Details for: OTC

Gene ID: 5009

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: OTC

Ensembl ID: ENSG00000036473

Description: ornithine transcarbamylase

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • colonocyte CL1000347
    CSI 2.41
    rCSI 3.46%
    PRS 94.34
  • intestinal epithelial cell CL0002563
    CSI 2.09
    rCSI 2.18%
    PRS 94.43
  • transit amplifying cell of small intestine CL0009012
    CSI 1.83
    rCSI 8.03%
    PRS 97.18
  • enterocyte CL0000584
    CSI 1.55
    rCSI 2.5%
    PRS 93.31
  • enterocyte of epithelium of small intestine CL1000334
    CSI 0.47
    rCSI 7.27%
    PRS 96.18

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

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  • Node Color (Target Cell CSI, relative to current network):
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    • High
    • Medium
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  • Node Size: Proportional to Target Cell CSI magnitude
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  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [OTC](/details-gene/5009), or Ornithine Transcarbamylase, is a crucial mitochondrial enzyme that catalyzes the second step of the urea cycle: the conversion of ornithine and carbamoyl phosphate to citrulline. This function is essential for the detoxification of ammonia and the biosynthesis of arginine. Deficiencies in [OTC](/details-gene/5009), an X-linked gene, lead to ornithine transcarbamylase deficiency ([311250](https://omim.org/entry/311250)), a severe metabolic disorder characterized by hyperammonemia. Expression data indicates that **Overall**, [OTC](/details-gene/5009) is a highly significant gene in the gastrointestinal tract, with its highest expression observed in cell types such as the [colonocyte](/details-cell/CL1000347) and [intestinal epithelial cell](/details-cell/CL0002563), underscoring the intestine's important role in nitrogen metabolism. ## Cellular Roles and Expression Landscape The expression profile of [OTC](/details-gene/5009) points to a specialized function within the epithelial lining of the intestine. **Overall**, it demonstrates the highest significance in mature absorptive cells like [colonocyte](/details-cell/CL1000347) (CSI: 2.41) and [enterocyte](/details-cell/CL0000584) (CSI: 1.55), as well as in proliferative progenitor cells, such as the [transit amplifying cell of small intestine](/details-cell/CL0009012) (CSI: 1.83). This pattern suggests that [OTC](/details-gene/5009) is not only a marker for terminally differentiated intestinal cells but is also integral to the metabolic machinery of their precursors. The high expression across the intestinal epithelium highlights the gut's significant contribution to whole-body ammonia detoxification and citrulline synthesis, a process classically associated primarily with the liver. The localization to these specific cell types is consistent with their role in processing nitrogenous compounds absorbed from the diet and produced by the gut microbiome. ## Pathways and Molecular Function Functionally, [OTC](/details-gene/5009) is unequivocally linked to nitrogen metabolism and amino acid biosynthesis. Its primary molecular function is [ornithine carbamoyltransferase activity](/details-pathway/GO:0004585), a cornerstone of the [Urea cycle](/details-pathway/GO:0000050) and the corresponding Reactome pathway, [Urea cycle](/details-pathway/R-HSA-70635). This activity directly contributes to the biological processes of [ammonium homeostasis](/details-pathway/GO:0097272) and the [arginine biosynthetic process via ornithine](/details-pathway/GO:0042450). Structurally, the enzyme is known to bind amino acids and phosphate ions ([Link](https://doi.org/10.1074/jbc.273.51.34247)). Consistent with its role as a key metabolic enzyme, [OTC](/details-gene/5009) is localized within the [mitochondrial matrix](/details-pathway/GO:0005759), the primary site of the urea cycle's initial reactions. The regulation of its activity is critical, as shown by studies demonstrating that post-translational modifications like acetylation can negatively impact its function ([Link](https://doi.org/10.1074/jbc.m901921200)). ## Research Directions The high expression of [OTC](/details-gene/5009) in the intestinal epithelium, a site of constant interaction between the host, diet, and microbiota, suggests several avenues for further investigation beyond its classical role in congenital metabolic disease. ### Proposed Hypotheses 1. **Hypothesis 1:** Intestinal [OTC](/details-gene/5009) activity is a critical first-pass defense mechanism against luminal ammonia produced by the gut microbiota. Its downregulation or dysfunction in conditions like inflammatory bowel disease (IBD) or small intestinal bacterial overgrowth (SIBO) could contribute to mucosal barrier damage and local inflammation by allowing for elevated tissue ammonia concentrations. 2. **Hypothesis 2:** The significant expression of [OTC](/details-gene/5009) in [transit amplifying cell of small intestine](/details-cell/CL0009012) suggests a role for urea cycle intermediates, particularly citrulline and arginine, in regulating the balance between proliferation and differentiation in the intestinal crypt. Impaired [OTC](/details-gene/5009) function may alter the local availability of these amino acids, thereby disrupting normal epithelial turnover and repair. ### Experimental Approach To test Hypothesis 1, an intestinal epithelial cell-specific conditional knockout of *Otc* could be generated in mice (e.g., *Otc*fl/fl;Villin-CreERT2). Following tamoxifen-induced deletion, these mice and their wild-type littermates could be challenged with a high-protein diet or a chemical colitogen like dextran sodium sulfate (DSS). The key experimental readouts would be: (1) quantification of ammonia levels in portal venous blood and colonic tissue; (2) histological and immunofluorescence analysis of the intestinal mucosa to assess barrier integrity (e.g., tight junction protein expression), cell death, and immune cell infiltration; and (3) single-cell RNA sequencing of the epithelium to identify compensatory metabolic pathways and stress response signatures. ### Therapeutic Potential As [OTC](/details-gene/5009) deficiency is a loss-of-function disorder, the therapeutic goal is **activation** or **replacement**, not inhibition. Its intracellular, mitochondrial location makes it inaccessible to conventional antibody-based therapies. The most promising strategies involve gene therapy, aimed at delivering a functional copy of the [OTC](/details-gene/5009) gene to hepatocytes. However, the prominent intestinal expression highlighted by this data suggests a complementary therapeutic strategy. Modalities designed to restore or enhance [OTC](/details-gene/5009) function specifically in the gut, such as engineered probiotics that express a functional OTC enzyme or orally delivered, stabilized mRNA, could potentially alleviate the metabolic burden on the liver and reduce systemic ammonia levels, offering a novel approach for managing [OTC](/details-gene/5009) deficiency.

Genular Protein ID: 3881518410

Symbol: OTC_HUMAN

Name: Ornithine carbamoyltransferase, mitochondrial

UniProtKB Accession Codes:

P00480 A8K9P2 D3DWB0 Q3KNR1 Q6B0I1 Q9NYJ5

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 BRENDA 1 Bgee 1 BindingDB 1 BioCyc 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CORUM 1 CTD 1 ChEBI 15 ChEMBL 1 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 DrugBank 4 EC 1 EMBL 16 EMDB 1 Ensembl 1 EvolutionaryTrace 1 ExpressionAtlas 1 GO 20 Gene3D 1 GeneCards 1 GeneReviews 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 5 KEGG 1 MANE-Select 1 MIM 3 MINT 1 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 NCBIfam 1 OMA 1 OpenTargets 1 Orphanet 1 OrthoDB 1 PANTHER 2 PDB 4 PDBsum 4 PIR 1 PRINTS 2 PRO 1 PROSITE 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 2 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 REPRODUCTION-2DPAGE 1 RNAct 1 Reactome 2 RefSeq 1 Rhea 2 SABIO-RK 1 SIGNOR 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TreeFam 1 UCSC 1 UniPathway 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 6372096

Title: Structure and expression of a complementary DNA for the nuclear coded precursor of human mitochondrial ornithine transcarbamylase.

PubMed ID: 6372096

DOI: 10.1126/science.6372096

PubMed ID: 2836378

Title: Structure of the human ornithine transcarbamylase gene.

PubMed ID: 2836378

DOI: 10.1093/oxfordjournals.jbchem.a122265

PubMed ID: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 15772651

Title: The DNA sequence of the human X chromosome.

PubMed ID: 15772651

DOI: 10.1038/nature03440

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 3895227

Title: Arginine in the leader peptide is required for both import and proteolytic cleavage of a mitochondrial precursor.

PubMed ID: 3895227

DOI: 10.1073/pnas.82.15.4930

PubMed ID: 3782067

Title: Isolation and characterization of the human ornithine transcarbamylase gene: structure of the 5'-end region.

PubMed ID: 3782067

DOI: 10.1093/oxfordjournals.jbchem.a121764

PubMed ID: 8081373

Title: A novel arginine (245) to glutamine change in exon 8 of the ornithine carbamoyl transferase gene in two unrelated children presenting with late onset deficiency and showing the same enzymatic pattern.

PubMed ID: 8081373

DOI: 10.1093/hmg/3.5.831

PubMed ID: 24275569

Title: An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome.

PubMed ID: 24275569

DOI: 10.1016/j.jprot.2013.11.014

PubMed ID: 8112735

Title: Expression of four mutant human ornithine transcarbamylase genes in cultured Cos 1 cells relates to clinical phenotypes.

PubMed ID: 8112735

DOI: 10.1007/bf00210596

PubMed ID: 19318352

Title: Lysine 88 acetylation negatively regulates ornithine carbamoyltransferase activity in response to nutrient signals.

PubMed ID: 19318352

DOI: 10.1074/jbc.m901921200

PubMed ID: 9852088

Title: 1.85-A resolution crystal structure of human ornithine transcarbamoylase complexed with N-phosphonacetyl-L-ornithine. Catalytic mechanism and correlation with inherited deficiency.

PubMed ID: 9852088

DOI: 10.1074/jbc.273.51.34247

PubMed ID: 10813810

Title: Crystal structure of human ornithine transcarbamylase complexed with carbamoyl phosphate and L-norvaline at 1.9 A resolution.

PubMed ID: 10813810

DOI: 10.1002/(sici)1097-0134(20000601)39:4<271::aid-prot10>3.3.co;2-5

PubMed ID: 8364586

Title: Mutations and polymorphisms in the human ornithine transcarbamylase gene.

PubMed ID: 8364586

DOI: 10.1002/humu.1380020304

PubMed ID: 7627182

Title: Mutations and polymorphisms in the human ornithine transcarbamylase gene: mutation update addendum.

PubMed ID: 7627182

DOI: 10.1002/humu.1380050404

PubMed ID: 8544185

Title: The molecular basis of ornithine transcarbamylase deficiency: modelling the human enzyme and the effects of mutations.

PubMed ID: 8544185

DOI: 10.1136/jmg.32.9.680

PubMed ID: 3170748

Title: Characterization of point mutations in the same arginine codon in three unrelated patients with ornithine transcarbamylase deficiency.

PubMed ID: 3170748

DOI: 10.1172/jci113738

PubMed ID: 2556444

Title: An arginine to glutamine mutation in residue 109 of human ornithine transcarbamylase completely abolishes enzymatic activity in Cos1 cells.

PubMed ID: 2556444

DOI: 10.1172/jci114360

PubMed ID: 2474822

Title: Scanning detection of mutations in human ornithine transcarbamoylase by chemical mismatch cleavage.

PubMed ID: 2474822

DOI: 10.1073/pnas.86.15.5888

PubMed ID: 2347583

Title: Use of denaturing gradient gel electrophoresis for detection of mutation and prospective diagnosis in late onset ornithine transcarbamylase deficiency.

PubMed ID: 2347583

DOI: 10.1016/0888-7543(90)90537-5

PubMed ID: 1671317

Title: Improved molecular diagnostics for ornithine transcarbamylase deficiency.

PubMed ID: 1671317

PubMed ID: 1721894

Title: Fatal hyperammonemia resulting from a C-to-T mutation at a MspI site of the ornithine transcarbamylase gene.

PubMed ID: 1721894

DOI: 10.1007/bf00206063

PubMed ID: 1480464

Title: Six new mutations in the ornithine transcarbamylase gene detected by single-strand conformational polymorphism.

PubMed ID: 1480464

DOI: 10.1203/00006450-199211000-00024

PubMed ID: 8099056

Title: Single-strand conformational polymorphism and direct sequencing applied to carrier testing in families with ornithine transcarbamylase deficiency.

PubMed ID: 8099056

DOI: 10.1007/bf00217350

PubMed ID: 8019569

Title: The ornithine transcarbamylase gene: new 'private' mutations in four patients and study of a polymorphism.

PubMed ID: 8019569

DOI: 10.1002/humu.1380030325

PubMed ID: 8081398

Title: Four newly identified ornithine transcarbamylase (OTC) mutations (D126G, R129H, I172M and W332X) in Japanese male patients with early-onset OTC deficiency.

PubMed ID: 8081398

DOI: 10.1002/humu.1380030415

PubMed ID: 7951259

Title: Seven new mutations in the human ornithine transcarbamylase gene.

PubMed ID: 7951259

DOI: 10.1002/humu.1380040109

PubMed ID: 8530002

Title: A splicing mutation, a nonsense mutation (Y167X) and two missense mutations (I159T and A209V) in Spanish patients with ornithine transcarbamylase deficiency.

PubMed ID: 8530002

DOI: 10.1007/bf00197410

PubMed ID: 7474905

Title: A novel point mutation at codon 269 of the ornithine transcarbamylase (OTC) gene causing neonatal onset of OTC deficiency.

PubMed ID: 7474905

DOI: 10.1007/bf00710430

PubMed ID: 8807340

Title: Partial duplication [dup. TCAC (178)] and novel point mutations (T125M, G188R, A209V, and H302L) of the ornithine transcarbamylase gene in congenital hyperammonemia.

PubMed ID: 8807340

DOI: 10.1002/(sici)1098-1004(1996)8:1<74::aid-humu11>3.0.co;2-o

PubMed ID: 8956038

Title: Ornithine transcarbamylase deficiency: characterization of gene mutations and polymorphisms.

PubMed ID: 8956038

DOI: 10.1002/(sici)1098-1004(1996)8:4<333::aid-humu6>3.0.co;2-8

PubMed ID: 8956045

Title: A 3-base pair in-frame deletion in exon 8 (delGlu272/273) of the ornithine transcarbamylase gene in late-onset hyperammonemic coma.

PubMed ID: 8956045

DOI: 10.1002/(sici)1098-1004(1996)8:4<373::aid-humu13>3.0.co;2-#

PubMed ID: 8830175

Title: Identification of new mutations in the ornithine transcarbamylase (OTC) gene in Korean families.

PubMed ID: 8830175

DOI: 10.1007/bf01799346

PubMed ID: 9286441

Title: The ornithine transcarbamylase (OTC) gene: mutations in 50 Japanese families with OTC deficiency.

PubMed ID: 9286441

DOI: 10.1002/(sici)1096-8628(19970905)71:4<378::aid-ajmg2>3.3.co;2-9

PubMed ID: 9065786

Title: Expression, purification and kinetic characterization of wild-type human ornithine transcarbamylase and a recurrent mutant that produces 'late onset' hyperammonaemia.

PubMed ID: 9065786

DOI: 10.1042/bj3220625

PubMed ID: 9143919

Title: Ornithine transcarbamylase deficiency: ten new mutations and high proportion of de novo mutations in heterozygous females.

PubMed ID: 9143919

DOI: 10.1002/(sici)1098-1004(1997)9:5<409::aid-humu5>3.0.co;2-z

PubMed ID: 9266388

Title: Identification of 'private' mutations in patients with ornithine transcarbamylase deficiency.

PubMed ID: 9266388

DOI: 10.1023/a:1005301513465

PubMed ID: 9452024

Title: Ten novel mutations of the ornithine transcarbamylase (OTC) gene in OTC deficiency.

PubMed ID: 9452024

DOI: 10.1002/humu.1380110103

PubMed ID: 9452049

Title: Novel intragenic deletions and point mutations of the ornithine transcarbamylase gene in congenital hyperammonemia.

PubMed ID: 9452049

DOI: 10.1002/humu.1380110128

PubMed ID: 9452065

Title: Y55D mutation in ornithine transcarbamylase associated with late-onset hyperammonemia in a male.

PubMed ID: 9452065

DOI: 10.1002/humu.1380110144

PubMed ID: 10502831

Title: Identification of a cytogenetic deletion and of four novel mutations (Q69X, I172F, G188V, G197R) affecting the gene for ornithine transcarbamylase (OTC) in Spanish patients with OTC deficiency.

PubMed ID: 10502831

DOI: 10.1002/(sici)1098-1004(199910)14:4<352::aid-humu15>3.0.co;2-d

PubMed ID: 10070627

Title: Three novel and one recurrent ornithine carbamoyltransferase gene mutations in Polish patients.

PubMed ID: 10070627

DOI: 10.1023/a:1005476021549

PubMed ID: 10737985

Title: Lymphocyte mRNA analysis of the ornithine transcarbamylase gene in Italian OTCD male patients and manifesting carriers: identification of novel mutations.

PubMed ID: 10737985

DOI: 10.1002/(sici)1098-1004(200004)15:4<380::aid-humu12>3.0.co;2-q

PubMed ID: 11793483

Title: Identification of seven novel missense mutations, two splice-site mutations, two microdeletions and a polymorphic amino acid substitution in the gene for ornithine transcarbamylase (OTC) in patients with OTC deficiency.

PubMed ID: 11793483

DOI: 10.1002/humu.9011

PubMed ID: 16959974

Title: The consensus coding sequences of human breast and colorectal cancers.

PubMed ID: 16959974

DOI: 10.1126/science.1133427

Sequence Information:

  • Length: 354
  • Mass: 39935
  • Checksum: AE15B734F6E27A3B
  • Sequence:
    • MLFNLRILLN NAAFRNGHNF MVRNFRCGQP LQNKVQLKGR DLLTLKNFTG EEIKYMLWLS 
ADLKFRIKQK GEYLPLLQGK SLGMIFEKRS TRTRLSTETG FALLGGHPCF LTTQDIHLGV 
NESLTDTARV LSSMADAVLA RVYKQSDLDT LAKEASIPII NGLSDLYHPI QILADYLTLQ 
EHYSSLKGLT LSWIGDGNNI LHSIMMSAAK FGMHLQAATP KGYEPDASVT KLAEQYAKEN 
GTKLLLTNDP LEAAHGGNVL ITDTWISMGQ EEEKKKRLQA FQGYQVTMKT AKVAASDWTF 
LHCLPRKPEE VDDEVFYSPR SLVFPEAENR KWTIMAVMVS LLTDYSPQLQ KPKF