Target Information

Target General Information

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Target ID

T47466 (Former ID: TTDI02359)

Target Name

Porphobilinogen deaminase (HMBS)

Synonyms

Preuroporphyrinogen synthase; PBGD; Hydroxymethylbilane synthase; HMBS

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Gene Name

HMBS

Target Type

Clinical trial target

[1]

Disease

[+] 1 Target-related Diseases

Inborn porphyrin/heme metabolism error [ICD-11: 5C58]

Function

Tetrapolymerization of the monopyrrole PBG into the hydroxymethylbilane pre-uroporphyrinogen in several discrete steps.

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BioChemical Class

Alkyl aryl transferase

UniProt ID

HEM3_HUMAN

EC Number

EC 2.5.1.61

Sequence

MSGNGNAAATAEENSPKMRVIRVGTRKSQLARIQTDSVVATLKASYPGLQFEIIAMSTTG
DKILDTALSKIGEKSLFTKELEHALEKNEVDLVVHSLKDLPTVLPPGFTIGAICKRENPH
DAVVFHPKFVGKTLETLPEKSVVGTSSLRRAAQLQRKFPHLEFRSIRGNLNTRLRKLDEQ
QEFSAIILATAGLQRMGWHNRVGQILHPEECMYAVGQGALGVEVRAKDQDILDLVGVLHD
PETLLRCIAERAFLRHLEGGCSVPVAVHTAMKDGQLYLTGGVWSLDGSDSIQETMQATIH
VPAQHEDGPEDDPQLVGITARNIPRGPQLAAQNLGISLANLLLSKGAKNILDVARQLNDA
H

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3D Structure

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PDB

HIT2.0 ID

T23J2A

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 1 Clinical Trial Drugs

P-9808

Drug Info

Phase 2

Porphyria

[2]

Mode of Action

[+] 1 Modes of Action

Modulator

[+] 1 Modulator drugs

P-9808

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: 3-[5-[[3-(2-carboxyethyl)-5-[[3-(2-carboxyethyl)-5-[[3-(2-carboxyethyl)-4-(carboxymethyl)-5-methyl-1H-pyrrol-2-yl]methyl]-4-(carboxymethyl)-1H-pyrrol-2-yl]methyl]-4-(carboxymethyl)-1H-pyrrol-2-yl]methyl]-4-(carboxymethyl)-1H-pyrrol-3-yl]propanoic acid

Ligand Info

Structure Description

Human porphobilinogen deaminase R173W mutant crystallized in the ES2 intermediate state

PDB:7AAK

Method

X-ray diffraction

Resolution

1.70 Å

Mutation

Yes

[3]

PDB Sequence

KMRVIRVGTR

²⁶

KSQLARIQTD

³⁶

SVVATLKASY

⁴⁶

PGLQFEIIAM

⁵⁶

STTGDKILDT

⁶⁶

ALSKIGEKSL

⁷⁶

FTKELEHALE

⁸⁶

KNEVDLVVHS

⁹⁶

LKDLPTVLPP

¹⁰⁶

GFTIGAICKR

¹¹⁶

ENPHDAVVFH

¹²⁶

PKFVGKTLET

¹³⁶

LPEKSVVGTS

¹⁴⁶

SLRRAAQLQR

¹⁵⁶

KFPHLEFRSI

¹⁶⁶

RGNLNTWLRK

¹⁷⁶

LDEQQEFSAI

¹⁸⁶

ILATAGLQRM

¹⁹⁶

GWHNRVGQIL

²⁰⁶

HPEECMYAVG

²¹⁶

QGALGVEVRA

²²⁶

KDQDILDLVG

²³⁶

VLHDPETLLR

²⁴⁶

CIAERAFLRH

²⁵⁶

LEGGCSVPVA

²⁶⁶

VHTAMKDGQL

²⁷⁶

YLTGGVWSLD

²⁸⁶

GSDSIQETMQ

²⁹⁶

ATIHVPAQHE

³⁰⁶

DGPEDDPQLV

³¹⁶

GITARNIPRG

³²⁶

PQLAAQNLGI

³³⁶

SLANLLLSKG

³⁴⁶

AKNILDVARQ

³⁵⁶

LNDAH

Residue

Distance (Å)

LEU30

4.547

GLN34

4.241

ILE71

3.762

LYS74

2.970

SER75

3.482

SER96

2.788

LEU97

4.480

LYS98

2.663

ASP99

2.858

LEU100

3.605

PRO101

3.665

THR102

2.746

VAL103

4.304

SER146

4.210

SER147

2.798

ARG149

2.820

ARG150

2.674

Residue

Distance (Å)

LEU188

3.600

ALA189

2.879

ALA191

4.456

GLY192

4.354

ARG195

2.952

ALA214

3.594

VAL215

2.719

GLY216

4.703

GLN217

3.500

GLY218

2.987

ALA219

4.949

ARG251

4.528

LEU254

3.645

GLY259

4.162

GLY260

4.320

CYS261

1.769

SER262

3.120

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Ligand Name: 3-[5-{[3-(2-Carboxyethyl)-4-(Carboxymethyl)-5-Methyl-1h-Pyrrol-2-Yl]methyl}-4-(Carboxymethyl)-1h-Pyrrol-3-Yl]propanoic Acid

Ligand Info

Structure Description

Human porphobilinogen deaminase in complex with cofactor

PDB:7AAJ

Method

X-ray diffraction

Resolution

1.80 Å

Mutation

[3]

PDB Sequence

KMRVIRVGTR

²⁶

KSQLARIQTD

³⁶

SVVATLKASY

⁴⁶

PGLQFEIIAM

⁵⁶

SSLFTKELEH

⁸³

ALEKNEVDLV

⁹³

VHSLKDLPTV

¹⁰³

LPPGFTIGAI

¹¹³

CKRENPHDAV

¹²³

VFHPKFVGKT

¹³³

LETLPEKSVV

¹⁴³

GTSSLRRAAQ

¹⁵³

LQRKFPHLEF

¹⁶³

RSIRGNLNTR

¹⁷³

LRKLDEQQEF

¹⁸³

SAIILATAGL

¹⁹³

QRMGWHNRVG

²⁰³

QILHPEECMY

²¹³

AVGQGALGVE

²²³

VRAKDQDILD

²³³

LVGVLHDPET

²⁴³

LLRCIAERAF

²⁵³

LRHLEGGCSV

²⁶³

PVAVHTAMKD

²⁷³

GQLYLTGGVW

²⁸³

SLDGSDSIQE

²⁹³

TMQATIHVPA

³⁰³

QHEDGPEDDP

³¹³

QLVGITARNI

³²³

PRGPQLAAQN

³³³

LGISLANLLL

³⁴³

SKGAKNILDV

³⁵³

ARQL

Residue

Distance (Å)

LEU30

4.138

GLN34

3.698

SER96

2.747

LYS98

2.665

ASP99

2.999

THR145

3.516

SER146

3.266

SER147

2.821

ARG149

2.666

ARG150

3.057

ILE166

4.221

LEU170

4.240

Residue

Distance (Å)

ARG173

2.463

LEU188

3.539

ALA189

2.623

ALA191

4.780

GLY192

4.437

ARG195

3.502

ALA214

3.809

GLY216

4.830

GLN217

3.700

GLY218

3.055

LEU220

4.909

CYS261

1.766

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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
Porphyrin metabolism	hsa00860	Affiliated Target
Class: Metabolism => Metabolism of cofactors and vitamins	Pathway Hierarchy

Degree	3	Degree centrality	3.22E-04	Betweenness centrality	0.00E+00
Closeness centrality	1.33E-01	Radiality	1.12E+01	Clustering coefficient	1.00E+00
Neighborhood connectivity	5.33E+00	Topological coefficient	6.67E-01	Eccentricity	13
Download	Click to Download the Full PPI Network of This Target

Target Affiliated Biological Pathways

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BioCyc

[+] 2 BioCyc Pathways

Heme biosynthesis

Tetrapyrrole biosynthesis

KEGG Pathway

[+] 2 KEGG Pathways

Porphyrin and chlorophyll metabolism

Metabolic pathways

Panther Pathway

[+] 1 Panther Pathways

Heme biosynthesis

Pathwhiz Pathway

[+] 1 Pathwhiz Pathways

Porphyrin Metabolism

WikiPathways

[+] 2 WikiPathways

Heme Biosynthesis

Metabolism of porphyrins

References

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REF 1

Safety, pharmacokinetics and pharmocodynamics of recombinant human porphobilinogen deaminase in healthy subjects and asymptomatic carriers of the acute intermittent porphyria gene who have increased porphyrin precursor excretion. Clin Pharmacokinet. 2007;46(4):335-49.

REF 2

ClinicalTrials.gov (NCT00418795) Porphozym in the Treatment of Acute Attacks in AIP. U.S. National Institutes of Health.

REF 3

Characterization of porphobilinogen deaminase mutants reveals that arginine-173 is crucial for polypyrrole elongation mechanism. iScience. 2021 Feb 6;24(3):102152.

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