Target Information

Target General Information

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Target ID

T52098

Target Name

Ornithine transcarbamylase (OTC)

Synonyms

OTCase; Ornithine carbamoyltransferase, mitochondrial

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Gene Name

OTC

Target Type

Clinical trial target

[1]

Disease

[+] 1 Target-related Diseases

Metabolism inborn error [ICD-11: 5C50]

Function

Catalyzes the second step of the urea cycle, the condensation of carbamoyl phosphate with L-ornithine to form L-citrulline. The urea cycle ensures the detoxification of ammonia by converting it to urea for excretion.

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UniProt ID

OTC_HUMAN

EC Number

EC 2.1.3.3

Sequence

MLFNLRILLNNAAFRNGHNFMVRNFRCGQPLQNKVQLKGRDLLTLKNFTGEEIKYMLWLS
ADLKFRIKQKGEYLPLLQGKSLGMIFEKRSTRTRLSTETGFALLGGHPCFLTTQDIHLGV
NESLTDTARVLSSMADAVLARVYKQSDLDTLAKEASIPIINGLSDLYHPIQILADYLTLQ
EHYSSLKGLTLSWIGDGNNILHSIMMSAAKFGMHLQAATPKGYEPDASVTKLAEQYAKEN
GTKLLLTNDPLEAAHGGNVLITDTWISMGQEEEKKKRLQAFQGYQVTMKTAKVAASDWTF
LHCLPRKPEEVDDEVFYSPRSLVFPEAENRKWTIMAVMVSLLTDYSPQLQKPKF

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3D Structure

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PDB

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 3 Clinical Trial Drugs

Avalotcagene ontaparvovec

Drug Info

Phase 3

Ornithine transcarbamylase deficiency

[2]

ARCT-810

Drug Info

Phase 2

Ornithine transcarbamylase deficiency

[3]

DTX301

Drug Info

Phase 1/2

Ornithine transcarbamylase deficiency

[4]

Mode of Action

[+] 1 Modes of Action

Replacement

[+] 1 Replacement drugs

DTX301

Drug Info

[1]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Drug Binding Sites of Target

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Ligand Name: Aminocarbonyl dihydrogen phosphate

Ligand Info

Structure Description

HUMAN ORNITHINE TRANSCARBAMYLASE: CRYSTALLOGRAPHIC INSIGHTS INTO SUBSTRATE RECOGNITION AND CATALYTIC MECHANISM

PDB:1C9Y

Method

X-ray diffraction

Resolution

1.90 Å

Mutation

[6]

PDB Sequence

KVQLKGRDLL

⁴³

TLKNFTGEEI

⁵³

KYMLWLSADL

⁶³

KFRIKQKGEY

⁷³

LPLLQGKSLG

⁸³

MIFEKRSTRT

⁹³

RLSTETGFAL

¹⁰³

LGGHPCFLTT

¹¹³

QDIHLGVNES

¹²³

LTDTARVLSS

¹³³

MADAVLARVY

¹⁴³

KQSDLDTLAK

¹⁵³

EASIPIINGL

¹⁶³

SDLYHPIQIL

¹⁷³

ADYLTLQEHY

¹⁸³

SSLKGLTLSW

¹⁹³

IGDGNNILHS

²⁰³

IMMSAAKFGM

²¹³

HLQAATPKGY

²²³

EPDASVTKLA

²³³

EQYAKENGTK

²⁴³

LLLTNDPLEA

²⁵³

AHGGNVLITD

²⁶³

TWISMGREEE

²⁷³

KKKRLQAFQG

²⁸³

YQVTMKTAKV

²⁹³

AASDWTFLHC

³⁰³

LPRKPEEVDD

³¹³

EVFYSPRSLV

³²³

FPEAENRKWT

³³³

IMAVMVSLLT

³⁴³

DYSPQLQKPK

³⁵³

Residue

Distance (Å)

ARG89

4.071

SER90

2.692

THR91

2.770

ARG92

2.790

THR93

2.795

ARG94

4.479

ARG141

2.770

LEU163

4.961

Residue

Distance (Å)

HIS168

2.903

GLN171

2.693

MET268

4.186

CYS303

2.926

LEU304

3.205

PRO305

4.109

ARG330

2.939

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Ligand Name: N-(Phosphonoacetyl)-L-ornithine

Ligand Info

Structure Description

CRYSTAL STRUCTURE OF HUMAN ORNITHINE TRANSCARBAMOYLASE COMPLEXED WITH N-PHOSPHONACETYL-L-ORNITHINE

PDB:1OTH

Method

X-ray diffraction

Resolution

1.85 Å

Mutation

[7]

PDB Sequence

KVQLKGRDLL

⁴³

TLKNFTGEEI

⁵³

KYMLWLSADL

⁶³

KFRIKQKGEY

⁷³

LPLLQGKSLG

⁸³

MIFEKRSTRT

⁹³

RLSTETGFAL

¹⁰³

LGGHPCFLTT

¹¹³

QDIHLGVNES

¹²³

LTDTARVLSS

¹³³

MADAVLARVY

¹⁴³

KQSDLDTLAK

¹⁵³

EASIPIINGL

¹⁶³

SDLYHPIQIL

¹⁷³

ADYLTLQEHY

¹⁸³

SSLKGLTLSW

¹⁹³

IGDGNNILHS

²⁰³

IMMSAAKFGM

²¹³

HLQAATPKGY

²²³

EPDASVTKLA

²³³

EQYAKENGTK

²⁴³

LLLTNDPLEA

²⁵³

AHGGNVLITD

²⁶³

TWISMGREEE

²⁷³

KKKRLQAFQG

²⁸³

YQVTMKTAKV

²⁹³

AASDWTFLHC

³⁰³

LPRKPEEVDD

³¹³

EVFYSPRSLV

³²³

FPEAENRKWT

³³³

IMAVMVSLLT

³⁴³

DYSPQLQKPK

³⁵³

Residue

Distance (Å)

ARG89

4.021

SER90

2.732

THR91

2.859

ARG92

2.863

THR93

2.774

ARG94

4.505

ARG141

2.787

LEU163

3.661

HIS168

2.811

GLN171

3.818

ASN198

3.307

Residue

Distance (Å)

ASN199

2.840

ILE200

3.883

ASP263

2.697

THR264

4.221

SER267

2.906

MET268

2.991

CYS303

3.731

LEU304

2.835

PRO305

4.188

ARG330

2.947

Click to View More Binding Site Information of This Target with Different Ligands

Different Human System Profiles of Target	Top
Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target. A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020). Human Tissue Distribution of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues. The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects (Nat Rev Drug Discov, 20: 64-81, 2021). Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function. Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006). Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database. The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017). Human Similarity Proteins Human Tissue Distribution Human Pathway Affiliation Biological Network Descriptors

Different Human System Profiles of Target

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Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.

A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020).

Human Tissue Distribution of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.

The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects (Nat Rev Drug Discov, 20: 64-81, 2021).

Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.

Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006).

Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.

The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017).

Human Similarity Proteins

Human Tissue Distribution

Human Pathway Affiliation

Biological Network Descriptors

There is no similarity protein (E value < 0.005) for this target


Note: If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.

KEGG Pathway	Pathway ID	Affiliated Target	Pathway Map
Arginine biosynthesis	hsa00220	Affiliated Target
Class: Metabolism => Amino acid metabolism	Pathway Hierarchy

Degree	7	Degree centrality	7.52E-04	Betweenness centrality	6.60E-06
Closeness centrality	1.71E-01	Radiality	1.27E+01	Clustering coefficient	3.81E-01
Neighborhood connectivity	7.14E+00	Topological coefficient	3.11E-01	Eccentricity	13
Download	Click to Download the Full PPI Network of This Target

References

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REF 1

Clinical pipeline report, company report or official report of Ultragenyx Pharmaceutical.

REF 2

ClinicalTrials.gov (NCT05345171) A Phase 3, Randomized, Double-blind, Placebo-controlled Study of Adeno-associated Virus (AAV) Serotype 8 (AAV8)-Mediated Gene Transfer of Human Ornithine Transcarbamylase (OTC) in Patients With Late-onset OTC Deficiency. U.S.National Institutes of Health.

REF 3

Clinical pipeline report, company report or official report of Arcturus Therapeutics

REF 4

ClinicalTrials.gov (NCT02991144) Safety and Dose-Finding Study of DTX301 (scAAV8OTC) in Adults With Late-Onset OTC Deficiency (CAPtivate). U.S. National Institutes of Health.

REF 5

Prednisolone reduces the interferon response to AAV in cynomolgus macaques and may increase liver gene expression. Mol Ther Methods Clin Dev. 2022 Jan 19;24:292-305.

REF 6

Crystal structure of human ornithine transcarbamylase complexed with carbamoyl phosphate and L-norvaline at 1.9 A resolution. Proteins. 2000 Jun 1;39(4):271-7.

REF 7

1.85-A resolution crystal structure of human ornithine transcarbamoylase complexed with N-phosphonacetyl-L-ornithine. Catalytic mechanism and correlation with inherited deficiency. J Biol Chem. 1998 Dec 18;273(51):34247-54.

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