Target Information

Target General Information

Target ID

T24373 (Former ID: TTDI02303)

Target Name

Lysosomal acid lipase (LIPA)

Synonyms

Sterol esterase; Lysosomal acid lipase/cholesteryl ester hydrolase; Lipase A; LIPA; LAL; Cholesteryl esterase; Acid cholesteryl ester hydrolase

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Gene Name

LIPA

Target Type

Successful target

[1]

Disease

[+] 1 Target-related Diseases

Enzyme deficiency [ICD-11: 5C51-5C57]

Function

Crucial for the intracellular hydrolysis of cholesteryl esters and triglycerides that have been internalized via receptor- mediated endocytosis of lipoprotein particles. Important in mediating the effect of LDL (low density lipoprotein) uptake on suppression of hydroxymethylglutaryl-CoA reductase and activation of endogenous cellular cholesteryl ester formation.

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BioChemical Class

Carboxylic ester hydrolase

UniProt ID

LICH_HUMAN

EC Number

EC 3.1.1.13

Sequence

MKMRFLGLVVCLVLWTLHSEGSGGKLTAVDPETNMNVSEIISYWGFPSEEYLVETEDGYI
LCLNRIPHGRKNHSDKGPKPVVFLQHGLLADSSNWVTNLANSSLGFILADAGFDVWMGNS
RGNTWSRKHKTLSVSQDEFWAFSYDEMAKYDLPASINFILNKTGQEQVYYVGHSQGTTIG
FIAFSQIPELAKRIKMFFALGPVASVAFCTSPMAKLGRLPDHLIKDLFGDKEFLPQSAFL
KWLGTHVCTHVILKELCGNLCFLLCGFNERNLNMSRVDVYTTHSPAGTSVQNMLHWSQAV
KFQKFQAFDWGSSAKNYFHYNQSYPPTYNVKDMLVPTAVWSGGHDWLADVYDVNILLTQI
TNLVFHESIPEWEHLDFIWGLDAPWRLYNKIINLMRKYQ

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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

SBC-102

Drug Info

Approved

Enzyme deficiency

[2]

Mode of Action

[+] 1 Modes of Action

Modulator

[+] 1 Modulator drugs

SBC-102

Drug Info

[1], [2]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

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). Human Similarity Proteins Human Tissue Distribution Human Pathway Affiliation

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).

Human Similarity Proteins

Human Tissue Distribution

Human Pathway Affiliation

Protein Name	Pfam ID	Percentage of Identity (%)	E value
Lipase member J (LIPJ)	PF04083	53.994 (196/363)	2.97E-147


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
Steroid biosynthesis	hsa00100	Affiliated Target
Class: Metabolism => Lipid metabolism	Pathway Hierarchy
Lysosome	hsa04142	Affiliated Target
Class: Cellular Processes => Transport and catabolism	Pathway Hierarchy
Cholesterol metabolism	hsa04979	Affiliated Target
Class: Organismal Systems => Digestive system	Pathway Hierarchy

Chemical Structure based Activity Landscape of Target

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Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 2 KEGG Pathways

Steroid biosynthesis

Lysosome

Panther Pathway

[+] 1 Panther Pathways

Androgen/estrogene/progesterone biosynthesis

Pathwhiz Pathway

[+] 2 Pathwhiz Pathways

Steroid Biosynthesis

Bile Acid Biosynthesis

WikiPathways

[+] 1 WikiPathways

Phase I biotransformations, non P450

References

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REF 1

A Phase 3 Trial of Sebelipase Alfa in Lysosomal Acid Lipase Deficiency. N Engl J Med. 2015 Sep 10;373(11):1010-20.

REF 2

ClinicalTrials.gov (NCT01757184) A Multicenter Study of SBC-102 (Sebelipase Alfa) in Patients With Lysosomal Acid Lipase Deficiency/ ARISE (Acid Lipase Replacement Investigating Safety and Efficacy).U.S. National Institutes of Health.

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