Target Information

Target General Information

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Target ID

T56496 (Former ID: TTDI03457)

Target Name

Phenylethanolamine N-methyltransferase (PNMT)

Synonyms

PNMTase; PENT; Noradrenaline N-methyltransferase

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Gene Name

PNMT

Target Type

Literature-reported target

[1]

Function

Converts noradrenaline to adrenaline.

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UniProt ID

PNMT_HUMAN

EC Number

EC 2.1.1.28

Sequence

MSGADRSPNAGAAPDSAPGQAAVASAYQRFEPRAYLRNNYAPPRGDLCNPNGVGPWKLRC
LAQTFATGEVSGRTLIDIGSGPTVYQLLSACSHFEDITMTDFLEVNRQELGRWLQEEPGA
FNWSMYSQHACLIEGKGECWQDKERQLRARVKRVLPIDVHQPQPLGAGSPAPLPADALVS
AFCLEAVSPDLASFQRALDHITTLLRPGGHLLLIGALEESWYLAGEARLTVVPVSEEEVR
EALVRSGYKVRDLRTYIMPAHLQTGVDDVKGVFFAWAQKVGL

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3D Structure

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PDB

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: Ademetionine

Ligand Info

Structure Description

Structure of hPNMT with inhibitor 3-fluoromethyl-7-thiomorpholinosulfonamide-THIQ and AdoMet

PDB:2G72

Method

X-ray diffraction

Resolution

2.00 Å

Mutation

[2]

PDB Sequence

APGQAAVASA

²⁶

YQRFEPRAYL

³⁶

RNNYAPPRGD

⁴⁶

LCNPNGVGPW

⁵⁶

KLRCLAQTFA

⁶⁶

TGEVSGRTLI

⁷⁶

DIGSGPTVYQ

⁸⁶

LLSACSHFED

⁹⁶

ITMTDFLEVN

¹⁰⁶

RQELGRWLQE

¹¹⁶

EPGAFNWSMY

¹²⁶

SQHACLIEGK

¹³⁶

GECWQDKERQ

¹⁴⁶

LRARVKRVLP

¹⁵⁶

IDVHQPQPLG

¹⁶⁶

AGSPAPLPAD

¹⁷⁶

ALVSAFCLEA

¹⁸⁶

VSPDLASFQR

¹⁹⁶

ALDHITTLLR

²⁰⁶

PGGHLLLIGA

²¹⁶

LEESWYLAGE

²²⁶

ARLTVVPVSE

²³⁶

EEVREALVRS

²⁴⁶

GYKVRDLRTY

²⁵⁶

IMPAHLQTGV

²⁶⁶

DDVKGVFFAW

²⁷⁶

AQKV

Residue

Distance (Å)

VAL23

4.986

TYR27

3.578

PHE30

4.565

TYR35

2.491

TYR40

2.657

ILE78

4.966

GLY79

2.722

SER80

3.202

GLY81

3.029

PRO82

4.661

THR83

3.394

TYR85

2.823

GLN86

4.155

ASP101

2.613

Residue

Distance (Å)

PHE102

3.326

LEU103

3.323

ASN106

3.012

ILE157

3.941

ASP158

3.143

VAL159

3.020

HIS160

3.512

ALA181

2.633

PHE182

3.394

CYS183

3.567

ALA186

4.323

VAL187

3.463

TYR222

3.339

Click to View More Binding Site Information of This Target and Ligand Pair

Ligand Name: Norepinephrine

Ligand Info

Structure Description

Crystal Structure of hPNMT in Complex With Noradrenaline and AdoHcy

PDB:3HCD

Method

X-ray diffraction

Resolution

2.39 Å

Mutation

[3]

PDB Sequence

ASAYQRFEPR

³³

AYLRNNYAPP

⁴³

RGDLCNPNGV

⁵³

GPWKLRCLAQ

⁶³

TFATGEVSGR

⁷³

TLIDIGSGPT

⁸³

VYQLLSACSH

⁹³

FEDITMTDFL

¹⁰³

EVNRQELGRW

¹¹³

LQEEPGAFNW

¹²³

SMYSQHACLI

¹³³

EGKGECWQDK

¹⁴³

ERQLRARVKR

¹⁵³

VLPIDVHQPQ

¹⁶³

PLGAGSPAPL

¹⁷³

PADALVSAFC

¹⁸³

LEAVSPDLAS

¹⁹³

FQRALDHITT

²⁰³

LLRPGGHLLL

²¹³

IGALEESWYL

²²³

AGEARLTVVP

²³³

VSEEEVREAL

²⁴³

VRSGYKVRDL

²⁵³

RTYIMPAHLQ

²⁶³

TGVDDVKGVF

²⁷³

FAWAQKV

Residue

Distance (Å)

TYR35

4.098

ASN39

3.899

TYR40

2.708

ARG44

3.159

VAL53

3.709

LYS57

3.090

TYR85

4.633

PHE182

3.469

Residue

Distance (Å)

ALA186

4.574

ALA216

4.468

GLU219

2.960

TYR222

3.345

MET258

4.164

ASP267

3.342

VAL269

4.004

VAL272

4.622

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
Tyrosine metabolism	hsa00350	Affiliated Target
Class: Metabolism => Amino acid metabolism	Pathway Hierarchy

Degree	2	Degree centrality	2.15E-04	Betweenness centrality	0.00E+00
Closeness centrality	1.48E-01	Radiality	1.19E+01	Clustering coefficient	1.00E+00
Neighborhood connectivity	5.50E+00	Topological coefficient	7.86E-01	Eccentricity	12
Download	Click to Download the Full PPI Network of This Target

Chemical Structure based Activity Landscape of Target

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Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

References

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REF 1

Properties of 8,9-dichloro-2,3,4,5-tetrahydro-1H-2-benzazepine, an inhibitor of norepinephrine N-methyltransferase. Biochem Pharmacol. 1981 Jun 1;30(11):1345-52.

REF 2

Enzyme adaptation to inhibitor binding: a cryptic binding site in phenylethanolamine N-methyltransferase. J Med Chem. 2007 Oct 4;50(20):4845-53.

REF 3

Molecular recognition of physiological substrate noradrenaline by the adrenaline-synthesizing enzyme PNMT and factors influencing its methyltransferase activity. Biochem J. 2009 Aug 27;422(3):463-71.

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