Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAM8SGF)

• DOT Name: Peripheral-type benzodiazepine receptor-associated protein 1 (TSPOAP1)
• Synonyms: PRAX-1; Peripheral benzodiazepine receptor-interacting protein; PBR-IP; RIMS-binding protein 1; RIM-BP1; TSPO-associated protein 1
• Gene Name: TSPOAP1
• Related Disease:
  Brain disease
  Alzheimer disease
  TH-deficient dopa-responsive dystonia
  Cardiomyopathy
• UniProt ID: RIMB1_HUMAN
• Pfam ID: PF07653 ; PF14604
• Sequence:
  MEQLTTLPRPGDPGAMEPWALPTWHSWTPGRGGEPSSAAPSIADTPPAALQLQELRSEES
  SKPKGDGSSRPVGGTDPEGAEACLPSLGQQASSSGPACQRPEDEEVEAFLKAKLNMSFGD
  RPNLELLRALGELRQRCAILKEENQMLRKSSFPETEEKVRRLKRKNAELAVIAKRLEERA
  RKLQETNLRVVSAPLPRPGTSLELCRKALARQRARDLSETASALLAKDKQIAALQRECRE
  LQARLTLVGKEGPQWLHVRDFDRLLRESQREVLRLQRQIALRNQRETLPLPPSWPPGPAL
  QARAGAPAPGAPGEATPQEDADNLPVILGEPEKEQRVQQLESELSKKRKKCESLEQEARK
  KQRRCEELELQLRQAQNENARLVEENSRLSGRATEKEQVEWENAELRGQLLGVTQERDSA
  LRKSQGLQSKLESLEQVLKHMREVAQRRQQLEVEHEQARLSLREKQEEVRRLQQAQAEAQ
  REHEGAVQLLESTLDSMQARVRELEEQCRSQTEQFSLLAQELQAFRLHPGPLDLLTSALD
  CGSLGDCPPPPCCCSIPQPCRGSGPKDLDLPPGSPGRCTPKSSEPAPATLTGVPRRTAKK
  AESLSNSSHSESIHNSPKSCPTPEVDTASEVEELEADSVSLLPAAPEGSRGGARIQVFLA
  RYSYNPFEGPNENPEAELPLTAGEYIYIYGNMDEDGFFEGELMDGRRGLVPSNFVERVSD
  DDLLTSLPPELADLSHSSGPELSFLSVGGGGSSSGGQSSVGRSQPRPEEEDAGDELSLSP
  SPEGLGEPPAVPYPRRLVVLKQLAHSVVLAWEPPPEQVELHGFHICVNGELRQALGPGAP
  PKAVLENLDLWAGPLHISVQALTSRGSSDPLRCCLAVGARAGVVPSQLRVHRLTATSAEI
  TWVPGNSNLAHAIYLNGEECPPASPSTYWATFCHLRPGTPYQAQVEAQLPPQGPWEPGWE
  RLEQRAATLQFTTLPAGPPDAPLDVQIEPGPSPGILIISWLPVTIDAAGTSNGVRVTGYA
  IYADGQKIMEVASPTAGSVLVELSQLQLLQVCREVVVRTMSPHGESADSIPAPITPALAP
  ASLPARVSCPSPHPSPEARAPLASASPGPGDPSSPLQHPAPLGTQEPPGAPPASPSREMA
  KGSHEDPPAPCSQEEAGAAVLGTSEERTASTSTLGEKDPGPAAPSLAKQEAEWTAGEACP
  ASSSTQGARAQQAPNTEMCQGGDPGSGLRPRAEKEDTAELGVHLVNSLVDHGRNSDLSDI
  QEEEEEEEEEEEEELGSRTCSFQKQVAGNSIRENGAKSQPDPFCETDSDEEILEQILELP
  LQQFCSKKLFSIPEEEEEEEEDEEEEKSGAGCSSRDPGPPEPALLGLGCDSGQPRRPGQC
  PLSPESSRAGDCLEDMPGLVGGSSRRRGGGSPEKPPSRRRPPDPREHCSRLLSNNGPQAS
  GRLGPTRERGGLPVIEGPRTGLEASGRGRLGPSRRCSRGRALEPGLASCLSPKCLEISIE
  YDSEDEQEAGSGGISITSSCYPGDGEAWGTATVGRPRGPPKANSGPKPYPRLPAWEKGEP
  ERRGRSATGRAKEPLSRATETGEARGQDGSGRRGPQKRGVRVLRPSTAELVPARSPSETL
  AYQHLPVRIFVALFDYDPVSMSPNPDAGEEELPFREGQILKVFGDKDADGFYQGEGGGRT
  GYIPCNMVAEVAVDSPAGRQQLLQRGYLSPDILLEGSGNGPFVYSTAHTTGPPPKPRRSK
  KAESEGPAQPCPGPPKLVPSADLKAPHSMVAAFDYNPQESSPNMDVEAELPFRAGDVITV
  FGGMDDDGFYYGELNGQRGLVPSNFLEGPGPEAGGLDREPRTPQAESQRTRRRRVQC
• Function: Required for synaptic transmission regulation. It probably controls the recruitement of voltage-gated calcium channels to the presynaptic membrane, and modulates neurotransmitter release.
• Tissue Specificity: Predominantly expressed in brain, pituitary gland and thymus in adults. In adult brain, highest expression found in temporal lobe and the putamen, followed by amygdala, caudate nucleus, cerebral cortex, occipital and frontal lobe. A high expression level is also observed in fetal tissues like brain, heart, kidney and thymus.
• Reactome Pathway:
  Norepinephrine Neurotransmitter Release Cycle (R-HSA-181430)
  Pregnenolone biosynthesis (R-HSA-196108)
  Glutamate Neurotransmitter Release Cycle (R-HSA-210500)
  Dopamine Neurotransmitter Release Cycle (R-HSA-212676)
  Acetylcholine Neurotransmitter Release Cycle (R-HSA-264642)
  Serotonin Neurotransmitter Release Cycle (R-HSA-181429)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Brain disease	DIS6ZC3X	Definitive	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[2]
TH-deficient dopa-responsive dystonia	DISLE7HP	Supportive	Autosomal recessive	[3]
Cardiomyopathy	DISUPZRG	Limited	Biomarker	[4]

10 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 Peripheral-type benzodiazepine receptor-associated protein 1 (TSPOAP1).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Peripheral-type benzodiazepine receptor-associated protein 1 (TSPOAP1).	[6]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Peripheral-type benzodiazepine receptor-associated protein 1 (TSPOAP1).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Peripheral-type benzodiazepine receptor-associated protein 1 (TSPOAP1).	[8]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Peripheral-type benzodiazepine receptor-associated protein 1 (TSPOAP1).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Peripheral-type benzodiazepine receptor-associated protein 1 (TSPOAP1).	[10]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 affects the expression of Peripheral-type benzodiazepine receptor-associated protein 1 (TSPOAP1).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Peripheral-type benzodiazepine receptor-associated protein 1 (TSPOAP1).	[12]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Peripheral-type benzodiazepine receptor-associated protein 1 (TSPOAP1).	[13]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Peripheral-type benzodiazepine receptor-associated protein 1 (TSPOAP1).	[14]

References

• [1] A genetic variant near adaptor-related protein complex 2 alpha 2 subunit gene is associated with coronary artery disease in a Chinese population.BMC Cardiovasc Disord. 2018 Aug 7;18(1):161. doi: 10.1186/s12872-018-0905-2.
• [2] A functional variant in the miR-142 promoter modulating its expression and conferring risk of Alzheimer disease.Hum Mutat. 2019 Nov;40(11):2131-2145. doi: 10.1002/humu.23872. Epub 2019 Aug 7.
• [3] Biallelic variants in TSPOAP1, encoding the active-zone protein RIMBP1, cause autosomal recessive dystonia. J Clin Invest. 2021 Apr 1;131(7):e140625. doi: 10.1172/JCI140625.
• [4] Effectiveness of whole exome sequencing in unsolved patients with a clinical suspicion of a mitochondrial disorder in Estonia.Mol Genet Metab Rep. 2018 Mar 15;15:80-89. doi: 10.1016/j.ymgmr.2018.03.004. eCollection 2018 Jun.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] 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.
• [7] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [8] Successful validation of genomic biomarkers for human immunotoxicity in Jurkat T cells in vitro. J Appl Toxicol. 2015 Jul;35(7):831-41.
• [9] 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.
• [10] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [11] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [12] 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.
• [13] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.
• [14] Transcriptome-based functional classifiers for direct immunotoxicity. Arch Toxicol. 2014 Mar;88(3):673-89.