Target Information
| Target General Information | Top | |||||
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| Target ID |
T94788
(Former ID: TTDR01028)
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| Target Name |
Branched-chain-amino-acid transaminase 2 (BCAT2)
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| Synonyms |
Placental protein 18; PP18; ECA39 protein; Branched-chain amino acid aminotransferase; BCAT2; BCAT(m); BCAT
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| Gene Name |
BCAT2
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| Target Type |
Literature-reported target
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| Function |
Catalyzes the first reaction in the catabolism of the essential branched chain amino acids leucine, isoleucine, and valine. May also function as a transporter of branched chain alpha-keto acids.
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| BioChemical Class |
Transaminase
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| UniProt ID | ||||||
| EC Number |
EC 2.6.1.42
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| Sequence |
MAAAALGQIWARKLLSVPWLLCGPRRYASSSFKAADLQLEMTQKPHKKPGPGEPLVFGKT
FTDHMLMVEWNDKGWGQPRIQPFQNLTLHPASSSLHYSLQLFEGMKAFKGKDQQVRLFRP WLNMDRMLRSAMRLCLPSFDKLELLECIRRLIEVDKDWVPDAAGTSLYVRPVLIGNEPSL GVSQPTRALLFVILCPVGAYFPGGSVTPVSLLADPAFIRAWVGGVGNYKLGGNYGPTVLV QQEALKRGCEQVLWLYGPDHQLTEVGTMNIFVYWTHEDGVLELVTPPLNGVILPGVVRQS LLDMAQTWGEFRVVERTITMKQLLRALEEGRVREVFGSGTACQVCPVHRILYKDRNLHIP TMENGPELILRFQKELKEIQYGIRAHEWMFPV 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: Pyridoxal phosphate | Ligand Info | |||||
| Structure Description | Single Amino Acid Variant of Human Mitochondrial Branched Chain Amino Acid Aminotransferase 2 | PDB:5MPR | ||||
| Method | X-ray diffraction | Resolution | 1.60 Å | Mutation | Yes | [3] |
| PDB Sequence |
GASSSFKAAD
9 LQLEMTQKPH19 KKPGPPLVFG31 KTFTDHMLMV41 EWNDKGWGQP51 RIQPFQNLTL 61 HPASSSLHYS71 LQLFEGMKAF81 KGKDQQVRLF91 RPWLNMDRML101 RSAMRLCLPS 111 FDKLELLECI121 RRLIEVDKDW131 VPDAAGTSLY141 VRPVLIGNEP151 SLGVSQPRRA 161 LLFVILCPVG171 AYFPGGSVTP181 VSLLADPAFI191 RAWVGGVGNY201 KLGGNYGPTV 211 LVQQEALKRG221 CEQVLWLYGP231 DHQLTEVGTM241 NIFVYWTHED251 GVLELVTPPL 261 NGVILPGVVR271 QSLLDMAQTW281 GEFRVVERTI291 TMKQLLRALE301 EGRVREVFGS 311 GTACQVCPVH321 RILYKDRNLH331 IPTMENGPEL341 ILRFQKELKE351 IQYGIRAHEW 361 MFPV
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: Gabapentin | Ligand Info | |||||
| Structure Description | X-ray crystal structure of human mitochondrial branched chain aminotransferase (BCATm) complexed with gabapentin | PDB:2A1H | ||||
| Method | X-ray diffraction | Resolution | 1.80 Å | Mutation | No | [4] |
| PDB Sequence |
SSFKAADLQL
12 EMTQKPHKKP22 GPGEPLVFGK32 TFTDHMLMVE42 WNDKGWGQPR52 IQPFQNLTLH 62 PASSSLHYSL72 QLFEGMKAFK82 GKDQQVRLFR92 PWLNMDRMLR102 SAMRLCLPSF 112 DKLELLECIR122 RLIEVDKDWV132 PDAAGTSLYV142 RPVLIGNEPS152 LGVSQPRRAL 162 LFVILCPVGA172 YFPGGSVTPV182 SLLADPAFIR192 AWVGGVGNYK202 LGGNYGPTVL 212 VQQEALKRGC222 EQVLWLYGPD232 HQLTEVGTMN242 IFVYWTHEDG252 VLELVTPPLN 262 GVILPGVVRQ272 SLLDMAQTWG282 EFRVVERTIT292 MKQLLRALEE302 GRVREVFGSG 312 TACQVCPVHR322 ILYKDRNLHI332 PTMENGPELI342 LRFQKELKEI352 QYGIRAHEWM 362 FPV
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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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| Cysteine and methionine metabolism | hsa00270 | Affiliated Target |
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| Class: Metabolism => Amino acid metabolism | Pathway Hierarchy | ||
| Valine, leucine and isoleucine degradation | hsa00280 | Affiliated Target |
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| Class: Metabolism => Amino acid metabolism | Pathway Hierarchy | ||
| Valine, leucine and isoleucine biosynthesis | hsa00290 | Affiliated Target |
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| Class: Metabolism => Amino acid metabolism | Pathway Hierarchy | ||
| Pantothenate and CoA biosynthesis | hsa00770 | Affiliated Target |
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| Class: Metabolism => Metabolism of cofactors and vitamins | Pathway Hierarchy | ||
| Degree | 3 | Degree centrality | 3.22E-04 | Betweenness centrality | 0.00E+00 |
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| Closeness centrality | 1.45E-01 | Radiality | 1.18E+01 | Clustering coefficient | 1.00E+00 |
| Neighborhood connectivity | 1.13E+01 | Topological coefficient | 7.08E-01 | Eccentricity | 14 |
| 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 Affiliated Biological Pathways | Top | |||||
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| BioCyc | [+] 3 BioCyc Pathways | + | ||||
| 1 | Leucine degradation | |||||
| 2 | Valine degradation | |||||
| 3 | Isoleucine degradation | |||||
| KEGG Pathway | [+] 7 KEGG Pathways | + | ||||
| 1 | Valine, leucine and isoleucine degradation | |||||
| 2 | Valine, leucine and isoleucine biosynthesis | |||||
| 3 | Pantothenate and CoA biosynthesis | |||||
| 4 | Metabolic pathways | |||||
| 5 | Biosynthesis of antibiotics | |||||
| 6 | 2-Oxocarboxylic acid metabolism | |||||
| 7 | Biosynthesis of amino acids | |||||
| Panther Pathway | [+] 4 Panther Pathways | + | ||||
| 1 | Alanine biosynthesis | |||||
| 2 | Isoleucine biosynthesis | |||||
| 3 | Leucine biosynthesis | |||||
| 4 | Valine biosynthesis | |||||
| WikiPathways | [+] 1 WikiPathways | + | ||||
| 1 | Metabolism of amino acids and derivatives | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6. | |||||
| REF 2 | The design and synthesis of human branched-chain amino acid aminotransferase inhibitors for treatment of neurodegenerative diseases. Bioorg Med Chem Lett. 2006 May 1;16(9):2337-40. | |||||
| REF 3 | Intact Protein Analysis at 21 Tesla and X-Ray Crystallography Define Structural Differences in Single Amino Acid Variants of Human Mitochondrial Branched-Chain Amino Acid Aminotransferase 2 (BCAT2). J Am Soc Mass Spectrom. 2017 Sep;28(9):1796-1804. | |||||
| REF 4 | Structural determinants for branched-chain aminotransferase isozyme-specific inhibition by the anticonvulsant drug gabapentin. J Biol Chem. 2005 Nov 4;280(44):37246-56. | |||||
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