Target Information

Target General Information

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Target ID

T01575 (Former ID: TTDI02173)

Target Name

Sphingosine-1-phosphate lyase 1 (SGPL1)

Synonyms

hSPL; Sphingosine-1-phosphate aldolase; SPL 1; SP-lyase 1; S1PL; KIAA1252

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Gene Name

SGPL1

Target Type

Clinical trial target

[1]

Disease

[+] 2 Target-related Diseases

Congenital ichthyosis [ICD-11: EC20]

Rheumatoid arthritis [ICD-11: FA20]

Function

Elevates stress-induced ceramide production and apoptosis. Required for global lipid homeostasis in liver and cholesterol homeostasis in fibroblasts. Involved in the regulation of pro-inflammatory response and neutrophil trafficking. Modulates neuronal autophagy via phosphoethanolamine production which regulates accumulation of aggregate-prone proteins such as APP. Seems to play a role in establishing neuronal contact sites and axonal maintenance. Cleaves phosphorylated sphingoid bases (PSBs), such as sphingosine-1-phosphate, into fatty aldehydes and phosphoethanolamine.

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BioChemical Class

Carbon-carbon lyase

UniProt ID

SGPL1_HUMAN

EC Number

EC 4.1.2.27

Sequence

MPSTDLLMLKAFEPYLEILEVYSTKAKNYVNGHCTKYEPWQLIAWSVVWTLLIVWGYEFV
FQPESLWSRFKKKCFKLTRKMPIIGRKIQDKLNKTKDDISKNMSFLKVDKEYVKALPSQG
LSSSAVLEKLKEYSSMDAFWQEGRASGTVYSGEEKLTELLVKAYGDFAWSNPLHPDIFPG
LRKIEAEIVRIACSLFNGGPDSCGCVTSGGTESILMACKAYRDLAFEKGIKTPEIVAPQS
AHAAFNKAASYFGMKIVRVPLTKMMEVDVRAMRRAISRNTAMLVCSTPQFPHGVIDPVPE
VAKLAVKYKIPLHVDACLGGFLIVFMEKAGYPLEHPFDFRVKGVTSISADTHKYGYAPKG
SSLVLYSDKKYRNYQFFVDTDWQGGIYASPTIAGSRPGGISAACWAALMHFGENGYVEAT
KQIIKTARFLKSELENIKGIFVFGNPQLSVIALGSRDFDIYRLSNLMTAKGWNLNQLQFP
PSIHFCITLLHARKRVAIQFLKDIRESVTQIMKNPKAKTTGMGAIYGMAQTTVDRNMVAE
LSSVFLDSLYSTDTVTQGSQMNGSPKPH

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3D Structure

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PDB

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 1 Clinical Trial Drugs

LX2931

Drug Info

Phase 2

Rheumatoid arthritis

[2]

Discontinued Drug(s)

[+] 1 Discontinued Drugs

LX-2932

Drug Info

Terminated

Autoimmune diabetes

[3]

Mode of Action

[+] 1 Modes of Action

Inhibitor

[+] 3 Inhibitor drugs

LX2931

Drug Info

[1], [4]

LX-2932

Drug Info

[5]

PMID24809814C31

Drug Info

[6]

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: PMID24809814C31

Ligand Info

Structure Description

Crystal structure of human sphingosine-1-phosphate lyase in complex with inhibitor 6-[(2R)-4-(4-benzyl-7-chlorophthalazin-1-yl)-2-methylpiperazin-1-yl]pyridine-3-carbonitrile

PDB:4Q6R

Method

X-ray diffraction

Resolution

2.40 Å

Mutation

[6]

PDB Sequence

EYVKALPSQG

¹²⁰

LSSSAVLEKL

¹³⁰

KEYSSMDAFW

¹⁴⁰

QEGRASGTVY

¹⁵⁰

SGEEKLTELL

¹⁶⁰

VKAYGDFAWS

¹⁷⁰

NPLHPDIFPG

¹⁸⁰

LRKIEAEIVR

¹⁹⁰

IACSLFNGGP

²⁰⁰

DSCGCVTSGG

²¹⁰

TESILMACKA

²²⁰

YRDLAFEKGI

²³⁰

KTPEIVAPQS

²⁴⁰

AHAAFNKAAS

²⁵⁰

YFGMKIVRVP

²⁶⁰

LTKMMEVDVR

²⁷⁰

AMRRAISRNT

²⁸⁰

AMLVCSTPQF

²⁹⁰

PHGVIDPVPE

³⁰⁰

VAKLAVKYKI

³¹⁰

PLHVDACLGG

³²⁰

FLIVFMEKAG

³³⁰

YPLEHPFDFR

³⁴⁰

VKGVTSISAD

³⁵⁰

THYGYAPKGS

³⁶¹

SLVLYSDKKY

³⁷¹

RNYQFFVDTD

³⁸¹

WQGGIYASPT

³⁹¹

IAGSRPGGIS

⁴⁰¹

AACWAALMHF

⁴¹¹

GENGYVEATK

⁴²¹

QIIKTARFLK

⁴³¹

SELENIKGIF

⁴⁴¹

VFGNPQLSVI

⁴⁵¹

ALGSRDFDIY

⁴⁶¹

RLSNLMTAKG

⁴⁷¹

WNLNQLQFPP

⁴⁸¹

SIHFCITLLH

⁴⁹¹

ARKRVAIQFL

⁵⁰¹

KDIRESVTQI

⁵¹¹

MKNPKAKTTG

⁵²¹

MGAIYGMAQT

⁵³¹

TVDRNMVAEL

⁵⁴¹

SSVFLDSLYS

⁵⁵¹

Residue

Distance (Å)

LEU173

3.113

HIS174

4.375

PRO175

3.529

ASP176

3.992

TRP382

4.272

Residue

Distance (Å)

GLY384

3.775

GLY385

4.820

ILE386

2.915

TYR387

3.548

ALA388

3.140

Ligand Name: N6-((3-Hydroxy-2-methyl-5-((phosphonooxy)methyl)-4-pyridinyl)methylene)-L-lysine

Ligand Info

Structure Description

Crystal structure of human sphingosine-1-phosphate lyase in complex with inhibitor 6-[(2R)-4-(4-benzyl-7-chlorophthalazin-1-yl)-2-methylpiperazin-1-yl]pyridine-3-carbonitrile

PDB:4Q6R

Method

X-ray diffraction

Resolution

2.40 Å

Mutation

[6]

PDB Sequence

EYVKALPSQG

¹²⁰

LSSSAVLEKL

¹³⁰

KEYSSMDAFW

¹⁴⁰

QEGRASGTVY

¹⁵⁰

SGEEKLTELL

¹⁶⁰

VKAYGDFAWS

¹⁷⁰

NPLHPDIFPG

¹⁸⁰

LRKIEAEIVR

¹⁹⁰

IACSLFNGGP

²⁰⁰

DSCGCVTSGG

²¹⁰

TESILMACKA

²²⁰

YRDLAFEKGI

²³⁰

KTPEIVAPQS

²⁴⁰

AHAAFNKAAS

²⁵⁰

YFGMKIVRVP

²⁶⁰

LTKMMEVDVR

²⁷⁰

AMRRAISRNT

²⁸⁰

AMLVCSTPQF

²⁹⁰

PHGVIDPVPE

³⁰⁰

VAKLAVKYKI

³¹⁰

PLHVDACLGG

³²⁰

FLIVFMEKAG

³³⁰

YPLEHPFDFR

³⁴⁰

VKGVTSISAD

³⁵⁰

THYGYAPKGS

³⁶¹

SLVLYSDKKY

³⁷¹

RNYQFFVDTD

³⁸¹

WQGGIYASPT

³⁹¹

IAGSRPGGIS

⁴⁰¹

AACWAALMHF

⁴¹¹

GENGYVEATK

⁴²¹

QIIKTARFLK

⁴³¹

SELENIKGIF

⁴⁴¹

VFGNPQLSVI

⁴⁵¹

ALGSRDFDIY

⁴⁶¹

RLSNLMTAKG

⁴⁷¹

WNLNQLQFPP

⁴⁸¹

SIHFCITLLH

⁴⁹¹

ARKRVAIQFL

⁵⁰¹

KDIRESVTQI

⁵¹¹

MKNPKAKTTG

⁵²¹

MGAIYGMAQT

⁵³¹

TVDRNMVAEL

⁵⁴¹

SSVFLDSLYS

⁵⁵¹

Residue

Distance (Å)

TYR150

3.294

GLY209

4.117

GLY210

3.137

THR211

2.609

ILE214

3.617

HIS242

3.411

PRO288

3.867

GLN289

4.695

PHE290

3.869

ASP315

2.812

Residue

Distance (Å)

CYS317

3.364

LEU318

3.262

ASP350

3.204

THR351

3.075

HIS352

1.342

TYR354

1.347

GLY355

3.112

TYR356

3.062

ALA357

4.749

LYS359

4.780

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
Sphingolipid metabolism	hsa00600	Affiliated Target
Class: Metabolism => Lipid metabolism	Pathway Hierarchy
Sphingolipid signaling pathway	hsa04071	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy

Degree	5	Degree centrality	5.37E-04	Betweenness centrality	3.33E-07
Closeness centrality	1.82E-01	Radiality	1.30E+01	Clustering coefficient	8.00E-01
Neighborhood connectivity	1.34E+01	Topological coefficient	5.15E-01	Eccentricity	11
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-interacting Proteins

Target-interacting Proteins Info

Target Profiles in Patients

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Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 3 KEGG Pathways

Sphingolipid metabolism

Metabolic pathways

Sphingolipid signaling pathway

Pathwhiz Pathway

[+] 1 Pathwhiz Pathways

Sphingolipid Metabolism

PID Pathway

[+] 1 PID Pathways

Sphingosine 1-phosphate (S1P) pathway

Reactome

[+] 1 Reactome Pathways

Sphingolipid de novo biosynthesis

WikiPathways

[+] 1 WikiPathways

Sphingolipid metabolism

References

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REF 1

Targeting the sphingosine-1-phosphate axis in cancer, inflammation and beyond. Nat Rev Drug Discov. 2013 Sep;12(9):688-702.

REF 2

ClinicalTrials.gov (NCT00903383) Study of LX3305 in Subjects With Active Rheumatoid Arthritis on Stable Methotrexate. U.S. National Institutes of Health.

REF 3

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800021957)

REF 4

S1P is associated with protection in human and experimental cerebral malaria. Mol Med. 2011;17(7-8):717-25.

REF 5

Inhibition of sphingosine 1-phosphate lyase for the treatment of rheumatoid arthritis: discovery of (E)-1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)ethanone oxime (LX2931) and (1R,2S,3R)-1-(2-(isoxazol-3-yl)-1H-imidazol-4-yl)butane-1,2,3,4-tetraol (LX2932). J Med Chem. 2010 Dec 23;53(24):8650-62.

REF 6

Orally active 7-substituted (4-benzylphthalazin-1-yl)-2-methylpiperazin-1-yl]nicotinonitriles as active-site inhibitors of sphingosine 1-phosphate lyase for the treatment of multiple sclerosis. J MedChem. 2014 Jun 26;57(12):5074-84.

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