Target Information

Target General Information

Target ID

T96014 (Former ID: TTDR00662)

Target Name

UDP-glucose 4-epimerase (GALE)

Synonyms

UDP-galactose4-epimerase; UDP-galactose4'-epimerase; UDP-galactose 4-epimerase; UDP-N-acetylglucosamine 4-epimerase; UDP-N-acetylgalactosamine 4-epimerase; UDP-GlcNAc 4-epimerase; UDP-GalNAc 4-epimerase; Galactowaldenase

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Gene Name

GALE

Target Type

Literature-reported target

[1]

Function

The reaction with UDP-Gal plays a critical role in the Leloir pathway of galactose catabolism in which galactose is converted to the glycolytic intermediate glucose 6-phosphate. It contributes to the catabolism of dietary galactose and enables the endogenous biosynthesis of both UDP-Gal and UDP-GalNAc when exogenous sources are limited. Both UDP-sugar interconversions are important in the synthesis of glycoproteins and glycolipids. Catalyzes two distinct but analogous reactions: the reversible epimerization of UDP-glucose to UDP-galactose and the reversible epimerization of UDP-N-acetylglucosamine to UDP-N-acetylgalactosamine.

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BioChemical Class

Racemases and epimerase

UniProt ID

GALE_HUMAN

EC Number

EC 5.1.3.2

Sequence

MAEKVLVTGGAGYIGSHTVLELLEAGYLPVVIDNFHNAFRGGGSLPESLRRVQELTGRSV
EFEEMDILDQGALQRLFKKYSFMAVIHFAGLKAVGESVQKPLDYYRVNLTGTIQLLEIMK
AHGVKNLVFSSSATVYGNPQYLPLDEAHPTGGCTNPYGKSKFFIEEMIRDLCQADKTWNA
VLLRYFNPTGAHASGCIGEDPQGIPNNLMPYVSQVAIGRREALNVFGNDYDTEDGTGVRD
YIHVVDLAKGHIAALRKLKEQCGCRIYNLGTGTGYSVLQMVQAMEKASGKKIPYKVVARR
EGDVAACYANPSLAQEELGWTAALGLDRMCEDLWRWQKQNPSGFGTQA

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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: NADH

Ligand Info

Structure Description

STRUCTURE OF HUMAN UDP-GALACTOSE 4-EPIMERASE COMPLEXED WITH NADH AND UDP-GLUCOSE

PDB:1EK6

Method

X-ray diffraction

Resolution

1.50 Å

Mutation

[5]

PDB Sequence

MAEKVLVTGG

¹⁰

AGYIGSHTVL

²⁰

ELLEAGYLPV

³⁰

VIDNFHNAFR

⁴⁰

GGGSLPESLR

⁵⁰

RVQELTGRSV

⁶⁰

EFEEMDILDQ

⁷⁰

GALQRLFKKY

⁸⁰

SFMAVIHFAG

⁹⁰

LKAVGESVQK

¹⁰⁰

PLDYYRVNLT

¹¹⁰

GTIQLLEIMK

¹²⁰

AHGVKNLVFS

¹³⁰

SSATVYGNPQ

¹⁴⁰

YLPLDEAHPT

¹⁵⁰

GGCTNPYGKS

¹⁶⁰

KFFIEEMIRD

¹⁷⁰

LCQADKTWNA

¹⁸⁰

VLLRYFNPTG

¹⁹⁰

AHASGCIGED

²⁰⁰

PQGIPNNLMP

²¹⁰

YVSQVAIGRR

²²⁰

EALNVFGNDY

²³⁰

DTEDGTGVRD

²⁴⁰

YIHVVDLAKG

²⁵⁰

HIAALRKLKE

²⁶⁰

QCGCRIYNLG

²⁷⁰

TGTGYSVLQM

²⁸⁰

VQAMEKASGK

²⁹⁰

KIPYKVVARR

³⁰⁰

EGDVAACYAN

³¹⁰

PSLAQEELGW

³²⁰

TAALGLDRMC

³³⁰

EDLWRWQKQN

³⁴⁰

PSGFGT

Residue

Distance (Å)

GLY9

3.358

ALA11

3.884

GLY12

3.203

TYR13

2.973

ILE14

2.856

GLY15

4.184

ILE32

4.701

ASP33

2.600

ASN34

3.114

PHE35

3.800

HIS36

3.126

ASN37

2.860

ALA38

3.490

MET65

3.604

ASP66

2.837

ILE67

3.104

LEU68

4.593

Residue

Distance (Å)

HIS87

4.970

PHE88

2.883

ALA89

3.471

GLY90

3.338

LEU91

4.288

LYS92

2.700

VAL107

3.771

SER130

3.500

SER131

3.251

SER132

3.606

TYR157

2.712

LYS161

2.805

TYR185

3.266

PHE186

3.946

ASN187

4.917

PRO188

3.067

ASN207

4.601

Ligand Name: Nicotinamide-Adenine-Dinucleotide

Ligand Info

Structure Description

HUMAN UDP-GALACTOSE 4-EPIMERASE: ACCOMMODATION OF UDP-N-ACETYLGLUCOSAMINE WITHIN THE ACTIVE SITE

PDB:1HZJ

Method

X-ray diffraction

Resolution

1.50 Å

Mutation

[6]

PDB Sequence

AEKVLVTGGA

¹¹

GYIGSHTVLE

²¹

LLEAGYLPVV

³¹

IDNFHNAFRG

⁴¹

GGSLPESLRR

⁵¹

VQELTGRSVE

⁶¹

FEEMDILDQG

⁷¹

ALQRLFKKYS

⁸¹

FMAVIHFAGL

⁹¹

KAVGESVQKP

¹⁰¹

LDYYRVNLTG

¹¹¹

TIQLLEIMKA

¹²¹

HGVKNLVFSS

¹³¹

SATVYGNPQY

¹⁴¹

LPLDEAHPTG

¹⁵¹

GCTNPYGKSK

¹⁶¹

FFIEEMIRDL

¹⁷¹

CQADKTWNVV

¹⁸¹

LLRYFNPTGA

¹⁹¹

HASGCIGEDP

²⁰¹

QGIPNNLMPY

²¹¹

VSQVAIGRRE

²²¹

ALNVFGNDYD

²³¹

TEDGTGVRDY

²⁴¹

IHVVDLAKGH

²⁵¹

IAALRKLKEQ

²⁶¹

CGCRIYNLGT

²⁷¹

GTGYSVLQMV

²⁸¹

QAMEKASGKK

²⁹¹

IPYKVVARRE

³⁰¹

GDVAACYANP

³¹¹

SLAQEELGWT

³²¹

AALGLDRMCE

³³¹

DLWRWQKQNP

³⁴¹

SGFGT

Residue

Distance (Å)

GLY9

3.374

ALA11

3.797

GLY12

3.107

TYR13

2.898

ILE14

2.818

GLY15

4.196

ILE32

4.616

ASP33

2.657

ASN34

2.995

PHE35

3.653

HIS36

3.060

ASN37

2.843

ALA38

3.703

MET65

3.604

ASP66

2.769

ILE67

3.257

LEU68

4.728

Residue

Distance (Å)

HIS87

4.961

PHE88

2.777

ALA89

3.544

GLY90

3.372

LEU91

4.234

LYS92

2.876

VAL107

3.761

SER130

3.542

SER131

3.166

SER132

3.458

TYR157

2.669

LYS161

2.845

TYR185

3.297

PHE186

4.075

PRO188

3.326

ASN207

4.552

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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

Protein Name	Pfam ID	Percentage of Identity (%)	E value
Putative short-chain dehydrogenase/reductase family 42E member 2 (SDR42E2)	PF01073	22.993 (63/274)	1.93E-05
Sterol-4-alpha-carboxylate 3-dehydrogenase, decarboxylating (NSDHL)	PF01073	26.538 (69/260)	4.53E-05
3-beta-HSD adrenal and gonadal type (HSD3B2)	PF01073	28.000 (77/275)	1.37E-04
GDP-L-fucose synthase (GFUS)	PF01370	24.715 (65/263)	2.05E-04
Short-chain dehydrogenase/reductase family 42E member 1 (SDR42E1)	PF01073	23.024 (67/291)	2.39E-04
3-beta-hydroxy-5-ene steroid dehydrogenase (HSD3B1)	PF01073	28.902 (50/173)	4.00E-03
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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
Galactose metabolism	hsa00052	Affiliated Target
Class: Metabolism => Carbohydrate metabolism	Pathway Hierarchy
Amino sugar and nucleotide sugar metabolism	hsa00520	Affiliated Target
Class: Metabolism => Carbohydrate metabolism	Pathway Hierarchy

Degree	7	Degree centrality	7.52E-04	Betweenness centrality	3.41E-04
Closeness centrality	1.51E-01	Radiality	1.20E+01	Clustering coefficient	2.38E-01
Neighborhood connectivity	4.43E+00	Topological coefficient	2.26E-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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Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Regulators

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Target-interacting Proteins

Target-interacting Proteins Info

Target Affiliated Biological Pathways

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BioCyc

[+] 3 BioCyc Pathways

D-galactose degradation V (Leloir pathway)

UDP-N-acetyl-D-galactosamine biosynthesis I

UDP-N-acetyl-D-galactosamine biosynthesis II

KEGG Pathway

[+] 3 KEGG Pathways

Galactose metabolism

Amino sugar and nucleotide sugar metabolism

Metabolic pathways

NetPath Pathway

[+] 1 NetPath Pathways

IL2 Signaling Pathway

Panther Pathway

[+] 1 Panther Pathways

Fructose galactose metabolism

Pathwhiz Pathway

[+] 2 Pathwhiz Pathways

Nucleotide Sugars Metabolism

Galactose Metabolism

WikiPathways

[+] 1 WikiPathways

Metabolism of carbohydrates

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 1

Crystal structure of beta1,4-galactosyltransferase complex with UDP-Gal reveals an oligosaccharide acceptor binding site. J Mol Biol. 2002 Apr 26;318(2):491-502.

REF 2

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

REF 3

Identification of novel inhibitors of UDP-Glc 4'-epimerase, a validated drug target for african sleeping sickness. Bioorg Med Chem Lett. 2006 Nov 15;16(22):5744-7.

REF 4

DrugBank 3.0: a comprehensive resource for 'omics' research on drugs. Nucleic Acids Res. 2011 Jan;39(Database issue):D1035-41.

REF 5

Crystallographic evidence for Tyr 157 functioning as the active site base in human UDP-galactose 4-epimerase. Biochemistry. 2000 May 16;39(19):5691-701.

REF 6

Human UDP-galactose 4-epimerase. Accommodation of UDP-N-acetylglucosamine within the active site. J Biol Chem. 2001 May 4;276(18):15131-6.

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