Target Information
| Target General Information | Top | |||||
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| Target ID |
T52189
(Former ID: TTDR01004)
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| Target Name |
ATP-citrate synthase (ACLY)
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| Synonyms |
Citrate cleavage enzyme; ATP-citrate (pro-S-)-lyase; ACL
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| Gene Name |
ACLY
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Hyper-lipoproteinaemia [ICD-11: 5C80] | |||||
| Function |
ATP-citrate synthase is the primary enzyme responsible for the synthesis of cytosolic acetyl-CoA in many tissues. Has a central role in de novo lipid synthesis. In nervous tissue it may be involved in the biosynthesis of acetylcholine.
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| BioChemical Class |
Acyltransferase
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| UniProt ID | ||||||
| EC Number |
EC 2.3.3.8
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| Sequence |
MSAKAISEQTGKELLYKFICTTSAIQNRFKYARVTPDTDWARLLQDHPWLLSQNLVVKPD
QLIKRRGKLGLVGVNLTLDGVKSWLKPRLGQEATVGKATGFLKNFLIEPFVPHSQAEEFY VCIYATREGDYVLFHHEGGVDVGDVDAKAQKLLVGVDEKLNPEDIKKHLLVHAPEDKKEI LASFISGLFNFYEDLYFTYLEINPLVVTKDGVYVLDLAAKVDATADYICKVKWGDIEFPP PFGREAYPEEAYIADLDAKSGASLKLTLLNPKGRIWTMVAGGGASVVYSDTICDLGGVNE LANYGEYSGAPSEQQTYDYAKTILSLMTREKHPDGKILIIGGSIANFTNVAATFKGIVRA IRDYQGPLKEHEVTIFVRRGGPNYQEGLRVMGEVGKTTGIPIHVFGTETHMTAIVGMALG HRPIPNQPPTAAHTANFLLNASGSTSTPAPSRTASFSESRADEVAPAKKAKPAMPQDSVP SPRSLQGKSTTLFSRHTKAIVWGMQTRAVQGMLDFDYVCSRDEPSVAAMVYPFTGDHKQK FYWGHKEILIPVFKNMADAMRKHPEVDVLINFASLRSAYDSTMETMNYAQIRTIAIIAEG IPEALTRKLIKKADQKGVTIIGPATVGGIKPGCFKIGNTGGMLDNILASKLYRPGSVAYV SRSGGMSNELNNIISRTTDGVYEGVAIGGDRYPGSTFMDHVLRYQDTPGVKMIVVLGEIG GTEEYKICRGIKEGRLTKPIVCWCIGTCATMFSSEVQFGHAGACANQASETAVAKNQALK EAGVFVPRSFDELGEIIQSVYEDLVANGVIVPAQEVPPPTVPMDYSWARELGLIRKPASF MTSICDERGQELIYAGMPITEVFKEEMGIGGVLGLLWFQKRLPKYSCQFIEMCLMVTADH GPAVSGAHNTIICARAGKDLVSSLTSGLLTIGDRFGGALDAAAKMFSKAFDSGIIPMEFV NKMKKEGKLIMGIGHRVKSINNPDMRVQILKDYVRQHFPATPLLDYALEVEKITTSKKPN LILNVDGLIGVAFVDMLRNCGSFTREEADEYIDIGALNGIFVLGRSMGFIGHYLDQKRLK QGLYRHPWDDISYVLPEHMSM Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| ADReCS ID | BADD_A01285 | |||||
| HIT2.0 ID | T14W2H | |||||
| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 1 Approved Drugs | + | ||||
| 1 | Bempedoic acid | Drug Info | Approved | Familial hypercholesterolemia | [2] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 3 Inhibitor drugs | + | ||||
| 1 | Bempedoic acid | Drug Info | [2] | |||
| 2 | (-)-hydroxycitrate | Drug Info | [3], [4] | |||
| 3 | SB-201076 | 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: Adenine | Ligand Info | |||||
| Structure Description | TEV Cleaved Human ATP Citrate Lyase Bound to 4S hydroxycitrate | PDB:5TDF | ||||
| Method | X-ray diffraction | Resolution | 1.80 Å | Mutation | No | [5] |
| PDB Sequence |
SAKAISEQTG
11 KELLYKFICT21 TSAIQNRFKY31 ARVTPDTDWA41 RLLQDHPWLL51 SQNLVVKPDQ 61 LIKRRGKLGL71 VGVNLTLDGV81 KSWLKPRLGQ91 EATVGKATGF101 LKNFLIEPFV 111 PHSQAEEFYV121 CIYATREGDY131 VLFHHEGGAQ150 KLLVGVDEKL160 NPEDIKKHLL 170 VHAPEDKKEI180 LASFISGLFN190 FYEDLYFTYL200 EINPLVVTKD210 GVYVLDLAAK 220 VDATADYICK230 VKWGDIEFPP240 PFGREAYPEE250 AYIADLDAKS260 GASLKLTLLN 270 PKGRIWTMVA280 GGGASVVYSD290 TICDLGGVNE300 LANYGEYSGA310 PSEQQTYDYA 320 KTILSLMTRE330 KHPDGKILII340 GGSIANFTNV350 AATFKGIVRA360 IRDYQGPLKE 370 HEVTIFVRRG380 GPNYQEGLRV390 MGEVGKTTGI400 PIHVFGTETH410 MTAIVGMALG 420 HRPIPENLYF430 Q
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| Ligand Name: Adenosine | Ligand Info | |||||
| Structure Description | TEV Cleaved Human ATP Citrate Lyase Bound to Tartrate and ADP | PDB:5TDZ | ||||
| Method | X-ray diffraction | Resolution | 2.00 Å | Mutation | No | [5] |
| PDB Sequence |
SAKAISEQTG
11 KELLYKFICT21 TSAIQNRFKY31 ARVTPDTDWA41 RLLQDHPWLL51 SQNLVVKPDQ 61 LIKRRGKLGL71 VGVNLTLDGV81 KSWLKPRLGQ91 EATVGKATGF101 LKNFLIEPFV 111 PHSQAEEFYV121 CIYATREGDY131 VLFHHAQKLL153 VGVDEKLNPE163 DIKKHLLVHA 173 PEDKKEILAS183 FISGLFNFYE193 DLYFTYLEIN203 PLVVTKDGVY213 VLDLAAKVDA 223 TADYICKVKW233 GDIEFPPPFG243 REAYPEEAYI253 ADLDAKSGAS263 LKLTLLNPKG 273 RIWTMVAGGG283 ASVVYSDTIC293 DLGGVNELAN303 YGEYSGAPSE313 QQTYDYAKTI 323 LSLMTREKHP333 DGKILIIGGS343 IANFTNVAAT353 FKGIVRAIRD363 YQGPLKEHEV 373 TIFVRRGGPN383 YQEGLRVMGE393 VGKTTGIPIH403 VFGTETHMTA413 IVGMALGHRP 423 IPENLYFQ
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| 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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| Citrate cycle (TCA cycle) | hsa00020 | Affiliated Target |
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| Class: Metabolism => Carbohydrate metabolism | Pathway Hierarchy | ||
| Degree | 13 | Degree centrality | 1.40E-03 | Betweenness centrality | 5.46E-04 |
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| Closeness centrality | 1.96E-01 | Radiality | 1.34E+01 | Clustering coefficient | 2.31E-01 |
| Neighborhood connectivity | 1.33E+01 | Topological coefficient | 1.61E-01 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "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 | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
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| Target-regulating microRNAs | ||||||
| Target-interacting Proteins | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| BioCyc | [+] 1 BioCyc Pathways | + | ||||
| 1 | Acetyl-CoA biosynthesis from citrate | |||||
| KEGG Pathway | [+] 3 KEGG Pathways | + | ||||
| 1 | Citrate cycle (TCA cycle) | |||||
| 2 | Metabolic pathways | |||||
| 3 | Biosynthesis of antibiotics | |||||
| NetPath Pathway | [+] 1 NetPath Pathways | + | ||||
| 1 | TGF_beta_Receptor Signaling Pathway | |||||
| Pathwhiz Pathway | [+] 1 Pathwhiz Pathways | + | ||||
| 1 | Transfer of Acetyl Groups into Mitochondria | |||||
| Reactome | [+] 2 Reactome Pathways | + | ||||
| 1 | ChREBP activates metabolic gene expression | |||||
| 2 | Fatty Acyl-CoA Biosynthesis | |||||
| WikiPathways | [+] 6 WikiPathways | + | ||||
| 1 | Fatty Acid Biosynthesis | |||||
| 2 | TCA Cycle and PDHc | |||||
| 3 | Butyrate-induced histone acetylation | |||||
| 4 | SREBP signalling | |||||
| 5 | Integration of energy metabolism | |||||
| 6 | Fatty acid, triacylglycerol, and ketone body metabolism | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | The biology and chemistry of hyperlipidemia. Bioorg Med Chem. 2007 Jul 15;15(14):4674-99. | |||||
| REF 2 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2020 | |||||
| REF 3 | 2-hydroxy-N-arylbenzenesulfonamides as ATP-citrate lyase inhibitors. Bioorg Med Chem Lett. 2007 Jun 1;17(11):3208-11. | |||||
| REF 4 | Synthesis of novel thiol-containing citric acid analogues. Kinetic evaluation of these and other potential active-site-directed and mechanism-based... J Med Chem. 1995 Feb 3;38(3):537-43. | |||||
| REF 5 | Binding of hydroxycitrate to human ATP-citrate lyase. Acta Crystallogr D Struct Biol. 2017 Aug 1;73(Pt 8):660-671. | |||||
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