Target Information

Target General Information

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Target ID

T65570

Target Name

Alcohol dehydrogenase 1A (ADH1A)

Synonyms

Alcohol dehydrogenase subunit alpha; ADH1

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Gene Name

ADH1A

Target Type

Successful target

[1]

Disease

[+] 1 Target-related Diseases

Eexposure to noxious substances harmful effect [ICD-11: NE61]

Function

Facilitates the interconversion between alcohols and aldehydes or ketones with the reduction of nicotinamide adenine dinucleotide (NAD+) to NADH.

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UniProt ID

ADH1A_HUMAN

EC Number

EC 1.1.1.1

Sequence

MSTAGKVIKCKAAVLWELKKPFSIEEVEVAPPKAHEVRIKMVAVGICGTDDHVVSGTMVT
PLPVILGHEAAGIVESVGEGVTTVKPGDKVIPLAIPQCGKCRICKNPESNYCLKNDVSNP
QGTLQDGTSRFTCRRKPIHHFLGISTFSQYTVVDENAVAKIDAASPLEKVCLIGCGFSTG
YGSAVNVAKVTPGSTCAVFGLGGVGLSAIMGCKAAGAARIIAVDINKDKFAKAKELGATE
CINPQDYKKPIQEVLKEMTDGGVDFSFEVIGRLDTMMASLLCCHEACGTSVIVGVPPDSQ
NLSMNPMLLLTGRTWKGAILGGFKSKECVPKLVADFMAKKFSLDALITHVLPFEKINEGF
DLLHSGKSIRTILMF

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3D Structure

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PDB

ADReCS ID

BADD_A01378 ; BADD_A03955 ; BADD_A05852

Drugs and Modes of Action

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Approved Drug(s)

[+] 1 Approved Drugs

Fomepizole

Drug Info

Approved

Athylene glycol or methanol poisoning

[2]

Mode of Action

[+] 1 Modes of Action

Modulator

[+] 1 Modulator drugs

Fomepizole

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: Nicotinamide-Adenine-Dinucleotide

Ligand Info

Structure Description

Crystal Structure of Human Alcohol Dehydrogenase Alpha-Alpha Isoform Complexed with N-Cyclopentyl-N-Cyclobutylformamide Determined to 2.5 Angstrom Resolution

PDB:1U3T

Method

X-ray diffraction

Resolution

2.49 Å

Mutation

[3]

PDB Sequence

STAGKVIKCK

¹⁰

AAVLWELKKP

²⁰

FSIEEVEVAP

³⁰

PKAHEVRIKM

⁴⁰

VAVGICGTDD

⁵⁰

HVVSGTMVTP

⁶⁰

LPVILGHEAA

⁷⁰

GIVESVGEGV

⁸⁰

TTVKPGDKVI

⁹⁰

PLAIPQCGKC

¹⁰⁰

RICKNPESNY

¹¹⁰

CLKNDVSNPQ

¹²⁰

GTLQDGTSRF

¹³⁰

TCRRKPIHHF

¹⁴⁰

LGISTFSQYT

¹⁵⁰

VVDENAVAKI

¹⁶⁰

DAASPLEKVC

¹⁷⁰

LIGCGFSTGY

¹⁸⁰

GSAVNVAKVT

¹⁹⁰

PGSTCAVFGL

²⁰⁰

GGVGLSAIMG

²¹⁰

CKAAGAARII

²²⁰

AVDINKDKFA

²³⁰

KAKELGATEC

²⁴⁰

INPQDYKKPI

²⁵⁰

QEVLKEMTDG

²⁶⁰

GVDFSFEVIG

²⁷⁰

RLDTMMASLL

²⁸⁰

CCHEACGTSV

²⁹⁰

IVGVPPDSQN

³⁰⁰

LSMNPMLLLT

³¹⁰

GRTWKGAILG

³²⁰

GFKSKECVPK

³³⁰

LVADFMAKKF

³⁴⁰

SLDALITHVL

³⁵⁰

PFEKINEGFD

³⁶⁰

LLHSGKSIRT

³⁷⁰

ILMF

Residue

Distance (Å)

CYS46

3.761

GLY47

3.036

THR48

2.633

HIS51

3.077

CYS174

3.391

THR178

3.239

GLY199

3.516

LEU200

3.257

GLY201

3.415

GLY202

3.268

VAL203

3.195

GLY204

4.101

VAL222

4.219

ASP223

2.624

ILE224

3.510

ASN225

3.945

LYS228

3.110

Residue

Distance (Å)

PRO243

4.873

VAL268

3.514

ILE269

3.077

GLY270

3.842

ARG271

3.818

THR274

4.022

VAL292

2.982

GLY293

3.461

VAL294

2.761

ALA317

3.246

ILE318

3.520

LEU319

2.985

GLY320

4.921

LEU362

3.457

ILE368

4.655

ARG369

2.799

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

Ligand Name: 4-Iodopyrazole

Ligand Info

Structure Description

HUMAN ALPHA ALCOHOL DEHYDROGENASE (ADH1A)

PDB:1HSO

Method

X-ray diffraction

Resolution

2.50 Å

Mutation

[4]

PDB Sequence

STAGKVIKCK

¹⁰

AAVLWELKKP

²⁰

FSIEEVEVAP

³⁰

PKAHEVRIKM

⁴⁰

VAVGICGTDD

⁵⁰

HVVSGTMVTP

⁶⁰

LPVILGHEAA

⁷⁰

GIVESVGEGV

⁸⁰

TTVKPGDKVI

⁹⁰

PLAIPQCGKC

¹⁰⁰

RICKNPESNY

¹¹⁰

CLKNDVSNPQ

¹²⁰

GTLQDGTSRF

¹³⁰

TCRRKPIHHF

¹⁴⁰

LGISTFSQYT

¹⁵⁰

VVDENAVAKI

¹⁶⁰

DAASPLEKVC

¹⁷⁰

LIGCGFSTGY

¹⁸⁰

GSAVNVAKVT

¹⁹⁰

PGSTCAVFGL

²⁰⁰

GGVGLSAIMG

²¹⁰

CKAAGAARII

²²⁰

AVDINKDKFA

²³⁰

KAKELGATEC

²⁴⁰

INPQDYKKPI

²⁵⁰

QEVLKEMTDG

²⁶⁰

GVDFSFEVIG

²⁷⁰

RLDTMMASLL

²⁸⁰

CCHEACGTSV

²⁹⁰

IVGVPPDSQN

³⁰⁰

LSMNPMLLLT

³¹⁰

GRTWKGAILG

³²⁰

GFKSKECVPK

³³⁰

LVADFMAKKF

³⁴⁰

SLDALITHVL

³⁵⁰

PFEKINEGFD

³⁶⁰

LLHSGKSIRT

³⁷⁰

ILMF

Residue

Distance (Å)

THR48

4.562

MET57

3.623

ALA93

4.981

VAL116

3.771

Residue

Distance (Å)

LEU141

3.928

VAL294

2.730

ILE318

3.714

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
Glycolysis / Gluconeogenesis	hsa00010	Affiliated Target
Class: Metabolism => Carbohydrate metabolism	Pathway Hierarchy
Fatty acid degradation	hsa00071	Affiliated Target
Class: Metabolism => Lipid metabolism	Pathway Hierarchy
Tyrosine metabolism	hsa00350	Affiliated Target
Class: Metabolism => Amino acid metabolism	Pathway Hierarchy
Pyruvate metabolism	hsa00620	Affiliated Target
Class: Metabolism => Carbohydrate metabolism	Pathway Hierarchy
Retinol metabolism	hsa00830	Affiliated Target
Class: Metabolism => Metabolism of cofactors and vitamins	Pathway Hierarchy
Metabolism of xenobiotics by cytochrome P450	hsa00980	Affiliated Target
Class: Metabolism => Xenobiotics biodegradation and metabolism	Pathway Hierarchy
Drug metabolism - cytochrome P450	hsa00982	Affiliated Target
Class: Metabolism => Xenobiotics biodegradation and metabolism	Pathway Hierarchy
Click to Show/Hide the Information of Affiliated Human Pathways

Degree	2	Degree centrality	2.15E-04	Betweenness centrality	0.00E+00
Closeness centrality	1.55E-01	Radiality	1.22E+01	Clustering coefficient	1.00E+00
Neighborhood connectivity	9.50E+00	Topological coefficient	5.94E-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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References

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REF 1

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.

REF 2

Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77.

REF 3

Structure of three class I human alcohol dehydrogenases complexed with isoenzyme specific formamide inhibitors. Biochemistry. 2004 Oct 5;43(39):12555-62.

REF 4

Three-dimensional structures of the three human class I alcohol dehydrogenases. Protein Sci. 2001 Apr;10(4):697-706.

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