Target Information
| Target General Information | Top | |||||
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| Target ID |
T91940
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| Target Name |
NAD-dependent deacetylase sirtuin-5 (SIRT5)
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| Synonyms |
SIR2L5; SIR2-like protein 5; Regulatory protein SIR2 homolog 5
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| Gene Name |
SIRT5
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| Target Type |
Literature-reported target
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[1] | ||||
| Function |
NAD-dependent lysine demalonylase, desuccinylase and deglutarylase that specifically removes malonyl, succinyl and glutaryl groups on target proteins (PubMed:21908771, PubMed:22076378, PubMed:24703693, PubMed:29180469). Activates CPS1 and contributes to the regulation of blood ammonia levels during prolonged fasting: acts by mediating desuccinylation and deglutarylation of CPS1, thereby increasing CPS1 activity in response to elevated NAD levels during fasting (PubMed:22076378, PubMed:24703693). Activates SOD1 by mediating its desuccinylation, leading to reduced reactive oxygen species (PubMed:24140062). Activates SHMT2 by mediating its desuccinylation (PubMed:29180469). Modulates ketogenesis through the desuccinylation and activation of HMGCS2. Has weak NAD-dependent protein deacetylase activity; however this activity may not be physiologically relevant in vivo. Can deacetylate cytochrome c (CYCS) and a number of other proteins in vitro such as UOX.
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| BioChemical Class |
Sirtuin family. Class III subfamily
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| UniProt ID | ||||||
| EC Number |
EC 3.5.1.-
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| Sequence |
MRPLQIVPSRLISQLYCGLKPPASTRNQICLKMARPSSSMADFRKFFAKAKHIVIISGAG
VSAESGVPTFRGAGGYWRKWQAQDLATPLAFAHNPSRVWEFYHYRREVMGSKEPNAGHRA IAECETRLGKQGRRVVVITQNIDELHRKAGTKNLLEIHGSLFKTRCTSCGVVAENYKSPI CPALSGKGAPEPGTQDASIPVEKLPRCEEAGCGGLLRPHVVWFGENLDPAILEEVDRELA HCDLCLVVGTSSVVYPAAMFAPQVAARGVPVAEFNTETTPATNRFRFHFQGPCGTTLPEA LACHENETVS 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: 7-amino-4-methyl-chromen-2-one | Ligand Info | |||||
| Structure Description | Crystal Structure of SIRT5 in Complex with a Coumarin-Labelled Succinyl Peptide | PDB:5BWL | ||||
| Method | X-ray diffraction | Resolution | 1.55 Å | Mutation | No | [2] |
| PDB Sequence |
PSSSMADFRK
45 FFAKAKHIVI55 ISGAGVSAES65 GVPTFRGAGG75 YWRKWQAQDL85 ATPLAFAHNP 95 SRVWEFYHYR105 REVMGSKEPN115 AGHRAIAECE125 TRLGKQGRRV135 VVITQNIDEL 145 HRKAGTKNLL155 EIHGSLFKTR165 CTSCGVVAEN175 YKSPICPALS185 GKGAPEPGTQ 195 DASIPVEKLP205 RCEEAGCGGL215 LRPHVVWFGE225 NLDPAILEEV235 DRELAHCDLC 245 LVVGTSSVVY255 PAAMFAPQVA265 ARGVPVAEFN275 TETTPATNRF285 RFHFQGPCGT 295 TLPEALA
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: Nicotinamide-Adenine-Dinucleotide | Ligand Info | |||||
| Structure Description | Sirt5 is an NAD-dependent protein lysine demalonylase and desuccinylase | PDB:3RIY | ||||
| Method | X-ray diffraction | Resolution | 1.55 Å | Mutation | No | [3] |
| PDB Sequence |
SFTARPSSSM
40 ADFRKFFAKA50 KHIVIISGAG60 VSAESGVPTF70 RGAGGYWRKW80 QAQDLATPLA 90 FAHNPSRVWE100 FYHYRREVMG110 SKEPNAGHRA120 IAECETRLGK130 QGRRVVVITQ 140 NIDELHRKAG150 TKNLLEIHGS160 LFKTRCTSCG170 VVAENYKSPI180 CPALSGKGAP 190 EPGTQDASIP200 VEKLPRCEEA210 GCGGLLRPHV220 VWFGENLDPA230 ILEEVDRELA 240 HCDLCLVVGT250 SSVVYPAAMF260 APQVAARGVP270 VAEFNTETTP280 ATNRFRFHFQ 290 GPCGTTLPEA300 LA
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GLY58
3.829
ALA59
2.924
GLY60
3.186
SER62
3.808
ALA63
3.830
GLU64
2.948
VAL67
3.616
PRO68
3.412
THR69
3.272
PHE70
2.830
ARG71
3.439
ARG105
4.222
MET109
4.829
GLN140
2.956
ASN141
2.873
ILE142
3.248
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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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| Nicotinate and nicotinamide metabolism | hsa00760 | Affiliated Target |
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| Class: Metabolism => Metabolism of cofactors and vitamins | Pathway Hierarchy | ||
| Degree | 2 | Degree centrality | 2.15E-04 | Betweenness centrality | 4.40E-05 |
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| Closeness centrality | 1.91E-01 | Radiality | 1.33E+01 | Clustering coefficient | 0.00E+00 |
| Neighborhood connectivity | 3.30E+01 | Topological coefficient | 5.00E-01 | Eccentricity | 11 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| References | Top | |||||
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| REF 1 | Sirtuin 5: a review of structure, known inhibitors and clues for developing new inhibitors. Sci China Life Sci. 2017 Mar;60(3):249-256. | |||||
| REF 2 | Crystal Structure of SIRT5 in Complex with a Coumarin-Labelled Succinyl Peptide | |||||
| REF 3 | Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase. Science. 2011 Nov 11;334(6057):806-9. | |||||
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