Target Information
| Target General Information | Top | |||||
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| Target ID |
T41195
(Former ID: TTDI03267)
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| Target Name |
Hydroxymethylglutaryl-CoA synthase 1 (HMGCS1)
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| Synonyms |
Hydroxymethylglutaryl-CoA synthase, cytoplasmic; HMGCS; HMG-CoA synthase; 3-hydroxy-3-methylglutaryl coenzyme A synthase 1
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| Gene Name |
HMGCS1
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| Target Type |
Literature-reported target
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[1] | ||||
| Function |
This enzyme condenses acetyl-CoA with acetoacetyl-CoA to form HMG-CoA, which is the substrate for HMG-CoA reductase.
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| UniProt ID | ||||||
| EC Number |
EC 2.3.3.10
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| Sequence |
MPGSLPLNAEACWPKDVGIVALEIYFPSQYVDQAELEKYDGVDAGKYTIGLGQAKMGFCT
DREDINSLCMTVVQNLMERNNLSYDCIGRLEVGTETIIDKSKSVKTNLMQLFEESGNTDI EGIDTTNACYGGTAAVFNAVNWIESSSWDGRYALVVAGDIAVYATGNARPTGGVGAVALL IGPNAPLIFERGLRGTHMQHAYDFYKPDMLSEYPIVDGKLSIQCYLSALDRCYSVYCKKI HAQWQKEGNDKDFTLNDFGFMIFHSPYCKLVQKSLARMLLNDFLNDQNRDKNSIYSGLEA FGDVKLEDTYFDRDVEKAFMKASSELFSQKTKASLLVSNQNGNMYTSSVYGSLASVLAQY SPQQLAGKRIGVFSYGSGLAATLYSLKVTQDATPGSALDKITASLCDLKSRLDSRTGVAP DVFAENMKLREDTHHLVNYIPQGSIDSLFEGTWYLVRVDEKHRRTYARRPTPNDDTLDEG VGLVHSNIATEHIPSPAKKVPRLPATAAEPEAAVISNGEH Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| 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: Coenzyme A | Ligand Info | |||||
| Structure Description | Crystal structure of human 3-hydroxy-3-methylglutaryl CoA synthase I | PDB:2P8U | ||||
| Method | X-ray diffraction | Resolution | 2.00 Å | Mutation | Yes | [3] |
| PDB Sequence |
NLYFQSMDVG
18 IVALEIYFPS28 QYVDQAELEK38 YDGVDAGKYT48 IGLGQAKMGF58 CTDREDINSL 68 CMTVVQNLME78 RNNLSYDCIG88 RLEVGTETII98 DKSKSVKTNL108 MQLFEESGNT 118 DIEGIDTTNA128 YGGTAAVFNA139 VNWIESSSWD149 GRYALVVAGD159 IAVYATGNAR 169 PTGGVGAVAL179 LIGPNAPLIF189 ERGLRGTHMQ199 HAYDFYKPDM209 LSEYPIVDGK 219 LSIQCYLSAL229 DRCYSVYCKK239 IHAQWQKEGN249 DKDFTLNDFG259 FMIFHSPYCK 269 LVQKSLARML279 LNDFLNDQNR289 DKNSIYSGLE299 AFGDVKLEDT309 YFDRDVEKAF 319 MKASSELFSQ329 KTKASLLVSN339 QNGNMYTSSV349 YGSLASVLAQ359 YSPQQLAGKR 369 IGVFSYGSGL379 AATLYSLKVT389 QDATPGSALD399 KITASLCDLK409 SRLDSRTGVA 419 PDVFAENMKL429 REDTHHLVNY439 IPQGSIDSLF449 EGTWYLVRVD459 EKHRRTYARR 469 P
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ASP43
3.597
ALA44
3.270
GLY45
3.486
LYS46
2.818
ILE49
3.946
GLY50
3.171
LEU51
4.217
TYR163
3.614
ASN167
2.628
ALA168
3.630
THR171
3.364
VAL216
3.760
GLY218
3.788
LYS219
4.790
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| Ligand Name: S-Acetyl-Cysteine | Ligand Info | |||||
| Structure Description | Crystal structure of human 3-hydroxy-3-methylglutaryl CoA synthase I | PDB:2P8U | ||||
| Method | X-ray diffraction | Resolution | 2.00 Å | Mutation | Yes | [3] |
| PDB Sequence |
NLYFQSMDVG
18 IVALEIYFPS28 QYVDQAELEK38 YDGVDAGKYT48 IGLGQAKMGF58 CTDREDINSL 68 CMTVVQNLME78 RNNLSYDCIG88 RLEVGTETII98 DKSKSVKTNL108 MQLFEESGNT 118 DIEGIDTTNA128 YGGTAAVFNA139 VNWIESSSWD149 GRYALVVAGD159 IAVYATGNAR 169 PTGGVGAVAL179 LIGPNAPLIF189 ERGLRGTHMQ199 HAYDFYKPDM209 LSEYPIVDGK 219 LSIQCYLSAL229 DRCYSVYCKK239 IHAQWQKEGN249 DKDFTLNDFG259 FMIFHSPYCK 269 LVQKSLARML279 LNDFLNDQNR289 DKNSIYSGLE299 AFGDVKLEDT309 YFDRDVEKAF 319 MKASSELFSQ329 KTKASLLVSN339 QNGNMYTSSV349 YGSLASVLAQ359 YSPQQLAGKR 369 IGVFSYGSGL379 AATLYSLKVT389 QDATPGSALD399 KITASLCDLK409 SRLDSRTGVA 419 PDVFAENMKL429 REDTHHLVNY439 IPQGSIDSLF449 EGTWYLVRVD459 EKHRRTYARR 469 P
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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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| Valine, leucine and isoleucine degradation | hsa00280 | Affiliated Target |
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| Class: Metabolism => Amino acid metabolism | Pathway Hierarchy | ||
| Butanoate metabolism | hsa00650 | Affiliated Target |
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| Class: Metabolism => Carbohydrate metabolism | Pathway Hierarchy | ||
| Terpenoid backbone biosynthesis | hsa00900 | Affiliated Target |
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| Class: Metabolism => Metabolism of terpenoids and polyketides | Pathway Hierarchy | ||
| PPAR signaling pathway | hsa03320 | Affiliated Target |
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| Class: Organismal Systems => Endocrine system | Pathway Hierarchy | ||
| Degree | 17 | Degree centrality | 1.83E-03 | Betweenness centrality | 7.88E-04 |
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| Closeness centrality | 2.00E-01 | Radiality | 1.35E+01 | Clustering coefficient | 2.43E-01 |
| Neighborhood connectivity | 1.38E+01 | Topological coefficient | 1.58E-01 | Eccentricity | 11 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| References | Top | |||||
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| REF 1 | Inhibition of 3-hydroxy-3-methylglutaryl-CoA synthase and cholesterol biosynthesis by beta-lactone inhibitors and binding of these inhibitors to the enzyme. Biochem J. 1993 Feb 1;289 ( Pt 3):889-95. | |||||
| REF 2 | A visible wavelength spectrophotometric assay suitable for high-throughput screening of 3-hydroxy-3-methylglutaryl-CoA synthase. Anal Biochem. 2010 Jan 1;396(1):96-102. | |||||
| REF 3 | Crystal structures of human HMG-CoA synthase isoforms provide insights into inherited ketogenesis disorders and inhibitor design. J Mol Biol. 2010 May 14;398(4):497-506. | |||||
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