Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTE2AGPC)

• DOT Name: A-kinase anchor protein 5 (AKAP5)
• Synonyms: AKAP-5; A-kinase anchor protein 79 kDa; AKAP 79; H21; cAMP-dependent protein kinase regulatory subunit II high affinity-binding protein
• Gene Name: AKAP5
• Related Disease:
  Alzheimer disease
  Chronic obstructive pulmonary disease
• UniProt ID: AKAP5_HUMAN
• PDB ID: 2H9R; 3LL8; 5NIN
• Pfam ID: PF03832
• Sequence:
  METTISEIHVENKDEKRSAEGSPGAERQKEKASMLCFKRRKKAAKALKPKAGSEAADVAR
  KCPQEAGASDQPEPTRGAWASLKRLVTRRKRSESSKQQKPLEGEMQPAINAEDADLSKKK
  AKSRLKIPCIKFPRGPKRSNHSKIIEDSDCSIKVQEEAEILDIQTQTPLNDQATKAKSTQ
  DLSEGISRKDGDEVCESNVSNSTTSGEKVISVELGLDNGHSAIQTGTLILEEIETIKEKQ
  DVQPQQASPLETSETDHQQPVLSDVPPLPAIPDQQIVEEASNSTLESAPNGKDYESTEIV
  AEETKPKDTELSQESDFKENGITEEKSKSEESKRMEPIAIIITDTEISEFDVTKSKNVPK
  QFLISAENEQVGVFANDNGFEDRTSEQYETLLIETASSLVKNAIQLSIEQLVNEMASDDN
  KINNLLQ
• Function: Multivalent scaffold protein that anchors the cAMP-dependent protein kinase/PKA to cytoskeletal and/or organelle-associated proteins, targeting the signal carried by cAMP to specific intracellular effectors. Association with the beta2-adrenergic receptor (beta2-AR) not only regulates beta2-AR signaling pathway, but also the activation by PKA by switching off the beta2-AR signaling cascade. Plays a role in long term synaptic potentiation by regulating protein trafficking from the dendritic recycling endosomes to the plasma membrane and controlling both structural and functional plasticity at excitatory synapses.
• Tissue Specificity: Predominantly in the cerebral cortex and the postsynaptic densities of the forebrain, and to a lesser extent in adrenal medulla, lung and anterior pituitary.
• Reactome Pathway:
  Trafficking of AMPA receptors (R-HSA-399719)
  ROBO receptors bind AKAP5 (R-HSA-9010642)
  Glucagon-like Peptide-1 (GLP1) regulates insulin secretion (R-HSA-381676)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Biomarker	[1]
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of A-kinase anchor protein 5 (AKAP5).	[3]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of A-kinase anchor protein 5 (AKAP5).	[5]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of A-kinase anchor protein 5 (AKAP5).	[6]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of A-kinase anchor protein 5 (AKAP5).	[7]

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 increases the methylation of A-kinase anchor protein 5 (AKAP5).	[4]

References

• [1] Genome-wide network-based pathway analysis of CSF t-tau/A1-42 ratio in the ADNI cohort.BMC Genomics. 2017 May 30;18(1):421. doi: 10.1186/s12864-017-3798-z.
• [2] A-kinase-anchoring proteins coordinate inflammatory responses to cigarette smoke in airway smooth muscle.Am J Physiol Lung Cell Mol Physiol. 2015 Apr 15;308(8):L766-75. doi: 10.1152/ajplung.00301.2014. Epub 2015 Jan 30.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] 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.
• [5] 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.
• [6] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [7] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.