Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTM3ZHGU)

• DOT Name: A-kinase anchor protein 8-like (AKAP8L)
• Synonyms: AKAP8-like protein; Helicase A-binding protein 95; HAP95; Homologous to AKAP95 protein; HA95; Neighbor of A-kinase-anchoring protein 95; Neighbor of AKAP95
• Gene Name: AKAP8L
• Related Disease:
  Autism
  Huntington disease
• UniProt ID: AKP8L_HUMAN
• Pfam ID: PF04988
• Sequence:
  MSYTGFVQGSETTLQSTYSDTSAQPTCDYGYGTWNSGTNRGYEGYGYGYGYGQDNTTNYG
  YGMATSHSWEMPSSDTNANTSASGSASADSVLSRINQRLDMVPHLETDMMQGGVYGSGGE
  RYDSYESCDSRAVLSERDLYRSGYDYSELDPEMEMAYEGQYDAYRDQFRMRGNDTFGPRA
  QGWARDARSGRPMASGYGRMWEDPMGARGQCMSGASRLPSLFSQNIIPEYGMFQGMRGGG
  AFPGGSRFGFGFGNGMKQMRRTWKTWTTADFRTKKKKRKQGGSPDEPDSKATRTDCSDNS
  DSDNDEGTEGEATEGLEGTEAVEKGSRVDGEDEEGKEDGREEGKEDPEKGALTTQDENGQ
  TKRKLQAGKKSQDKQKKRQRDRMVERIQFVCSLCKYRTFYEDEMASHLDSKFHKEHFKYV
  GTKLPKQTADFLQEYVTNKTKKTEELRKTVEDLDGLIQQIYRDQDLTQEIAMEHFVKKVE
  AAHCAACDLFIPMQFGIIQKHLKTMDHNRNRRLMMEQSKKSSLMVARSILNNKLISKKLE
  RYLKGENPFTDSPEEEKEQEEAEGGALDEGAQGEAAGISEGAEGVPAQPPVPPEPAPGAV
  SPPPPPPPEEEEEGAVPLLGGALQRQIRGIPGLDVEDDEEGGGGAP
• Function: Could play a role in constitutive transport element (CTE)-mediated gene expression by association with DHX9. Increases CTE-dependent nuclear unspliced mRNA export. Proposed to target PRKACA to the nucleus but does not seem to be implicated in the binding of regulatory subunit II of PKA. May be involved in nuclear envelope breakdown and chromatin condensation. May be involved in anchoring nuclear membranes to chromatin in interphase and in releasing membranes from chromating at mitosis. May regulate the initiation phase of DNA replication when associated with TMPO isoform Beta. Required for cell cycle G2/M transition and histone deacetylation during mitosis. In mitotic cells recruits HDAC3 to the vicinity of chromatin leading to deacetylation and subsequent phosphorylation at 'Ser-10' of histone H3; in this function seems to act redundantly with AKAP8. May be involved in regulation of pre-mRNA splicing ; (Microbial infection) In case of EBV infection, may target PRKACA to EBNA-LP-containing nuclear sites to modulate transcription from specific promoters; (Microbial infection) Can synergize with DHX9 to activate the CTE-mediated gene expression of type D retroviruses; (Microbial infection) In case of HIV-1 infection, involved in the DHX9-promoted annealing of host tRNA(Lys3) to viral genomic RNA as a primer in reverse transcription; in vitro negatively regulates DHX9 annealing activity.
• Tissue Specificity: Ubiquitously expressed. Expressed in the brain cortex (at protein level).
• Reactome Pathway: Formation of WDR5-containing histone-modifying complexes (R-HSA-9772755)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autism	DISV4V1Z	Strong	Biomarker	[1]
Huntington disease	DISQPLA4	Strong	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of A-kinase anchor protein 8-like (AKAP8L).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of A-kinase anchor protein 8-like (AKAP8L).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of A-kinase anchor protein 8-like (AKAP8L).	[5]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of A-kinase anchor protein 8-like (AKAP8L).	[6]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of A-kinase anchor protein 8-like (AKAP8L).	[7]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of A-kinase anchor protein 8-like (AKAP8L).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of A-kinase anchor protein 8-like (AKAP8L).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of A-kinase anchor protein 8-like (AKAP8L).	[11]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of A-kinase anchor protein 8-like (AKAP8L).	[12]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of A-kinase anchor protein 8-like (AKAP8L).	[13]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of A-kinase anchor protein 8-like (AKAP8L).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of A-kinase anchor protein 8-like (AKAP8L).	[9]

References

• [1] Reciprocal Relationship between Head Size, an Autism Endophenotype, and Gene Dosage at 19p13.12 Points to AKAP8 and AKAP8L.PLoS One. 2015 Jun 15;10(6):e0129270. doi: 10.1371/journal.pone.0129270. eCollection 2015.
• [2] Interaction of the nuclear matrix protein NAKAP with HypA and huntingtin: implications for nuclear toxicity in Huntington's disease pathogenesis.Neuromolecular Med. 2005;7(4):297-310. doi: 10.1385/NMM:7:4:297.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [7] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [8] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [9] 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.
• [10] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [11] 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.
• [12] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [13] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [14] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.