100 proteins (MitoCoP)
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-8986181	ACCEPT	Summary: Reactome (TAS) matrix localization within the presequence-proteolysis (PITRM1) reaction. Correct compartment for OTC. Reason: Matrix localization is well supported; the Reactome presequence-processing model correctly places OTC in the matrix.
GO:0000050 urea cycle	IDA PMID:2556444 An arginine to glutamine mutation in residue 109 of human or...	ACCEPT	Summary: Direct experimental annotation placing OTC in the urea cycle, from functional analysis of OTC and its deficiency in ammonia detoxification. Core process. Reason: OTC catalyzes an essential step of the urea cycle; loss of activity impairs ureagenesis and causes hyperammonemia. Supporting Evidence: PMID:2556444 Ornithine transcarbamylase (OTC) is an important enzyme in the detoxification of ammonia to urea, and its deficiency is the most common inborn error of ureagenesis in humans.
GO:0004585 ornithine carbamoyltransferase activity	IDA PMID:2556444 An arginine to glutamine mutation in residue 109 of human or...	ACCEPT	Summary: Direct assay of OTC enzymatic activity (wild-type versus Arg109Gln mutant) confirming the ornithine carbamoyltransferase activity. Core molecular function. Reason: Specific activity of expressed wild-type OTC was measured directly and contrasted with an inactive mutant, demonstrating the catalytic function. Supporting Evidence: PMID:2556444 the specific activity of mutant OTC was 100-fold lower than that of wild type
GO:0004585 ornithine carbamoyltransferase activity	IDA PMID:8112735 Expression of four mutant human ornithine transcarbamylase g...	ACCEPT	Summary: Direct measurement of OTC activity for wild-type and mutant cDNAs expressed in Cos1 cells, confirming ornithine carbamoyltransferase activity. Core molecular function. Reason: Enzyme activities of expressed OTC variants were quantified directly (0-8.9% of normal for mutants), demonstrating the catalytic function. Supporting Evidence: PMID:8112735 Predicted OTC activities of mutant OTC cDNAs ranged from 0% to 8.9% of the normal level
GO:0005739 mitochondrion	IDA PMID:3472484 Targeting of nuclear-encoded proteins to the mitochondrial m...	ACCEPT	Summary: Curated (IDA) mitochondrial localization from work on targeting of nuclear-encoded proteins to the mitochondrial matrix. Correct compartment. Reason: OTC is a well-established nuclear-encoded protein targeted to mitochondria; the more specific matrix term is also annotated.
GO:0005739 mitochondrion	IDA PMID:6372096 Structure and expression of a complementary DNA for the nucl...	ACCEPT	Summary: Curated (IDA) mitochondrial localization from characterization of the OTC precursor as a nuclear-encoded mitochondrial-matrix enzyme. Correct compartment. Reason: OTC was characterized as a human mitochondrial matrix enzyme whose precursor is imported into mitochondria. Supporting Evidence: PMID:6372096 We have deduced the complete primary structure of the precursor of a human mitochondrial matrix enzyme, ornithine transcarbamylase (OTC)
GO:0006593 L-ornithine catabolic process	IDA PMID:2556444 An arginine to glutamine mutation in residue 109 of human or...	KEEP AS NON CORE	Summary: Direct annotation of OTC's involvement in L-ornithine consumption. L-ornithine is the amino acid substrate consumed in the OTC reaction; this is a substrate-centric framing of the same catalytic function. Reason: Accurate (ornithine is consumed by OTC), but this is the substrate side of the citrulline-biosynthetic reaction rather than a distinct core process; OTC's core role is better captured by the citrulline-biosynthetic / urea cycle terms.
GO:0006593 L-ornithine catabolic process	IDA PMID:8112735 Expression of four mutant human ornithine transcarbamylase g...	KEEP AS NON CORE	Summary: Direct annotation of OTC's role in L-ornithine consumption, from expression analysis of OTC variants. Substrate-centric framing of the OTC reaction. Reason: Ornithine is the consumed substrate of OTC; retained as an accurate but non-core substrate-side description of the same catalytic activity.
GO:0019240 L-citrulline biosynthetic process	IDA PMID:2556444 An arginine to glutamine mutation in residue 109 of human or...	ACCEPT	Summary: Direct experimental annotation of OTC in L-citrulline biosynthesis (the product of the OTC reaction), from functional analysis of wild-type versus inactive mutant OTC. Core process. Reason: L-citrulline is the direct product of OTC; enzyme-activity assays of wild-type and mutant OTC directly demonstrate this biosynthetic role. Supporting Evidence: PMID:2556444 the specific activity of mutant OTC was 100-fold lower than that of wild type
GO:0019240 L-citrulline biosynthetic process	IDA PMID:8112735 Expression of four mutant human ornithine transcarbamylase g...	ACCEPT	Summary: Direct experimental annotation of OTC in L-citrulline biosynthesis from expression/activity analysis of OTC variants in Cos1 cells. Core process. Reason: Measured OTC activities of variants directly demonstrate the enzyme's L-citrulline-biosynthetic role. Supporting Evidence: PMID:8112735 Predicted OTC activities of mutant OTC cDNAs ranged from 0% to 8.9% of the normal level
GO:0097272 ammonium homeostasis	IMP PMID:2556444 An arginine to glutamine mutation in residue 109 of human or...	ACCEPT	Summary: IMP annotation linking OTC function to ammonium homeostasis: loss of OTC activity impairs ammonia detoxification (hyperammonemia). Physiologically central and well supported. Reason: OTC deficiency is the most common inborn error of ureagenesis and causes hyperammonemia, directly implicating OTC in ammonium homeostasis via the urea cycle. Supporting Evidence: PMID:2556444 Ornithine transcarbamylase (OTC) is an important enzyme in the detoxification of ammonia to urea, and its deficiency is the most common inborn error of ureagenesis in humans.
GO:0097272 ammonium homeostasis	IMP PMID:2575934 Structure of the ornithine transcarbamylase (OTC) gene and D...	ACCEPT	Summary: IMP annotation of OTC in ammonium homeostasis, from OTC gene/mutation analysis in OTC deficiency. Consistent with the urea-cycle role in ammonia detoxification. Reason: OTC deficiency (studied via gene structure and DNA diagnosis) manifests as a urea-cycle failure with hyperammonemia, supporting OTC's role in ammonium homeostasis.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-70560	ACCEPT	Summary: Reactome (TAS) matrix localization within the core catalytic reaction (carbamoyl phosphate + ornithine => citrulline + orthophosphate). Correct compartment for the functional enzyme. Reason: The catalytic reaction occurs in the matrix; Reactome correctly localizes OTC there.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-9956502	ACCEPT	Summary: Reactome (TAS) matrix localization from the OTC precursor targeting/processing reaction (post-import, matrix-processed form). Correct compartment for the mature enzyme. Reason: The processed OTC resides in the matrix; this Reactome annotation captures the correct mature-enzyme compartment.
GO:0005759 mitochondrial matrix	NAS PMID:6372096 Structure and expression of a complementary DNA for the nucl...	ACCEPT	Summary: Non-traceable author statement (NAS) that OTC is a mitochondrial-matrix enzyme, consistent with the experimental EXP/IDA matrix annotations. Correct compartment. Reason: Concordant with the well-supported matrix localization of OTC. Supporting Evidence: PMID:6372096 We have deduced the complete primary structure of the precursor of a human mitochondrial matrix enzyme, ornithine transcarbamylase (OTC)

Gene Description

Existing Annotations Review

Core Functions

Ornithine carbamoyltransferase activity in the mitochondrial matrix, catalyzing the condensation of carbamoyl phosphate with L-ornithine to form L-citrulline and inorganic phosphate (EC 2.1.3.3), the citrulline-forming step of the urea cycle.

References

Deep Research

Falcon

📚 Additional Documentation

Notes

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