Target Information
| Target General Information | Top | |||||
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| Target ID |
T05661
(Former ID: TTDI02111)
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| Target Name |
Lecithin-cholesterol acyltransferase (LCAT)
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| Synonyms |
Phospholipidcholesterolacyltransferase; Phospholipid-cholesterol acyltransferase; Phosphatidylcholinesterol acyltransferase; Phosphatidylcholine-sterol acyltransferase
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| Gene Name |
LCAT
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 2 Target-related Diseases | + | ||||
| 1 | Coronary atherosclerosis [ICD-11: BA80] | |||||
| 2 | Myocardial infarction [ICD-11: BA41-BA43] | |||||
| Function |
Synthesized mainly in the liver and secreted into plasma where it converts cholesterol and phosphatidylcholines (lecithins) to cholesteryl esters and lysophosphatidylcholines on the surface of high and low density lipoproteins (HDLs and LDLs). The cholesterol ester is then transported back to the liver. Has a preference for plasma 16:0-18:2 or 18:O-18:2 phosphatidylcholines. Also produced in the brain by primary astrocytes, and esterifies free cholesterol on nascent APOE-containing lipoproteins secreted from glia and influences cerebral spinal fluid (CSF) APOE- and APOA1 levels. Together with APOE and the cholesterol transporter ABCA1, plays a key role in the maturation of glial-derived, nascent lipoproteins. Required for remodeling high-density lipoprotein particles into their spherical forms. Central enzyme in the extracellular metabolism of plasma lipoproteins.
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| BioChemical Class |
Acyltransferase
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| UniProt ID | ||||||
| EC Number |
EC 2.3.1.43
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| Sequence |
MGPPGSPWQWVTLLLGLLLPPAAPFWLLNVLFPPHTTPKAELSNHTRPVILVPGCLGNQL
EAKLDKPDVVNWMCYRKTEDFFTIWLDLNMFLPLGVDCWIDNTRVVYNRSSGLVSNAPGV QIRVPGFGKTYSVEYLDSSKLAGYLHTLVQNLVNNGYVRDETVRAAPYDWRLEPGQQEEY YRKLAGLVEEMHAAYGKPVFLIGHSLGCLHLLYFLLRQPQAWKDRFIDGFISLGAPWGGS IKPMLVLASGDNQGIPIMSSIKLKEEQRITTTSPWMFPSRMAWPEDHVFISTPSFNYTGR DFQRFFADLHFEEGWYMWLQSRDLLAGLPAPGVEVYCLYGVGLPTPRTYIYDHGFPYTDP VGVLYEDGDDTVATRSTELCGLWQGRQPQPVHLLPLHGIQHLNMVFSNLTLEHINAILLG AYRQGPPASPTASPEPPPPE Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | MEDI6012 | Drug Info | Phase 2 | Coronary artery disease | [2] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Modulator | [+] 1 Modulator drugs | + | ||||
| 1 | MEDI6012 | Drug Info | [1] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: 6-{4-[(4R)-4-hydroxy-6-oxo-4-(trifluoromethyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]piperidin-1-yl}-4-(trifluoromethyl)pyridine-3-carbonitrile | Ligand Info | |||||
| Structure Description | Crystal structure of Lecithin:cholesterol acyltransferase (LCAT) in complex with isopropyl dodec-11-enylfluorophosphonate (IDFP) and a small molecule activator | PDB:6MVD | ||||
| Method | X-ray diffraction | Resolution | 3.10 Å | Mutation | No | [3] |
| PDB Sequence |
HTRPVILVPG
30 CLGNQLEAKL40 DKPDVVNWMC50 YRKTEDFFTI60 WLDLNMFLPL70 GVDCWIDNTR 80 VVYNRSSGLV90 SNAPGVQIRV100 PGFGKTYSVE110 YLDSSKLAGY120 LHTLVQNLVN 130 NGYVRDETVR140 AAPYDWRLEP150 GQQEEYYRKL160 AGLVEEMHAA170 YGKPVFLIGH 180 SLGCLHLLYF190 LLRQPQAWKD200 RFIDGFISLG210 APWGGSIKPM220 LVLASGDNQG 230 IPIMSSIKEE242 QRITTTSPWM252 FPSRMAWPED262 HVFISTPSFN272 YTGRDFQRFF 282 ADLHFEEGWY292 MWLQSRDLLA302 GLPAPGVEVY312 CLYGVGLPTP322 RTYIYDHGFP 332 YTDPVGVLYE342 DGDDTVATRS352 TELCGLWQGR362 QPQPVHLLPL372 HGIQHLNMVF 382 SNLTLEHINA392 ILLGAH
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| Ligand Name: propan-2-yl hydrogen (R)-ethylphosphonate | Ligand Info | |||||
| Structure Description | Crystal structure of Lecithin:cholesterol acyltransferase (LCAT) in complex with isopropyl dodec-11-enylfluorophosphonate (IDFP) and a small molecule activator | PDB:6MVD | ||||
| Method | X-ray diffraction | Resolution | 3.10 Å | Mutation | No | [3] |
| PDB Sequence |
HTRPVILVPG
30 CLGNQLEAKL40 DKPDVVNWMC50 YRKTEDFFTI60 WLDLNMFLPL70 GVDCWIDNTR 80 VVYNRSSGLV90 SNAPGVQIRV100 PGFGKTYSVE110 YLDSSKLAGY120 LHTLVQNLVN 130 NGYVRDETVR140 AAPYDWRLEP150 GQQEEYYRKL160 AGLVEEMHAA170 YGKPVFLIGH 180 SLGCLHLLYF190 LLRQPQAWKD200 RFIDGFISLG210 APWGGSIKPM220 LVLASGDNQG 230 IPIMSSIKEE242 QRITTTSPWM252 FPSRMAWPED262 HVFISTPSFN272 YTGRDFQRFF 282 ADLHFEEGWY292 MWLQSRDLLA302 GLPAPGVEVY312 CLYGVGLPTP322 RTYIYDHGFP 332 YTDPVGVLYE342 DGDDTVATRS352 TELCGLWQGR362 QPQPVHLLPL372 HGIQHLNMVF 382 SNLTLEHINA392 ILLGAH
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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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
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There is no similarity protein (E value < 0.005) for this target
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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.
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Glycerophospholipid metabolism | hsa00564 | Affiliated Target |
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| Class: Metabolism => Lipid metabolism | Pathway Hierarchy | ||
| Cholesterol metabolism | hsa04979 | Affiliated Target |
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| Class: Organismal Systems => Digestive system | Pathway Hierarchy | ||
| Degree | 2 | Degree centrality | 2.15E-04 | Betweenness centrality | 0.00E+00 |
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| Closeness centrality | 1.75E-01 | Radiality | 1.28E+01 | Clustering coefficient | 1.00E+00 |
| Neighborhood connectivity | 1.90E+01 | Topological coefficient | 5.43E-01 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Target Regulators | Top | |||||
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| Target-regulating Transcription Factors | ||||||
| Target-interacting Proteins | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 1 KEGG Pathways | + | ||||
| 1 | Glycerophospholipid metabolism | |||||
| Reactome | [+] 1 Reactome Pathways | + | ||||
| 1 | HDL-mediated lipid transport | |||||
| WikiPathways | [+] 2 WikiPathways | + | ||||
| 1 | Statin Pathway | |||||
| 2 | Lipid digestion, mobilization, and transport | |||||
| References | Top | |||||
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| REF 1 | Familial lecithin-cholesterol acyltransferase (LCAT) deficiency; a differential of proteinuria. J Nephropathol. 2015 January; 4(1): 25-28. | |||||
| REF 2 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 3 | Molecular basis for activation of lecithin:cholesterol acyltransferase by a compound that increases HDL cholesterol. Elife. 2018 Nov 27;7:e41604. | |||||
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