Target Information

Target General Information

Target ID

T13259 (Former ID: TTDS00054)

Target Name

Succinate-semialdehyde dehydrogenase (ALDH5A1)

Synonyms

Succinic dehydrogenase; Succinate-semialdehyde dehydrogenase, mitochondrial; SSADH; NAD(+)-dependent succinic semialdehyde dehydrogenase; Aldehyde dehydrogenase family 5 member A1

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Gene Name

ALDH5A1

Target Type

Successful target

[1]

Disease

[+] 2 Target-related Diseases

Diagnostic imaging [ICD-11: N.A.]

Nutritional deficiency [ICD-11: 5B50-5B71]

Function

Catalyzes one step in the degradation of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA).

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BioChemical Class

Aldehyde/oxo donor oxidoreductase

UniProt ID

SSDH_HUMAN

EC Number

EC 1.2.1.24

Sequence

MATCIWLRSCGARRLGSTFPGCRLRPRAGGLVPASGPAPGPAQLRCYAGRLAGLSAALLR
TDSFVGGRWLPAAATFPVQDPASGAALGMVADCGVREARAAVRAAYEAFCRWREVSAKER
SSLLRKWYNLMIQNKDDLARIITAESGKPLKEAHGEILYSAFFLEWFSEEARRVYGDIIH
TPAKDRRALVLKQPIGVAAVITPWNFPSAMITRKVGAALAAGCTVVVKPAEDTPFSALAL
AELASQAGIPSGVYNVIPCSRKNAKEVGEAICTDPLVSKISFTGSTTTGKILLHHAANSV
KRVSMELGGLAPFIVFDSANVDQAVAGAMASKFRNTGQTCVCSNQFLVQRGIHDAFVKAF
AEAMKKNLRVGNGFEEGTTQGPLINEKAVEKVEKQVNDAVSKGATVVTGGKRHQLGKNFF
EPTLLCNVTQDMLCTHEETFGPLAPVIKFDTEEEAIAIANAADVGLAGYFYSQDPAQIWR
VAEQLEVGMVGVNEGLISSVECPFGGVKQSGLGREGSKYGIDEYLELKYVCYGGL

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3D Structure

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PDB

Drugs and Modes of Action

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Approved Drug(s)

[+] 2 Approved Drugs

Chlormerodrin

Drug Info

Approved

Diagnostic imaging

[2]

Succinic acid

Drug Info

Approved

Malnutrition

[3], [4]

Mode of Action

[+] 2 Modes of Action

Modulator

[+] 1 Modulator drugs

Chlormerodrin

Drug Info

[5]

Inhibitor

[+] 3 Inhibitor drugs

Succinic acid

Drug Info

[1], [6], [7]

T83193

Drug Info

[8]

1-(4-hydroxyphenyl)prop-2-en-1-one

Drug Info

[8]

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: adenosine diphosphate

Ligand Info

Structure Description

The crystal structure of human SSADH in complex with NAD+

PDB:2W8R

Method

X-ray diffraction

Resolution

2.40 Å

Mutation

Yes

[1]

PDB Sequence

LAGLSAALLR

⁶⁰

TDSFVGGRWL

⁷⁰

PAAATFPVQD

⁸⁰

PASGAALGMV

⁹⁰

ADCGVREARA

¹⁰⁰

AVRAAYEAFC

¹¹⁰

RWREVSAKER

¹²⁰

SSLLRKWYNL

¹³⁰

MIQNKDDLAR

¹⁴⁰

IITAESGKPL

¹⁵⁰

KEAHGEILYS

¹⁶⁰

AFFLEWFSEE

¹⁷⁰

ARRVYGDIIH

¹⁸⁰

TPAKDRRALV

¹⁹⁰

LKQPIGVAAV

²⁰⁰

ITPWNFPSAM

²¹⁰

ITRKVGAALA

²²⁰

AGCTVVVKPA

²³⁰

EDTPFSALAL

²⁴⁰

AELASQAGIP

²⁵⁰

SGVYNVIPCS

²⁶⁰

RKNAKEVGEA

²⁷⁰

ICTDPLVSKI

²⁸⁰

SFTGSTTTGK

²⁹⁰

ILLHHAANSV

³⁰⁰

KRVSMELGGL

³¹⁰

APFIVFDSAN

³²⁰

VDQAVAGAMA

³³⁰

SKFRNTGQTA

³⁴⁰

VCSNQFLVQR

³⁵⁰

GIHDAFVKAF

³⁶⁰

AEAMKKNLRV

³⁷⁰

GNGFEEGTTQ

³⁸⁰

GPLINEKAVE

³⁹⁰

KVEKQVNDAV

⁴⁰⁰

SKGATVVTGG

⁴¹⁰

KRHQLGKNFF

⁴²⁰

EPTLLCNVTQ

⁴³⁰

DMLCTHEETF

⁴⁴⁰

GPLAPVIKFD

⁴⁵⁰

TEEEAIAIAN

⁴⁶⁰

AADVGLAGYF

⁴⁷⁰

YSQDPAQIWR

⁴⁸⁰

VAEQLEVGMV

⁴⁹⁰

GVNEGLISSV

⁵⁰⁰

ECPFGGVKQS

⁵¹⁰

GLGREGSKYG

⁵²⁰

IDEYLELKYV

⁵³⁰

CYGGL

Residue

Distance (Å)

ILE201

3.745

THR202

2.861

PRO203

3.957

TRP204

3.643

ASN205

4.407

LYS228

2.614

PRO229

3.836

ALA230

3.465

GLU231

3.169

ALA264

3.514

LYS265

3.899

Residue

Distance (Å)

GLY268

3.693

GLU269

4.940

PHE282

3.681

THR283

4.637

GLY284

4.225

SER285

2.661

THR288

2.700

ILE291

4.060

LEU292

4.039

PHE440

4.640

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

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

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
Alanine, aspartate and glutamate metabolism	hsa00250	Affiliated Target
Class: Metabolism => Amino acid metabolism	Pathway Hierarchy
Butanoate metabolism	hsa00650	Affiliated Target
Class: Metabolism => Carbohydrate metabolism	Pathway Hierarchy

Degree	1	Degree centrality	1.07E-04	Betweenness centrality	0.00E+00
Closeness centrality	1.43E-01	Radiality	1.17E+01	Clustering coefficient	0.00E+00
Neighborhood connectivity	8.00E+00	Topological coefficient	1.00E+00	Eccentricity	13
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-regulating microRNAs

Target-regulating microRNAs Info

Target Affiliated Biological Pathways

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BioCyc

[+] 2 BioCyc Pathways

GABA shunt

4-aminobutyrate degradation

KEGG Pathway

[+] 3 KEGG Pathways

Alanine, aspartate and glutamate metabolism

Butanoate metabolism

Metabolic pathways

Panther Pathway

[+] 2 Panther Pathways

Aminobutyrate degradation

Gamma-aminobutyric acid synthesis

Pathwhiz Pathway

[+] 1 Pathwhiz Pathways

Glutamate Metabolism

WikiPathways

[+] 1 WikiPathways

GABA synthesis, release, reuptake and degradation

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 1

Redox-switch modulation of human SSADH by dynamic catalytic loop. EMBO J. 2009 Apr 8;28(7):959-68.

REF 2

Drug information of Chlormerodrin, 2008. eduDrugs.

REF 3

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: 3637).

REF 4

Handbook of Food Analysis: Residues and other food component analysis. 2006, P914. By Leo M. L. Nollet.

REF 5

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

REF 6

Succinic semialdehyde couples stress response to quorum-sensing signal decay in Agrobacterium tumefaciens. Mol Microbiol. 2006 Oct;62(1):45-56.

REF 7

The GABA shunt: an attractive and potential therapeutic target in the treatment of epileptic disorders. Curr Drug Metab. 2005 Apr;6(2):127-39.

REF 8

Inhibition of GABA shunt enzymes' activity by 4-hydroxybenzaldehyde derivatives. Bioorg Med Chem Lett. 2006 Feb;16(3):592-5.

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