Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1MYL3L)

• DOT Name: Neurotrypsin (PRSS12)
• Synonyms: EC 3.4.21.-; Leydin; Motopsin; Serine protease 12
• Gene Name: PRSS12
• Related Disease:
  Intellectual disability, autosomal recessive 1
  Autosomal recessive non-syndromic intellectual disability
  Non-syndromic intellectual disability
• UniProt ID: NETR_HUMAN
• EC Number: 3.4.21.-
• Pfam ID: PF00051 ; PF00530 ; PF00089
• Sequence:
  MTLARFVLALMLGALPEVVGFDSVLNDSLHHSHRHSPPAGPHYPYYLPTQQRPPRTRPPP
  PLPRFPRPPRALPAQRPHALQAGHTPRPHPWGCPAGEPWVSVTDFGAPCLRWAEVPPFLE
  RSPPASWAQLRGQRHNFCRSPDGAGRPWCFYGDARGKVDWGYCDCRHGSVRLRGGKNEFE
  GTVEVYASGVWGTVCSSHWDDSDASVICHQLQLGGKGIAKQTPFSGLGLIPIYWSNVRCR
  GDEENILLCEKDIWQGGVCPQKMAAAVTCSFSHGPTFPIIRLAGGSSVHEGRVELYHAGQ
  WGTVCDDQWDDADAEVICRQLGLSGIAKAWHQAYFGEGSGPVMLDEVRCTGNELSIEQCP
  KSSWGEHNCGHKEDAGVSCTPLTDGVIRLAGGKGSHEGRLEVYYRGQWGTVCDDGWTELN
  TYVVCRQLGFKYGKQASANHFEESTGPIWLDDVSCSGKETRFLQCSRRQWGRHDCSHRED
  VSIACYPGGEGHRLSLGFPVRLMDGENKKEGRVEVFINGQWGTICDDGWTDKDAAVICRQ
  LGYKGPARARTMAYFGEGKGPIHVDNVKCTGNERSLADCIKQDIGRHNCRHSEDAGVICD
  YFGKKASGNSNKESLSSVCGLRLLHRRQKRIIGGKNSLRGGWPWQVSLRLKSSHGDGRLL
  CGATLLSSCWVLTAAHCFKRYGNSTRSYAVRVGDYHTLVPEEFEEEIGVQQIVIHREYRP
  DRSDYDIALVRLQGPEEQCARFSSHVLPACLPLWRERPQKTASNCYITGWGDTGRAYSRT
  LQQAAIPLLPKRFCEERYKGRFTGRMLCAGNLHEHKRVDSCQGDSGGPLMCERPGESWVV
  YGVTSWGYGCGVKDSPGVYTKVSAFVPWIKSVTKL
• Function: Plays a role in neuronal plasticity and the proteolytic action may subserve structural reorganizations associated with learning and memory operations.
• Tissue Specificity: Brain and Leydig cells of the testis.

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability, autosomal recessive 1	DISINB3A	Definitive	Autosomal recessive	[1]
Autosomal recessive non-syndromic intellectual disability	DISJWRZZ	Supportive	Autosomal recessive	[1]
Non-syndromic intellectual disability	DISTFIZ6	Limited	Autosomal recessive	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
DTI-015	DMXZRW0	Approved	Neurotrypsin (PRSS12) affects the response to substance of DTI-015.	[19]

16 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 Neurotrypsin (PRSS12).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Neurotrypsin (PRSS12).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Neurotrypsin (PRSS12).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Neurotrypsin (PRSS12).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Neurotrypsin (PRSS12).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Neurotrypsin (PRSS12).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Neurotrypsin (PRSS12).	[10]
Marinol	DM70IK5	Approved	Marinol increases the expression of Neurotrypsin (PRSS12).	[11]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Neurotrypsin (PRSS12).	[12]
Azacitidine	DMTA5OE	Approved	Azacitidine decreases the expression of Neurotrypsin (PRSS12).	[13]
Phenytoin	DMNOKBV	Approved	Phenytoin increases the expression of Neurotrypsin (PRSS12).	[14]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Neurotrypsin (PRSS12).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Neurotrypsin (PRSS12).	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Neurotrypsin (PRSS12).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Neurotrypsin (PRSS12).	[17]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of Neurotrypsin (PRSS12).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Neurotrypsin (PRSS12).	[9]

References

• [1] Truncating neurotrypsin mutation in autosomal recessive nonsyndromic mental retardation. Science. 2002 Nov 29;298(5599):1779-81. doi: 10.1126/science.1076521.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [5] 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.
• [6] RNA sequence analysis of inducible pluripotent stem cell-derived cardiomyocytes reveals altered expression of DNA damage and cell cycle genes in response to doxorubicin. Toxicol Appl Pharmacol. 2018 Oct 1;356:44-53.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [9] Effect of prenatal arsenic exposure on DNA methylation and leukocyte subpopulations in cord blood. Epigenetics. 2014 May;9(5):774-82. doi: 10.4161/epi.28153. Epub 2014 Feb 13.
• [10] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [11] Genomic and proteomic analysis of the effects of cannabinoids on normal human astrocytes. Brain Res. 2008 Jan 29;1191:1-11.
• [12] 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.
• [13] The effect of DNA methylation inhibitor 5-Aza-2'-deoxycytidine on human endometrial stromal cells. Hum Reprod. 2010 Nov;25(11):2859-69.
• [14] Role of phenytoin in wound healing: microarray analysis of early transcriptional responses in human dermal fibroblasts. Biochem Biophys Res Commun. 2004 Feb 13;314(3):661-6. doi: 10.1016/j.bbrc.2003.12.146.
• [15] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [16] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [17] 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.
• [18] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.
• [19] Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 2006 Jan 10;24(2):274-87. doi: 10.1200/JCO.2005.02.9405. Epub 2005 Dec 19.