Target Information
| Target General Information | Top | |||||
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| Target ID |
T89918
(Former ID: TTDR01240)
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| Target Name |
Glycinamide ribonucleotide formyltransferase (GART)
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| Synonyms |
Trifunctional purine biosynthetic protein adenosine-3; PRGS; PGFT
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| Gene Name |
GART
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
| Function |
A trifunctional polypeptide. Has Phosphoribosylamineglycine ligase, Phosphoribosylglycinamide formyltransferase, AIR synthetase (FGAM cyclase) activity which is required for de novo purine biosynthesis.
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| BioChemical Class |
Carbon-nitrogen ligase
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| UniProt ID | ||||||
| Sequence |
MAARVLIIGSGGREHTLAWKLAQSHHVKQVLVAPGNAGTACSEKISNTAISISDHTALAQ
FCKEKKIEFVVVGPEAPLAAGIVGNLRSAGVQCFGPTAEAAQLESSKRFAKEFMDRHGIP TAQWKAFTKPEEACSFILSADFPALVVKASGLAAGKGVIVAKSKEEACKAVQEIMQEKAF GAAGETIVIEELLDGEEVSCLCFTDGKTVAPMPPAQDHKRLLEGDGGPNTGGMGAYCPAP QVSNDLLLKIKDTVLQRTVDGMQQEGTPYTGILYAGIMLTKNGPKVLEFNCRFGDPECQV ILPLLKSDLYEVIQSTLDGLLCTSLPVWLENHTALTVVMASKGYPGDYTKGVEITGFPEA QALGLEVFHAGTALKNGKVVTHGGRVLAVTAIRENLISALEEAKKGLAAIKFEGAIYRKD VGFRAIAFLQQPRSLTYKESGVDIAAGNMLVKKIQPLAKATSRSGCKVDLGGFAGLFDLK AAGFKDPLLASGTDGVGTKLKIAQLCNKHDTIGQDLVAMCVNDILAQGAEPLFFLDYFSC GKLDLSVTEAVVAGIAKACGKAGCALLGGETAEMPDMYPPGEYDLAGFAVGAMERDQKLP HLERITEGDVVVGIASSGLHSNGFSLVRKIVAKSSLQYSSPAPDGCGDQTLGDLLLTPTR IYSHSLLPVLRSGHVKAFAHITGGGLLENIPRVLPEKLGVDLDAQTWRIPRVFSWLQQEG HLSEEEMARTFNCGVGAVLVVSKEQTEQILRDIQQHKEEAWVIGSVVARAEGSPRVKVKN LIESMQINGSVLKNGSLTNHFSFEKKKARVAVLISGTGSNLQALIDSTREPNSSAQIDIV ISNKAAVAGLDKAERAGIPTRVINHKLYKNRVEFDSAIDLVLEEFSIDIVCLAGFMRILS GPFVQKWNGKMLNIHPSLLPSFKGSNAHEQALETGVTVTGCTVHFVAEDVDAGQIILQEA VPVKRGDTVATLSERVKLAEHKIFPAALQLVASGTVQLGENGKICWVKEE 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) | [+] 2 Clinical Trial Drugs | + | ||||
| 1 | PELITREXOL | Drug Info | Phase 2 | Solid tumour/cancer | [2] | |
| 2 | LY309887 | Drug Info | Phase 1 | Solid tumour/cancer | [3] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 7 Inhibitor drugs | + | ||||
| 1 | PELITREXOL | Drug Info | [1], [4] | |||
| 2 | LY309887 | Drug Info | [5], [6] | |||
| 3 | (10r)-10-Formyl-5,8,10-Trideazafolic Acid | Drug Info | [7] | |||
| 4 | 10-Formyl-5,8,10-Trideazafolic Acid | Drug Info | [7] | |||
| 5 | 10-trifluoroacetyl-DDACTHF | Drug Info | [8] | |||
| 6 | Dideazaacyclotetrahydrofolic acid | Drug Info | [9] | |||
| 7 | Glycinamide Ribonucleotide | Drug Info | [7] | |||
| 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: Adenosine triphosphate | Ligand Info | |||||
| Structure Description | Human glycinamide ribonucleotide synthetase | PDB:2QK4 | ||||
| Method | X-ray diffraction | Resolution | 2.45 Å | Mutation | Yes | [10] |
| PDB Sequence |
SMAARVLIIG
9 SGGREHTLAW19 KLAQSHHVKQ29 VLVAPGNAGT39 ACSEKISNTA49 ISISDHTALA 59 QFCKEKKIEF69 VVVGPEAPLA79 AGIVGNLRSA89 GVQCFGPTAE99 AAQLESSKRF 109 AKEFMDRHGI119 PTAQWKAFTK129 PEEACSFILS139 ADFPALVVKA149 SGLKGVIVAK 162 SKEEACKAVQ172 EIMQEETIVI189 EELLDGEEVS199 CLCFTDGKTV209 APMPPAQDHK 219 RLLEGDGGPN229 TGGMGAYCPA239 PQVSNDLLLK249 IKDTVLQRTV259 DGMQQEGTPY 269 TGILYAGIML279 TKNGPKVLEF289 NCRFGDPECQ299 VILPLLKSDL309 YEVIQSTLDG 319 LLCTSLPVWL329 ENHTALTVVM339 ASKGYPGDYT349 KGVEITGFPE359 AQALGLEVFH 369 AGTALKNGKV379 VTHGGRVLAV389 TAIRENLISA399 LEEAKKGLAA409 IKFEGAIYRK 419 DIGFRAIAFL429
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| Ligand Name: Glycinamide Ribonucleotide | Ligand Info | |||||
| Structure Description | HUMAN GAR TRANSFORMYLASE IN COMPLEX WITH GAR AND (S)-2-({4-[3-(2-AMINO-4-OXO-4,7-DIHYDRO-3H-PYRROLO[2,3-D]PYRIMIDIN-6-YL)-PROPYL]-THIOPHENE-2-CARBONYL}-AMINO)-PENTANEDIOIC ACID | PDB:4ZZ1 | ||||
| Method | X-ray diffraction | Resolution | 1.35 Å | Mutation | No | [11] |
| PDB Sequence |
ARVAVLISGT
817 GSNLQALIDS827 TREPNSSAQI837 DIVISNKAAV847 AGLDKAERAG857 IPTRVINHKL 867 YKNRVEFDSA877 IDLVLEEFSI887 DIVCLAGFMR897 ILSGPFVQKW907 NGKMLNIHPS 917 LLPSFKGSNA927 HEQALETGVT937 VTGCTVHFVA947 EDVDAGQIIL957 QEAVPVKRGD 967 TVATLSERVK977 LAEHKIFPAA987 LQLVASGTVQ997 LGENGKICWV1007 |
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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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| Purine metabolism | hsa00230 | Affiliated Target |
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| Class: Metabolism => Nucleotide metabolism | Pathway Hierarchy | ||
| One carbon pool by folate | hsa00670 | Affiliated Target |
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| Class: Metabolism => Metabolism of cofactors and vitamins | Pathway Hierarchy | ||
| Degree | 17 | Degree centrality | 1.83E-03 | Betweenness centrality | 2.70E-04 |
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| Closeness centrality | 1.79E-01 | Radiality | 1.30E+01 | Clustering coefficient | 4.19E-01 |
| Neighborhood connectivity | 1.32E+01 | Topological coefficient | 1.95E-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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| 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 | Purine nucleotides de novo biosynthesis | |||||
| 2 | 5-aminoimidazole ribonucleotide biosynthesis | |||||
| 3 | Tetrahydrofolate salvage from 5,10-methenyltetrahydrofolate | |||||
| KEGG Pathway | [+] 4 KEGG Pathways | + | ||||
| 1 | Purine metabolism | |||||
| 2 | One carbon pool by folate | |||||
| 3 | Metabolic pathways | |||||
| 4 | Biosynthesis of antibiotics | |||||
| NetPath Pathway | [+] 1 NetPath Pathways | + | ||||
| 1 | TCR Signaling Pathway | |||||
| Panther Pathway | [+] 1 Panther Pathways | + | ||||
| 1 | De novo purine biosynthesis | |||||
| Pathwhiz Pathway | [+] 1 Pathwhiz Pathways | + | ||||
| 1 | Purine Metabolism | |||||
| Reactome | [+] 1 Reactome Pathways | + | ||||
| 1 | Purine ribonucleoside monophosphate biosynthesis | |||||
| WikiPathways | [+] 3 WikiPathways | + | ||||
| 1 | One Carbon Metabolism | |||||
| 2 | Metabolism of nucleotides | |||||
| 3 | Folate Metabolism | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | Results of 2 phase I studies of intravenous (iv) pelitrexol (AG2037), a glycinamide ribonucleotide formyltransferase (GARFT) inhibitor, in patients (pts) with solid tumors. J Clin Oncol (Meeting Abstracts) July 2004 vol. 22 no. 14_suppl 3075. | |||||
| REF 2 | ClinicalTrials.gov (NCT00078468) Study of the GARFT Inhibitor AG2037 in Patients With Metastatic Colorectal Cancer Who Failed Treatment. U.S. National Institutes of Health. | |||||
| REF 3 | Phase I and pharmacokinetic study of LY309887: a specific inhibitor of purine biosynthesis. Cancer Chemother Pharmacol. 2001 Jun;47(6):525-31. | |||||
| REF 4 | Phase I study of AG2034, a targeted GARFT inhibitor, administered once every 3 weeks. Cancer Chemother Pharmacol. 2000;45(5):423-7. | |||||
| REF 5 | New antimetabolites in cancer chemotherapy and their clinical impact. Br J Cancer. 1998;78 Suppl 3:1-7. | |||||
| REF 6 | Cellular pharmacology of MTA: a correlation of MTA-induced cellular toxicity and in vitro enzyme inhibition with its effect on intracellular folate and nucleoside triphosphate pools in CCRF-CEM cells. Semin Oncol. 1999 Apr;26(2 Suppl 6):48-54. | |||||
| REF 7 | How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6. | |||||
| REF 8 | Discovery of a potent, nonpolyglutamatable inhibitor of glycinamide ribonucleotide transformylase. J Med Chem. 2006 May 18;49(10):2998-3002. | |||||
| REF 9 | Asymmetric synthesis of inhibitors of glycinamide ribonucleotide transformylase. J Med Chem. 2008 Sep 11;51(17):5441-8. | |||||
| REF 10 | Structural studies of tri-functional human GART. Nucleic Acids Res. 2010 Nov;38(20):7308-19. | |||||
| REF 11 | 6-Substituted Pyrrolo[2,3-d]pyrimidine Thienoyl Regioisomers as Targeted Antifolates for Folate Receptor Alpha and the Proton-Coupled Folate Transporter in Human Tumors. J Med Chem. 2015 Sep 10;58(17):6938-59. | |||||
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