Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTF2PUUI)

• DOT Name: Disks large-associated protein 1 (DLGAP1)
• Synonyms: DAP-1; Guanylate kinase-associated protein; hGKAP; PSD-95/SAP90-binding protein 1; SAP90/PSD-95-associated protein 1; SAPAP1
• Gene Name: DLGAP1
• Related Disease:
  Adult glioblastoma
  Glioblastoma multiforme
  Neurodevelopmental disorder
  Attention deficit hyperactivity disorder
  Autism spectrum disorder
  Head and neck neoplasm
  Lipodystrophy
  Narcolepsy
  Neoplasm
  Obsessive compulsive disorder
  Pancreatic neuroendocrine tumor
  Age-related macular degeneration
  Breast cancer
  Breast carcinoma
  Neuroblastoma
  Oral cavity squamous cell carcinoma
• UniProt ID: DLGP1_HUMAN
• PDB ID: 5YPO; 6TNQ; 6TQ0
• Pfam ID: PF03359
• Sequence:
  MKGLSGSRSHHHGVTCDSACDSLSHHSDRKPYLLSPVEHHPADHPYYTQRNSFQAECVGP
  FSDPLASSTFPRRHYTSQQELKDECALVPRTLATKANRIPANLLDQFERQLPLSRDGYHT
  LQYKRTAVEHRSDSPGRIRHLVHSVQKLFTKSHSLEGPSKGSVNGGKASPDEAQAARYGK
  RSKSKERRAEPKARPSTSPGWWSSDDNLDGDMCIYHAPSGVMTMGRCPDRSASQYFLEAY
  NTISEQAVKASRSNNDVKCSTCANLPVSLDTPLLKKSAWSSTLTVSRAREVYQKASVNMD
  QAMVKSESCQQERSCQYLQVPQDEWTGYTPRGKDDEIPCRRMRSGSYIKAMGDEDSGDSD
  TSPKPSPKVAARRESYLKATQPSLTELTTLKISNEHSPKLQIRSHSYLRAVSEVSINRSL
  DSLDPAGLLTSPKFRSRNESYMRAMSTISQVSEMEVNGQFESVCESVFSELESQAVEALD
  LPMPGCFRMRSHSYVRAIEKGCSQDDECVSLRSSSPPRTTTTVRTIQSSTVSSCITTYKK
  TPPPVPPRTTTKPFISITAQSSTESAQDAYMDGQGQRGDIISQSGLSNSTESLDSMKALT
  AAIEAANAQIHGPASQHMGNNTATVTTTTTIATVTTEDRKKDHFKKNRCLSIGIQVDDAE
  EPDKTGENKAPSKFQSVGVQVEEEKCFRRFTRSNSVTTAVQADLDFHDNLENSLESIEDN
  SCPGPMARQFSRDASTSTVSIQGSGNHYHACAADDDFDTDFDPSILPPPDPWIDSITEDP
  LEAVQRSVCHRDGHWFLKLLQAERDRMEGWCQQMEREERENNLPEDILGKIRTAVGSAQL
  LMAQKFYQFRELCEENLNPNAHPRPTSQDLAGFWDMLQLSIENISMKFDELHQLKANNWK
  QMDPLDKKERRAPPPVPKKPAKGPAPLIRERSLESSQRQEARKRLMAAKRAASVRQNSAT
  ESAESIEIYIPEAQTRL
• Function: Part of the postsynaptic scaffold in neuronal cells.
• Tissue Specificity: Expressed in brain.
• KEGG Pathway: Glutamatergic sy.pse (hsa04724)
• Reactome Pathway: Neurexins and neuroligins (R-HSA-6794361)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Definitive	Biomarker	[1]
Glioblastoma multiforme	DISK8246	Definitive	Altered Expression	[1]
Neurodevelopmental disorder	DIS372XH	Definitive	Biomarker	[2]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Biomarker	[3]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[4]
Head and neck neoplasm	DIS1OB2G	Strong	Altered Expression	[5]
Lipodystrophy	DIS3SGVD	Strong	Genetic Variation	[6]
Narcolepsy	DISLCNLI	Strong	Genetic Variation	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[8]
Obsessive compulsive disorder	DIS1ZMM2	Strong	Genetic Variation	[9]
Pancreatic neuroendocrine tumor	DISDMPU0	Strong	Biomarker	[8]
Age-related macular degeneration	DIS0XS2C	moderate	Genetic Variation	[10]
Breast cancer	DIS7DPX1	moderate	Biomarker	[11]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[11]
Neuroblastoma	DISVZBI4	moderate	Biomarker	[12]
Oral cavity squamous cell carcinoma	DISQVJVA	moderate	Altered Expression	[13]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Disks large-associated protein 1 (DLGAP1).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Disks large-associated protein 1 (DLGAP1).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Disks large-associated protein 1 (DLGAP1).	[18]

4 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Disks large-associated protein 1 (DLGAP1).	[15]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of Disks large-associated protein 1 (DLGAP1).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Disks large-associated protein 1 (DLGAP1).	[19]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Disks large-associated protein 1 (DLGAP1).	[20]

References

• [1] The role of microRNA-148a and downstream DLGAP1 on the molecular regulation and tumor progression on human glioblastoma.Oncogene. 2019 Nov;38(47):7234-7248. doi: 10.1038/s41388-019-0922-3. Epub 2019 Sep 2.
• [2] Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Nat Genet. 2017 Apr;49(4):515-526. doi: 10.1038/ng.3792. Epub 2017 Feb 13.
• [3] DLGAP1 and NMDA receptor-associated postsynaptic density protein genes influence executive function in attention deficit hyperactivity disorder.Brain Behav. 2018 Jan 23;8(2):e00914. doi: 10.1002/brb3.914. eCollection 2018 Feb.
• [4] Cognitive impairment and autistic-like behaviour in SAPAP4-deficient mice.Transl Psychiatry. 2019 Jan 16;9(1):7. doi: 10.1038/s41398-018-0327-z.
• [5] HOTAIRM1 competed endogenously with miR-148a to regulate DLGAP1 in head and neck tumor cells.Cancer Med. 2018 Jul;7(7):3143-3156. doi: 10.1002/cam4.1523. Epub 2018 Jun 14.
• [6] Genome-Wide Association Study of HIV-Related Lipoatrophy in Thai Patients: Association of a DLGAP1 Polymorphism with Fat Loss.AIDS Res Hum Retroviruses. 2015 Aug;31(8):792-6. doi: 10.1089/AID.2014.0266. Epub 2015 Jun 15.
• [7] Genome-wide association database developed in the Japanese Integrated Database Project.J Hum Genet. 2009 Sep;54(9):543-6. doi: 10.1038/jhg.2009.68. Epub 2009 Jul 24.
• [8] GKAP Acts as a Genetic Modulator of NMDAR Signaling to Govern Invasive Tumor Growth.Cancer Cell. 2018 Apr 9;33(4):736-751.e5. doi: 10.1016/j.ccell.2018.02.011. Epub 2018 Mar 29.
• [9] Dlgap1 knockout mice exhibit alterations of the postsynaptic density and selective reductions in sociability.Sci Rep. 2018 Feb 2;8(1):2281. doi: 10.1038/s41598-018-20610-y.
• [10] Rare variants and loci for age-related macular degeneration in the Ohio and Indiana Amish.Hum Genet. 2019 Oct;138(10):1171-1182. doi: 10.1007/s00439-019-02050-4. Epub 2019 Jul 31.
• [11] Effect of the knockdown of death-associated protein 1 expression on cell adhesion, growth and migration in breast cancer cells.Oncol Rep. 2015 Mar;33(3):1450-8. doi: 10.3892/or.2014.3686. Epub 2014 Dec 22.
• [12] Antisense palmitoyl protein thioesterase 1 (PPT1) treatment inhibits PPT1 activity and increases cell death in LA-N-5 neuroblastoma cells.J Neurosci Res. 2000 Oct 15;62(2):234-40. doi: 10.1002/1097-4547(20001015)62:2<234::AID-JNR8>3.0.CO;2-8.
• [13] DAP1 high expression increases risk of lymph node metastases in squamous cell carcinoma of the oral cavity.Genet Mol Res. 2015 Sep 8;14(3):10515-23. doi: 10.4238/2015.September.8.13.
• [14] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [15] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [16] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [17] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [18] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [19] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [20] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.