Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIIB2JB)

• DOT Name: A-kinase anchor protein 1, mitochondrial (AKAP1)
• Synonyms: A-kinase anchor protein 149 kDa; AKAP 149; Dual specificity A-kinase-anchoring protein 1; D-AKAP-1; Protein kinase A-anchoring protein 1; PRKA1; Spermatid A-kinase anchor protein 84; S-AKAP84
• Gene Name: AKAP1
• Related Disease:
  Advanced cancer
  Nervous system disease
  Autism
  Autosomal dominant optic atrophy, classic form
  Breast cancer
  Breast carcinoma
  Cardiac failure
  Congestive heart failure
  Diabetic kidney disease
  Neoplasm
  Obesity
  Prostate cancer
  Prostate carcinoma
  Adult glioblastoma
  Cardiovascular disease
  Gastric cancer
  Glioblastoma multiforme
  Stomach cancer
  Hepatocellular carcinoma
  Sickle-cell anaemia
  Stroke
  Type-1/2 diabetes
• UniProt ID: AKAP1_HUMAN
• Pfam ID: PF00013 ; PF00567
• Sequence:
  MAIQFRSLFPLALPGMLALLGWWWFFSRKKGHVSSHDEQQVEAGAVQLRADPAIKEPLPV
  EDVCPKVVSTPPSVTEPPEKELSTVSKLPAEPPALLQTHPPCRRSESSGILPNTTDMRLR
  PGTRRDDSTKLELALTGGEAKSIPLECPLSSPKGVLFSSKSAEVCKQDSPFSRVPRKVQP
  GYPVVPAEKRSSGERARETGGAEGTGDAVLGEKVLEEALLSREHVLELENSKGPSLASLE
  GEEDKGKSSSSQVVGPVQEEEYVAEKLPSRFIESAHTELAKDDAAPAPPVADAKAQDRGV
  EGELGNEESLDRNEEGLDRNEEGLDRNEESLDRNEEGLDRNEEIKRAAFQIISQVISEAT
  EQVLATTVGKVAGRVCQASQLQGQKEESCVPVHQKTVLGPDTAEPATAEAAVAPPDAGLP
  LPGLPAEGSPPPKTYVSCLKSLLSSPTKDSKPNISAHHISLASCLALTTPSEELPDRAGI
  LVEDATCVTCMSDSSQSVPLVASPGHCSDSFSTSGLEDSCTETSSSPRDKAITPPLPEST
  VPFSNGVLKGELSDLGAEDGWTMDAEADHSGGSDRNSMDSVDSCCSLKKTESFQNAQAGS
  NPKKVDLIIWEIEVPKHLVGRLIGKQGRYVSFLKQTSGAKIYISTLPYTQSVQICHIEGS
  QHHVDKALNLIGKKFKELNLTNIYAPPLPSLALPSLPMTSWLMLPDGITVEVIVVNQVNA
  GHLFVQQHTHPTFHALRSLDQQMYLCYSQPGIPTLPTPVEITVICAAPGADGAWWRAQVV
  ASYEETNEVEIRYVDYGGYKRVKVDVLRQIRSDFVTLPFQGAEVLLDSVMPLSDDDQFSP
  EADAAMSEMTGNTALLAQVTSYSPTGLPLIQLWSVVGDEVVLINRSLVERGLAQWVDSYY
  TSL
• Function: Binds to type I and II regulatory subunits of protein kinase A and anchors them to the cytoplasmic face of the mitochondrial outer membrane. Involved in mitochondrial-mediated antiviral innate immunity. Promotes translocation of NDUFS1 into mitochondria to regulate mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) activity.
• Tissue Specificity: Isoform 1 is detected in thymus, prostate, testis, ovary, colon and small intestine . Isoform 2 is highly expressed in testis and detected at much lower levels in kidney, pancreas, liver, lung and brain .
• Reactome Pathway:
  Factors involved in megakaryocyte development and platelet production (R-HSA-983231)
  Mitochondrial calcium ion transport (R-HSA-8949215)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Genetic Variation	[1]
Nervous system disease	DISJ7GGT	Definitive	Biomarker	[2]
Autism	DISV4V1Z	Strong	Genetic Variation	[3]
Autosomal dominant optic atrophy, classic form	DISXUAV9	Strong	Genetic Variation	[4]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[1]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[1]
Cardiac failure	DISDC067	Strong	Biomarker	[5]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[5]
Diabetic kidney disease	DISJMWEY	Strong	Biomarker	[6]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[1]
Obesity	DIS47Y1K	Strong	Biomarker	[7]
Prostate cancer	DISF190Y	Strong	Biomarker	[8]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[8]
Adult glioblastoma	DISVP4LU	moderate	Altered Expression	[9]
Cardiovascular disease	DIS2IQDX	moderate	Biomarker	[10]
Gastric cancer	DISXGOUK	moderate	Altered Expression	[11]
Glioblastoma multiforme	DISK8246	moderate	Altered Expression	[9]
Stomach cancer	DISKIJSX	moderate	Altered Expression	[11]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[12]
Sickle-cell anaemia	DIS5YNZB	Limited	Biomarker	[13]
Stroke	DISX6UHX	Limited	Biomarker	[14]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[15]

13 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 1, mitochondrial (AKAP1).	[16]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of A-kinase anchor protein 1, mitochondrial (AKAP1).	[17]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of A-kinase anchor protein 1, mitochondrial (AKAP1).	[18]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of A-kinase anchor protein 1, mitochondrial (AKAP1).	[19]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of A-kinase anchor protein 1, mitochondrial (AKAP1).	[20]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of A-kinase anchor protein 1, mitochondrial (AKAP1).	[21]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of A-kinase anchor protein 1, mitochondrial (AKAP1).	[22]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the expression of A-kinase anchor protein 1, mitochondrial (AKAP1).	[22]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of A-kinase anchor protein 1, mitochondrial (AKAP1).	[23]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of A-kinase anchor protein 1, mitochondrial (AKAP1).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of A-kinase anchor protein 1, mitochondrial (AKAP1).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of A-kinase anchor protein 1, mitochondrial (AKAP1).	[27]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of A-kinase anchor protein 1, mitochondrial (AKAP1).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of A-kinase anchor protein 1, mitochondrial (AKAP1).	[26]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of A-kinase anchor protein 1, mitochondrial (AKAP1).	[26]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid decreases the phosphorylation of A-kinase anchor protein 1, mitochondrial (AKAP1).	[28]

References

• [1] Exome sequencing of primary breast cancers with paired metastatic lesions reveals metastasis-enriched mutations in the A-kinase anchoring protein family (AKAPs).BMC Cancer. 2018 Feb 12;18(1):174. doi: 10.1186/s12885-018-4021-6.
• [2] Potential for therapeutic targeting of AKAP signaling complexes in nervous system disorders.Pharmacol Ther. 2018 May;185:99-121. doi: 10.1016/j.pharmthera.2017.12.004. Epub 2017 Dec 17.
• [3] 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.
• [4] Mitochondrial Reactive Oxygen Species in Lipotoxic Hearts Induce Post-Translational Modifications of AKAP121, DRP1, and OPA1 That Promote Mitochondrial Fission.Circ Res. 2018 Jan 5;122(1):58-73. doi: 10.1161/CIRCRESAHA.117.311307. Epub 2017 Nov 1.
• [5] Loss of Akap1 Exacerbates Pressure Overload-Induced Cardiac Hypertrophy and Heart Failure.Front Physiol. 2018 May 28;9:558. doi: 10.3389/fphys.2018.00558. eCollection 2018.
• [6] Increased mitochondrial fission of glomerular podocytes in diabetic nephropathy.Endocr Connect. 2019 Aug;8(8):1206-1212. doi: 10.1530/EC-19-0234.
• [7] A dysregulation in CES1, APOE and other lipid metabolism-related genes is associated to cardiovascular risk factors linked to obesity.Obes Facts. 2010 Oct;3(5):312-8. doi: 10.1159/000321451. Epub 2010 Oct 15.
• [8] Tissue transglutaminase interacts with protein kinase A anchor protein 13 in prostate cancer.Urol Oncol. 2005 Nov-Dec;23(6):407-12. doi: 10.1016/j.urolonc.2005.04.002.
• [9] Mitochondrial AKAP1 supports mTOR pathway and tumor growth.Cell Death Dis. 2017 Jun 1;8(6):e2842. doi: 10.1038/cddis.2017.241.
• [10] A-kinase anchoring protein 1 (AKAP1) and its role in some cardiovascular diseases.J Mol Cell Cardiol. 2020 Jan;138:99-109. doi: 10.1016/j.yjmcc.2019.11.154. Epub 2019 Nov 26.
• [11] MicroRNA-148a-3p enhances cisplatin cytotoxicity in gastric cancer through mitochondrial fission induction and cyto-protective autophagy suppression.Cancer Lett. 2017 Dec 1;410:212-227. doi: 10.1016/j.canlet.2017.09.035. Epub 2017 Sep 28.
• [12] Higher expression of A-kinase anchoring-protein 1 predicts poor prognosis in human hepatocellular carcinoma.Oncol Lett. 2018 Jul;16(1):131-136. doi: 10.3892/ol.2018.8685. Epub 2018 May 10.
• [13] Regulation of Active ICAM-4 on Normal and Sickle Cell Disease RBCs via AKAPs Is Revealed by AFM.Biophys J. 2017 Jan 10;112(1):143-152. doi: 10.1016/j.bpj.2016.11.3204.
• [14] AKAP1 Protects from Cerebral Ischemic Stroke by Inhibiting Drp1-Dependent Mitochondrial Fission.J Neurosci. 2018 Sep 19;38(38):8233-8242. doi: 10.1523/JNEUROSCI.0649-18.2018. Epub 2018 Aug 9.
• [15] Ser1928 phosphorylation by PKA stimulates the L-type Ca2+ channel CaV1.2 and vasoconstriction during acute hyperglycemia and diabetes.Sci Signal. 2017 Jan 24;10(463):eaaf9647. doi: 10.1126/scisignal.aaf9647.
• [16] 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.
• [17] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [18] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [19] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [20] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [21] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [22] Arsenite and cadmium promote the development of mammary tumors. Carcinogenesis. 2020 Jul 14;41(7):1005-1014. doi: 10.1093/carcin/bgz176.
• [23] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [24] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [25] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [26] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [27] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.
• [28] Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.