Target Information
| Target General Information | Top | |||||
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| Target ID |
T60636
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| Target Name |
Alpha-ketoglutarate dehydrogenase (OGDH)
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| Synonyms |
OGDC-E1; 2-oxoglutarate dehydrogenase, mitochondrial; 2-oxoglutarate dehydrogenase complex component E1
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| Gene Name |
OGDH
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 2 Target-related Diseases | + | ||||
| 1 | Acute myeloid leukaemia [ICD-11: 2A60] | |||||
| 2 | Pancreatic cancer [ICD-11: 2C10] | |||||
| Function |
The 2-oxoglutarate dehydrogenase complex catalyzes the overall conversion of 2-oxoglutarate to succinyl-CoA and CO(2). The 2-oxoglutarate dehydrogenase complex is mainly active in the mitochondrion. A fraction of the 2-oxoglutarate dehydrogenase complex also localizes in the nucleus and is required for lysine succinylation of histones: associates with KAT2A on chromatin and provides succinyl-CoA to histone succinyltransferase KAT2A. 2-oxoglutarate dehydrogenase (E1) component of the 2-oxoglutarate dehydrogenase complex, which mediates the decarboxylation of alpha-ketoglutarate.
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| BioChemical Class |
Aldehyde/oxo donor oxidoreductase
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| UniProt ID | ||||||
| EC Number |
EC 1.2.4.2
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| Sequence |
MFHLRTCAAKLRPLTASQTVKTFSQNRPAAARTFQQIRCYSAPVAAEPFLSGTSSNYVEE
MYCAWLENPKSVHKSWDIFFRNTNAGAPPGTAYQSPLPLSRGSLAAVAHAQSLVEAQPNV DKLVEDHLAVQSLIRAYQIRGHHVAQLDPLGILDADLDSSVPADIISSTDKLGFYGLDES DLDKVFHLPTTTFIGGQESALPLREIIRRLEMAYCQHIGVEFMFINDLEQCQWIRQKFET PGIMQFTNEEKRTLLARLVRSTRFEEFLQRKWSSEKRFGLEGCEVLIPALKTIIDKSSEN GVDYVIMGMPHRGRLNVLANVIRKELEQIFCQFDSKLEAADEGSGDVKYHLGMYHRRINR VTDRNITLSLVANPSHLEAADPVVMGKTKAEQFYCGDTEGKKVMSILLHGDAAFAGQGIV YETFHLSDLPSYTTHGTVHVVVNNQIGFTTDPRMARSSPYPTDVARVVNAPIFHVNSDDP EAVMYVCKVAAEWRSTFHKDVVVDLVCYRRNGHNEMDEPMFTQPLMYKQIRKQKPVLQKY AELLVSQGVVNQPEYEEEISKYDKICEEAFARSKDEKILHIKHWLDSPWPGFFTLDGQPR SMSCPSTGLTEDILTHIGNVASSVPVENFTIHGGLSRILKTRGEMVKNRTVDWALAEYMA FGSLLKEGIHIRLSGQDVERGTFSHRHHVLHDQNVDKRTCIPMNHLWPNQAPYTVCNSSL SEYGVLGFELGFAMASPNALVLWEAQFGDFHNTAQCIIDQFICPGQAKWVRQNGIVLLLP HGMEGMGPEHSSARPERFLQMCNDDPDVLPDLKEANFDINQLYDCNWVVVNCSTPGNFFH VLRRQILLPFRKPLIIFTPKSLLRHPEARSSFDEMLPGTHFQRVIPEDGPAAQNPENVKR LLFCTGKVYYDLTRERKARDMVGQVAITRIEQLSPFPFDLLLKEVQKYPNAELAWCQEEH KNQGYYDYVKPRLRTTISRAKPVWYAGRDPAAAPATGNKKTHLTELQRLLDTAFDLDVFK NFS Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | CPI-613 | Drug Info | Phase 3 | Acute myeloid leukaemia | [2], [3] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Modulator | [+] 1 Modulator drugs | + | ||||
| 1 | CPI-613 | 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: Thiamin diphosphate | Ligand Info | |||||
| Structure Description | Cryo-electron microscopic structure of the 2-oxoglutarate dehydrogenase (E1) component of the human alpha-ketoglutarate (2-oxoglutarate) dehydrogenase complex | PDB:7WGR | ||||
| Method | Electron microscopy | Resolution | 2.92 Å | Mutation | No | [4] |
| PDB Sequence |
AVQSLIRAYQ
138 IRGHHVAQLD148 PLGILDADLD158 SSVPADIISS168 TDKLGFYGLD178 ESDLDKVFHL 188 PTTTFIGGQE198 SALPLREIIR208 RLEMAYCQHI218 GVEFMFINDL228 EQCQWIRQKF 238 ETPGIMQFTN248 EEKRTLLARL258 VRSTRFEEFL268 QRKWSSEKRF278 GLEGCEVLIP 288 ALKTIIDKSS298 ENGVDYVIMG308 MPHRGRLNVL318 ANVIRKELEQ328 IFCQFDSKLE 338 AADEGSGDNI366 TLSLVANPSH376 LEAADPVVMG386 KTKAEQFYCG396 DTEGKKVMSI 406 LLHGDAAFAG416 QGIVYETFHL426 SDLPSYTTHG436 TVHVVVNNQI446 GFTTDPRMAR 456 SSPYPTDVAR466 VVNAPIFHVN476 SDDPEAVMYV486 CKVAAEWRST496 FHKDVVVDLV 506 CYRRNGHNEM516 DEPMFTQPLM526 YKQIRKQKPV536 LQKYAELLVS546 QGVVNQPEYE 556 EEISKYDKIC566 EEAFARSKMS603 CPSTGLTEDI613 LTHIGNVASS623 VPVENFTIHG 633 GLSRILKTRG643 EMVKNRTVDW653 ALAEYMAFGS663 LLKEGIHIRL673 SGQDVERGTF 683 SHRHHVLHDQ693 NVDKRTCIPM703 NHLWPNQAPY713 TVCNSSLSEY723 GVLGFELGFA 733 MASPNALVLW743 EAQFGDFHNT753 AQCIIDQFIC763 PGQAKWVRQN773 GIVLLLPHGM 783 EGMGPEHSSA793 RPERFLQMCN803 DDPDVLPDLK813 EANFDINQLY823 DCNWVVVNCS 833 TPGNFFHVLR843 RQILLPFRKP853 LIIFTPKSLL863 RHPEARSSFD873 EMLPGTHFQR 883 VIPEDGPAAQ893 NPENVKRLLF903 CTGKVYYDLT913 RERKARDMVG923 QVAITRIEQL 933 SPFPFDLLLK943 EVQKYPNAEL953 AWCQEEHKNQ963 GYYDYVKPRL973 RTTISRAKPV 983 WYAGRDPAAA993 PATGNKKTHL1003 TELQRLLDTA1013 FDLDVFKNFS1023 |
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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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| Citrate cycle (TCA cycle) | hsa00020 | Affiliated Target |
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| Class: Metabolism => Carbohydrate metabolism | Pathway Hierarchy | ||
| Degree | 16 | Degree centrality | 1.72E-03 | Betweenness centrality | 9.28E-05 |
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| Closeness centrality | 1.75E-01 | Radiality | 1.28E+01 | Clustering coefficient | 3.25E-01 |
| Neighborhood connectivity | 1.54E+01 | Topological coefficient | 1.95E-01 | Eccentricity | 13 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Target Regulators | Top | |||||
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| Target-interacting Proteins | ||||||
| References | Top | |||||
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| REF 1 | A strategically designed small molecule attacks alpha-ketoglutarate dehydrogenase in tumor cells through a redox process. Cancer Metab. 2014 Mar 10;2(1):4. | |||||
| REF 2 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 3 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 4 | Structural basis for the activity and regulation of human alpha-ketoglutarate dehydrogenase revealed by Cryo-EM. doi:10.1016/j.bbrc.2022.02.093. | |||||
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