Target Information

Target General Information

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Target ID

T37046 (Former ID: TTDS00494)

Target Name

Biliverdin reductase A (BLVRA)

Synonyms

Biliverdin-IX alpha-reductase; BVR A; BVR; BLVRA; BLVR

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Gene Name

BLVRA

Target Type

Successful target

[1]

Disease

[+] 1 Target-related Diseases

Autoimmune liver disease [ICD-11: DB96]

Function

Reduces the gamma-methene bridge of the open tetrapyrrole, biliverdin IX alpha, to bilirubin with the concomitant oxidation of a NADH or NADPH cofactor.

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BioChemical Class

CH-CH donor oxidoreductase

UniProt ID

BIEA_HUMAN

EC Number

EC 1.3.1.24

Sequence

MNAEPERKFGVVVVGVGRAGSVRMRDLRNPHPSSAFLNLIGFVSRRELGSIDGVQQISLE
DALSSQEVEVAYICSESSSHEDYIRQFLNAGKHVLVEYPMTLSLAAAQELWELAEQKGKV
LHEEHVELLMEEFAFLKKEVVGKDLLKGSLLFTAGPLEEERFGFPAFSGISRLTWLVSLF
GELSLVSATLEERKEDQYMKMTVCLETEKKSPLSWIEEKGPGLKRNRYLSFHFKSGSLEN
VPNVGVNKNIFLKDQNIFVQKLLGQFSEKELAAEKKRILHCLGLAEEIQKYCCSRK

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3D Structure

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PDB

Drugs and Modes of Action

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Approved Drug(s)

[+] 1 Approved Drugs

Ursodeoxycholic acid

Drug Info

Approved

Primary biliary cirrhosis

[2], [3]

Mode of Action

[+] 2 Modes of Action

Activator

[+] 1 Activator drugs

Ursodeoxycholic acid

Drug Info

[1], [4]

Inhibitor

[+] 1 Inhibitor drugs

Nicotinamide-Adenine-Dinucleotide

Drug Info

[5]

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: NADP+

Ligand Info

Structure Description

Crystal Structure of Human Biliverdin Reductase A

PDB:2H63

Method

X-ray diffraction

Resolution

2.70 Å

Mutation

[6]

PDB Sequence

MRKFGVVVVG

¹⁵

VGRAGSVRMR

²⁵

DLRNPHPSSA

³⁵

FLNLIGFVSR

⁴⁵

RELGSIDGVQ

⁵⁵

QISLEDALSS

⁶⁵

QEVEVAYICS

⁷⁵

ESSSHEDYIR

⁸⁵

QFLNAGKHVL

⁹⁵

VEYPMTLSLA

¹⁰⁵

AAQELWELAE

¹¹⁵

QKGKVLHEEH

¹²⁵

VELLMEEFAF

¹³⁵

LKKEVVGKDL

¹⁴⁵

LKGSLLFTAG

¹⁵⁵

PLEEERFGFP

¹⁶⁵

AFSGISRLTW

¹⁷⁵

LVSLFGELSL

¹⁸⁵

VSATLEERKQ

¹⁹⁷

YMKMTVCLET

²⁰⁷

EKKSPLSWIE

²¹⁷

EKGPGLKRNR

²²⁷

YLSFHFKSGS

²³⁷

LENVPNVGVN

²⁴⁷

KNIFLKDQNI

²⁵⁷

FVQKLLGQFS

²⁶⁷

EKELAAEKKR

²⁷⁷

ILHCLGLAEE

²⁸⁷

IQKY

Residue

Distance (Å)

VAL14

4.950

GLY15

3.061

VAL16

2.979

GLY17

3.588

ARG18

3.003

ALA19

2.605

GLY20

4.413

VAL43

4.396

SER44

2.649

ARG45

2.474

ARG46

2.888

LEU48

4.730

CYS74

3.417

SER75

3.384

Residue

Distance (Å)

GLU76

4.005

SER77

3.051

HIS80

3.062

TYR83

4.847

GLU97

3.275

TYR98

2.708

PRO99

3.809

GLU124

3.714

VAL126

4.807

ARG161

4.276

PHE162

3.470

ARG225

4.923

PHE251

4.036

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	5.63E-05
Closeness centrality	1.81E-01	Radiality	1.30E+01	Clustering coefficient	6.67E-01
Neighborhood connectivity	4.00E+00	Topological coefficient	5.71E-01	Eccentricity	12
Download	Click to Download the Full PPI Network of This Target

Target Affiliated Biological Pathways

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BioCyc

[+] 1 BioCyc Pathways

Heme degradation

KEGG Pathway

[+] 1 KEGG Pathways

Porphyrin and chlorophyll metabolism

Pathwhiz Pathway

[+] 1 Pathwhiz Pathways

Porphyrin Metabolism

References

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REF 1

Role of vitamin C transporters and biliverdin reductase in the dual pro-oxidant and anti-oxidant effect of biliary compounds on the placental-fetal... Toxicol Appl Pharmacol. 2008 Oct 15;232(2):327-36.

REF 2

URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7104).

REF 3

Drug information of Ursodeoxycholic acid, 2008. eduDrugs.

REF 4

Influence of ursodeoxycholic acid on the mortality and malignancy associated with primary biliary cirrhosis: a population-based cohort study. Hepatology. 2007 Oct;46(4):1131-7.

REF 5

How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.

REF 6

Crystal Structure of Human Biliverdin Reductase A

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