Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTH5JIFE)

• DOT Name: Store-operated calcium entry-associated regulatory factor (SARAF)
• Synonyms: SARAF; SOCE-associated regulatory factor; HBV X-transactivated gene 3 protein; HBV XAg-transactivated protein 3; Protein FOAP-7; Transmembrane protein 66
• Gene Name: SARAF
• Related Disease:
  Pancreatitis
  Prostate cancer
  Prostate carcinoma
• UniProt ID: SARAF_HUMAN
• PDB ID: 6O2U; 6O2V; 6O2W
• Pfam ID: PF06682
• Sequence:
  MAAACGPGAAGYCLLLGLHLFLLTAGPALGWNDPDRMLLRDVKALTLHYDRYTTSRRLDP
  IPQLKCVGGTAGCDSYTPKVIQCQNKGWDGYDVQWECKTDLDIAYKFGKTVVSCEGYESS
  EDQYVLRGSCGLEYNLDYTELGLQKLKESGKQHGFASFSDYYYKWSSADSCNMSGLITIV
  VLLGIAFVVYKLFLSDGQYSPPPYSEYPPFSHRYQRFTNSAGPPPPGFKSEFTGPQNTGH
  GATSGFGSAFTGQQGYENSGPGFWTGLGTGGILGYLFGSNRAATPFSDSWYYPSYPPSYP
  GTWNRAYSPLHGGSGSYSVCSNSDTKTRTASGYGGTRRR
• Function: Negative regulator of store-operated Ca(2+) entry (SOCE) involved in protecting cells from Ca(2+) overfilling. In response to cytosolic Ca(2+) elevation after endoplasmic reticulum Ca(2+) refilling, promotes a slow inactivation of STIM (STIM1 or STIM2)-dependent SOCE activity: possibly act by facilitating the deoligomerization of STIM to efficiently turn off ORAI when the endoplasmic reticulum lumen is filled with the appropriate Ca(2+) levels, and thus preventing the overload of the cell with excessive Ca(2+) ions.
• Tissue Specificity: Highly expressed in macrophages.

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Pancreatitis	DIS0IJEF	Strong	Biomarker	[1]
Prostate cancer	DISF190Y	Strong	Biomarker	[2]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Store-operated calcium entry-associated regulatory factor (SARAF).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Store-operated calcium entry-associated regulatory factor (SARAF).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Store-operated calcium entry-associated regulatory factor (SARAF).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Store-operated calcium entry-associated regulatory factor (SARAF).	[6]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Store-operated calcium entry-associated regulatory factor (SARAF).	[7]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Store-operated calcium entry-associated regulatory factor (SARAF).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Store-operated calcium entry-associated regulatory factor (SARAF).	[10]
chloropicrin	DMSGBQA	Investigative	chloropicrin affects the expression of Store-operated calcium entry-associated regulatory factor (SARAF).	[11]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Store-operated calcium entry-associated regulatory factor (SARAF).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Store-operated calcium entry-associated regulatory factor (SARAF).	[9]

References

• [1] Ca(2+) Influx Channel Inhibitor SARAF Protects Mice From Acute Pancreatitis.Gastroenterology. 2019 Dec;157(6):1660-1672.e2. doi: 10.1053/j.gastro.2019.08.042. Epub 2019 Sep 4.
• [2] Novel biomarkers for prostate cancer including noncoding transcripts.Am J Pathol. 2009 Dec;175(6):2264-76. doi: 10.2353/ajpath.2009.080868. Epub 2009 Nov 5.
• [3] 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.
• [4] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [8] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [9] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [10] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [11] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [12] 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.