Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTY0YGT9)

• DOT Name: Activating molecule in BECN1-regulated autophagy protein 1 (AMBRA1)
• Synonyms: DDB1- and CUL4-associated factor 3
• Gene Name: AMBRA1
• Related Disease:
  Neuroblastoma
  Parkinson disease
  Advanced cancer
  Autism
  B-cell neoplasm
  Breast cancer
  Breast carcinoma
  Chronic kidney disease
  Inflammatory bowel disease
  Melanoma
  Multiple sclerosis
  Neoplasm
  Prostate cancer
  Prostate carcinoma
  Venous thromboembolism
  Schizophrenia
  Neuralgia
  Neurodevelopmental disorder
  Prediabetes syndrome
• UniProt ID: AMRA1_HUMAN
• Pfam ID: PF00400
• Sequence:
  MKVVPEKNAVRILWGRERGARAMGAQRLLQELVEDKTRWMKWEGKRVELPDSPRSTFLLA
  FSPDRTLLASTHVNHNIYITEVKTGKCVHSLIGHRRTPWCVTFHPTISGLIASGCLDGEV
  RIWDLHGGSESWFTDSNNAIASLAFHPTAQLLLIATANEIHFWDWSRREPFAVVKTASEM
  ERVRLVRFDPLGHYLLTAIVNPSNQQGDDEPEIPIDGTELSHYRQRALLQSQPVRRTPLL
  HNFLHMLSSRSSGIQVGEQSTVQDSATPSPPPPPPQPSTERPRTSAYIRLRQRVSYPTAE
  CCQHLGILCLCSRCSGTRVPSLLPHQDSVPPASARATTPSFSFVQTEPFHPPEQASSTQQ
  DQGLLNRPSAFSTVQSSTAGNTLRNLSLGPTRRSLGGPLSSHPSRYHREIAPGLTGSEWT
  RTVLSLNSRSEAESMPPPRTSASSVSLLSVLRQQEGGSQASVYTSATEGRGFPASGLATE
  SDGGNGSSQNNSGSIRHELQCDLRRFFLEYDRLQELDQSLSGEAPQTQQAQEMLNNNIES
  ERPGPSHQPTPHSSENNSNLSRGHLNRCRACHNLLTFNNDTLRWERTTPNYSSGEASSSW
  QVPSSFESVPSSGSQLPPLERTEGQTPSSSRLELSSSASPQEERTVGVAFNQETGHWERI
  YTQSSRSGTVSQEALHQDMPEESSEEDSLRRRLLESSLISLSRYDGAGSREHPIYPDPAR
  LSPAAYYAQRMIQYLSRRDSIRQRSMRYQQNRLRSSTSSSSSDNQGPSVEGTDLEFEDFE
  DNGDRSRHRAPRNARMSAPSLGRFVPRRFLLPEYLPYAGIFHERGQPGLATHSSVNRVLA
  GAVIGDGQSAVASNIANTTYRLQWWDFTKFDLPEISNASVNVLVQNCKIYNDASCDISAD
  GQLLAAFIPSSQRGFPDEGILAVYSLAPHNLGEMLYTKRFGPNAISVSLSPMGRYVMVGL
  ASRRILLHPSTEHMVAQVFRLQQAHGGETSMRRVFNVLYPMPADQRRHVSINSARWLPEP
  GLGLAYGTNKGDLVICRPEALNSGVEYYWDQLNETVFTVHSNSRSSERPGTSRATWRTDR
  DMGLMNAIGLQPRNPATSVTSQGTQTLALQLQNAETQTEREVPEPGTAASGPGEGEGSEY
  GASGEDALSRIQRLMAEGGMTAVVQREQSTTMASMGGFGNNIIVSHRIHRSSQTGTEPGA
  AHTSSPQPSTSRGLLPEAGQLAERGLSPRTASWDQPGTPGREPTQPTLPSSSPVPIPVSL
  PSAEGPTLHCELTNNNHLLDGGSSRGDAAGPRGEPRNR
• Function: Substrate-recognition component of a DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complex involved in cell cycle control and autophagy. The DCX(AMBRA1) complex specifically mediates the polyubiquitination of target proteins such as BECN1, CCND1, CCND2, CCND3, ELOC and ULK1. Acts as an upstream master regulator of the transition from G1 to S cell phase: AMBRA1 specifically recognizes and binds phosphorylated cyclin-D (CCND1, CCND2 and CCND3), leading to cyclin-D ubiquitination by the DCX(AMBRA1) complex and subsequent degradation. By controlling the transition from G1 to S phase and cyclin-D degradation, AMBRA1 acts as a tumor suppressor that promotes genomic integrity during DNA replication and counteracts developmental abnormalities and tumor growth. AMBRA1 also regulates the cell cycle by promoting MYC dephosphorylation and degradation independently of the DCX(AMBRA1) complex: acts via interaction with the catalytic subunit of protein phosphatase 2A (PPP2CA), which enhances interaction between PPP2CA and MYC, leading to MYC dephosphorylation and degradation. Acts as a regulator of Cul5-RING (CRL5) E3 ubiquitin-protein ligase complexes by mediating ubiquitination and degradation of Elongin-C (ELOC) component of CRL5 complexes. Acts as a key regulator of autophagy by modulating the BECN1-PIK3C3 complex: controls protein turnover during neuronal development, and regulates normal cell survival and proliferation. In normal conditions, AMBRA1 is tethered to the cytoskeleton via interaction with dyneins DYNLL1 and DYNLL2. Upon autophagy induction, AMBRA1 is released from the cytoskeletal docking site to induce autophagosome nucleation by mediating ubiquitination of proteins involved in autophagy. The DCX(AMBRA1) complex mediates 'Lys-63'-linked ubiquitination of BECN1, increasing the association between BECN1 and PIK3C3 to promote PIK3C3 activity. In collaboration with TRAF6, AMBRA1 mediates 'Lys-63'-linked ubiquitination of ULK1 following autophagy induction, promoting ULK1 stability and kinase activity. Also activates ULK1 via interaction with TRIM32: TRIM32 stimulates ULK1 through unanchored 'Lys-63'-linked polyubiquitin chains. Also acts as an activator of mitophagy via interaction with PRKN and LC3 proteins (MAP1LC3A, MAP1LC3B or MAP1LC3C); possibly by bringing damaged mitochondria onto autophagosomes. Also activates mitophagy by acting as a cofactor for HUWE1; acts by promoting HUWE1-mediated ubiquitination of MFN2. AMBRA1 is also involved in regulatory T-cells (Treg) differentiation by promoting FOXO3 dephosphorylation independently of the DCX(AMBRA1) complex: acts via interaction with PPP2CA, which enhances interaction between PPP2CA and FOXO3, leading to FOXO3 dephosphorylation and stabilization. May act as a regulator of intracellular trafficking, regulating the localization of active PTK2/FAK and SRC. Also involved in transcription regulation by acting as a scaffold for protein complexes at chromatin.
• KEGG Pathway:
  Mitophagy - animal (hsa04137)
  Autophagy - animal (hsa04140)
  Alzheimer disease (hsa05010)
  Amyotrophic lateral sclerosis (hsa05014)
  Huntington disease (hsa05016)
  Spinocerebellar ataxia (hsa05017)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
• Reactome Pathway: Macroautophagy (R-HSA-1632852)

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neuroblastoma	DISVZBI4	Definitive	Biomarker	[1]
Parkinson disease	DISQVHKL	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Autism	DISV4V1Z	Strong	Biomarker	[3]
B-cell neoplasm	DISVY326	Strong	Biomarker	[4]
Breast cancer	DIS7DPX1	Strong	Biomarker	[5]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[5]
Chronic kidney disease	DISW82R7	Strong	Altered Expression	[6]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[7]
Melanoma	DIS1RRCY	Strong	Altered Expression	[8]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[9]
Neoplasm	DISZKGEW	Strong	Biomarker	[10]
Prostate cancer	DISF190Y	Strong	Biomarker	[11]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[11]
Venous thromboembolism	DISUR7CR	Strong	Genetic Variation	[12]
Schizophrenia	DISSRV2N	moderate	Biomarker	[3]
Neuralgia	DISWO58J	Limited	Biomarker	[13]
Neurodevelopmental disorder	DIS372XH	Limited	Altered Expression	[14]
Prediabetes syndrome	DISH2I53	Limited	Biomarker	[13]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Activating molecule in BECN1-regulated autophagy protein 1 (AMBRA1) decreases the response to substance of Cisplatin.	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Activating molecule in BECN1-regulated autophagy protein 1 (AMBRA1).	[15]
Promethazine	DM6I5GR	Approved	Promethazine decreases the expression of Activating molecule in BECN1-regulated autophagy protein 1 (AMBRA1).	[17]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Activating molecule in BECN1-regulated autophagy protein 1 (AMBRA1).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Activating molecule in BECN1-regulated autophagy protein 1 (AMBRA1).	[19]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Activating molecule in BECN1-regulated autophagy protein 1 (AMBRA1).	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Activating molecule in BECN1-regulated autophagy protein 1 (AMBRA1).	[22]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of Activating molecule in BECN1-regulated autophagy protein 1 (AMBRA1).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Activating molecule in BECN1-regulated autophagy protein 1 (AMBRA1).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Activating molecule in BECN1-regulated autophagy protein 1 (AMBRA1).	[21]

References

• [1] AMBRA1-Mediated Mitophagy Counteracts Oxidative Stress and Apoptosis Induced by Neurotoxicity in Human Neuroblastoma SH-SY5Y Cells.Front Cell Neurosci. 2018 Apr 18;12:92. doi: 10.3389/fncel.2018.00092. eCollection 2018.
• [2] Ambra1 spatially regulates Src activity and Src/FAK-mediated cancer cell invasion via trafficking networks.Elife. 2017 Mar 31;6:e23172. doi: 10.7554/eLife.23172.
• [3] Neurodevelopmental Disorders: Functional Role of Ambra1 in Autism and Schizophrenia.Mol Neurobiol. 2019 Oct;56(10):6716-6724. doi: 10.1007/s12035-019-1557-7. Epub 2019 Mar 26.
• [4] Autophagy and apoptosis are regulated by stress on Bcl2 by AMBRA1 in the endoplasmic reticulum and mitochondria.Theor Biol Med Model. 2019 Oct 29;16(1):18. doi: 10.1186/s12976-019-0113-5.
• [5] Ambra1 inhibits paclitaxel-induced apoptosis in breast cancer cells by modulating the Bim/mitochondrial pathway.Neoplasma. 2019 May 23;66(3):377-385. doi: 10.4149/neo_2018_180710N467. Epub 2019 Feb 14.
• [6] Mitsugumin 53 promotes mitochondrial autophagy through regulating Ambra1 expression in C2C12 myoblast cells.Cell Biol Int. 2019 Mar;43(3):290-298. doi: 10.1002/cbin.11097. Epub 2019 Feb 7.
• [7] Autophagy and inflammatory bowel disease: Association between variants of the autophagy-related IRGM gene and susceptibility to Crohn's disease.Dig Liver Dis. 2015 Sep;47(9):744-50. doi: 10.1016/j.dld.2015.05.012. Epub 2015 May 21.
• [8] Epidermal autophagy and beclin 1 regulator 1 and loricrin: a paradigm shift in the prognostication and stratification of the American Joint Committee on Cancer stage I melanomas.Br J Dermatol. 2020 Jan;182(1):156-165. doi: 10.1111/bjd.18086. Epub 2019 Jun 19.
• [9] AMBRA1 Controls Regulatory T-Cell Differentiation and Homeostasis Upstream of the FOXO3-FOXP3 Axis.Dev Cell. 2018 Dec 3;47(5):592-607.e6. doi: 10.1016/j.devcel.2018.11.010.
• [10] AMBRA1 links autophagy to cell proliferation and tumorigenesis by promoting c-Myc dephosphorylation and degradation.Nat Cell Biol. 2015 Jan;17(1):20-30. doi: 10.1038/ncb3072. Epub 2014 Dec 1.
• [11] Ambra1 induces autophagy and desensitizes human prostate cancer cells to cisplatin.Biosci Rep. 2019 Aug 23;39(8):BSR20170770. doi: 10.1042/BSR20170770. Print 2019 Aug 30.
• [12] Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism.Blood. 2019 Nov 7;134(19):1645-1657. doi: 10.1182/blood.2019000435.
• [13] Effects of caloric restriction on neuropathic pain, peripheral nerve degeneration and inflammation in normometabolic and autophagy defective prediabetic Ambra1 mice.PLoS One. 2018 Dec 10;13(12):e0208596. doi: 10.1371/journal.pone.0208596. eCollection 2018.
• [14] Ambra1 Shapes Hippocampal Inhibition/Excitation Balance: Role in Neurodevelopmental Disorders.Mol Neurobiol. 2018 Oct;55(10):7921-7940. doi: 10.1007/s12035-018-0911-5. Epub 2018 Feb 27.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [17] AMPK activation induced by promethazine increases NOXA expression and Beclin-1 phosphorylation and drives autophagy-associated apoptosis in chronic myeloid leukemia. Chem Biol Interact. 2020 Jan 5;315:108888. doi: 10.1016/j.cbi.2019.108888. Epub 2019 Nov 2.
• [18] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [19] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [20] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [21] 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.
• [22] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [23] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
• [24] shRNA-mediated AMBRA1 knockdown reduces the cisplatin-induced autophagy and sensitizes ovarian cancer cells to cisplatin. J Toxicol Sci. 2016 Feb;41(1):45-53. doi: 10.2131/jts.41.45.