Details of Drug Off-Target (DOT)

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

• DOT Name: Serine/threonine-protein phosphatase 4 regulatory subunit 1 (PPP4R1)
• Gene Name: PPP4R1
• Related Disease: Fetal growth restriction
• UniProt ID: PP4R1_HUMAN
• Pfam ID: PF02985 ; PF15017
• Sequence:
  MADLSLLQEDLQEDADGFGVDDYSSESDVIIIPSALDFVSQDEMLTPLGRLDKYAASENI
  FNRQMVARSLLDTLREVCDDERDCIAVLERISRLADDSEPTVRAELMEQVPHIALFCQEN
  RPSIPYAFSKFLLPIVVRYLADQNNQVRKTSQAALLALLEQELIERFDVETKVCPVLIEL
  TAPDSNDDVKTEAVAIMCKMAPMVGKDITERLILPRFCEMCCDCRMFHVRKVCAANFGDI
  CSVVGQQATEEMLLPRFFQLCSDNVWGVRKACAECFMAVSCATCQEIRRTKLSALFINLI
  SDPSRWVRQAAFQSLGPFISTFANPSSSGQYFKEESKSSEEMSVENKNRTRDQEAPEDVQ
  VRPEDTPSDLSVSNSSVILENTMEDHAAEASGKPLGEISVPLDSSLLCTLSSESHQEAAS
  NENDKKPGNYKSMLRPEVGTTSQDSALLDQELYNSFHFWRTPLPEIDLDIELEQNSGGKP
  SPEGPEEESEGPVPSSPNITMATRKELEEMIENLEPHIDDPDVKAQVEVLSAALRASSLD
  AHEETISIEKRSDLQDELDINELPNCKINQEDSVPLISDAVENMDSTLHYIHSDSDLSNN
  SSFSPDEERRTKVQDVVPQALLDQYLSMTDPSRAQTVDTEIAKHCAYSLPGVALTLGRQN
  WHCLRETYETLASDMQWKVRRTLAFSIHELAVILGDQLTAADLVPIFNGFLKDLDEVRIG
  VLKHLHDFLKLLHIDKRREYLYQLQEFLVTDNSRNWRFRAELAEQLILLLELYSPRDVYD
  YLRPIALNLCADKVSSVRWISYKLVSEMVKKLHAATPPTFGVDLINELVENFGRCPKWSG
  RQAFVFVCQTVIEDDCLPMDQFAVHLMPHLLTLANDRVPNVRVLLAKTLRQTLLEKDYFL
  ASASCHQEAVEQTIMALQMDRDSDVKYFASIHPASTKISEDAMSTASSTY
• Function: Regulatory subunit of serine/threonine-protein phosphatase 4. May play a role in regulation of cell division in renal glomeruli. The PPP4C-PPP4R1 PP4 complex may play a role in dephosphorylation and regulation of HDAC3.
• Tissue Specificity: Widely expressed with high expression in cultured mesangial cells. Isoform 1 and isoform 2 are expressed in renal tissues.

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Fetal growth restriction	DIS5WEJ5	moderate	Altered Expression	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Serine/threonine-protein phosphatase 4 regulatory subunit 1 (PPP4R1).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Serine/threonine-protein phosphatase 4 regulatory subunit 1 (PPP4R1).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Serine/threonine-protein phosphatase 4 regulatory subunit 1 (PPP4R1).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Serine/threonine-protein phosphatase 4 regulatory subunit 1 (PPP4R1).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Serine/threonine-protein phosphatase 4 regulatory subunit 1 (PPP4R1).	[6]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Serine/threonine-protein phosphatase 4 regulatory subunit 1 (PPP4R1).	[7]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID increases the expression of Serine/threonine-protein phosphatase 4 regulatory subunit 1 (PPP4R1).	[9]

1 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 decreases the phosphorylation of Serine/threonine-protein phosphatase 4 regulatory subunit 1 (PPP4R1).	[8]

References

• [1] Duplication of 7p11.2-p13, including GRB10, in Silver-Russell syndrome.Am J Hum Genet. 2000 Jan;66(1):36-46. doi: 10.1086/302717.
• [2] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [3] 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.
• [4] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [7] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [8] 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.
• [9] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.