Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDORW5C)

• DOT Name: Sigma non-opioid intracellular receptor 1 (SIGMAR1)
• Synonyms: Aging-associated gene 8 protein; SR31747-binding protein; SR-BP; Sigma 1-type opioid receptor; SIG-1R; Sigma1-receptor; Sigma1R; hSigmaR1
• Gene Name: SIGMAR1
• Related Disease:
  Amyotrophic lateral sclerosis type 16
  Autosomal recessive distal spinal muscular atrophy 2
  Juvenile amyotrophic lateral sclerosis
• UniProt ID: SGMR1_HUMAN
• PDB ID: 5HK1; 5HK2; 6DJZ; 6DK0; 6DK1
• Pfam ID: PF04622
• Sequence:
  MQWAVGRRWAWAALLLAVAAVLTQVVWLWLGTQSFVFQREEIAQLARQYAGLDHELAFSR
  LIVELRRLHPGHVLPDEELQWVFVNAGGWMGAMCLLHASLSEYVLLFGTALGSRGHSGRY
  WAEISDTIISGTFHQWREGTTKSEVFYPGETVVHGPGEATAVEWGPNTWMVEYGRGVIPS
  TLAFALADTVFSTQDFLTLFYTLRSYARGLRLELTTYLFGQDP
• Function: Functions in lipid transport from the endoplasmic reticulum and is involved in a wide array of cellular functions probably through regulation of the biogenesis of lipid microdomains at the plasma membrane. Involved in the regulation of different receptors it plays a role in BDNF signaling and EGF signaling. Also regulates ion channels like the potassium channel and could modulate neurotransmitter release. Plays a role in calcium signaling through modulation together with ANK2 of the ITP3R-dependent calcium efflux at the endoplasmic reticulum. Plays a role in several other cell functions including proliferation, survival and death. Originally identified for its ability to bind various psychoactive drugs it is involved in learning processes, memory and mood alteration. Necessary for proper mitochondrial axonal transport in motor neurons, in particular the retrograde movement of mitochondria. Plays a role in protecting cells against oxidative stress-induced cell death via its interaction with RNF112.
• Tissue Specificity: Widely expressed with higher expression in liver, colon, prostate, placenta, small intestine, heart and pancreas. Expressed in the retina by retinal pigment epithelial cells. Expressed in alpha-motor neurons .
• KEGG Pathway:
  Amyotrophic lateral sclerosis (hsa05014)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
• Reactome Pathway: Potential therapeutics for SARS (R-HSA-9679191)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Amyotrophic lateral sclerosis type 16	DISZGLRJ	Strong	Autosomal recessive	[1]
Autosomal recessive distal spinal muscular atrophy 2	DIS0ASM5	Supportive	Autosomal recessive	[2]
Juvenile amyotrophic lateral sclerosis	DISKDZC9	Supportive	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Sigma non-opioid intracellular receptor 1 (SIGMAR1).	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Sigma non-opioid intracellular receptor 1 (SIGMAR1).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Sigma non-opioid intracellular receptor 1 (SIGMAR1).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Sigma non-opioid intracellular receptor 1 (SIGMAR1).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Sigma non-opioid intracellular receptor 1 (SIGMAR1).	[7]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Sigma non-opioid intracellular receptor 1 (SIGMAR1).	[8]
Bardoxolone methyl	DMODA2X	Phase 3	Bardoxolone methyl decreases the expression of Sigma non-opioid intracellular receptor 1 (SIGMAR1).	[10]
URSOLIC ACID	DM4SOAW	Phase 2	URSOLIC ACID increases the expression of Sigma non-opioid intracellular receptor 1 (SIGMAR1).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Sigma non-opioid intracellular receptor 1 (SIGMAR1).	[4]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Sigma non-opioid intracellular receptor 1 (SIGMAR1).	[10]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Cocaine	DMSOX7I	Approved	Cocaine affects the binding of Sigma non-opioid intracellular receptor 1 (SIGMAR1).	[9]

References

• [1] A mutation in sigma-1 receptor causes juvenile amyotrophic lateral sclerosis. Ann Neurol. 2011 Dec;70(6):913-9. doi: 10.1002/ana.22534. Epub 2011 Aug 12.
• [2] A SIGMAR1 splice-site mutation causes distal hereditary motor neuropathy. Neurology. 2015 Jun 16;84(24):2430-7. doi: 10.1212/WNL.0000000000001680. Epub 2015 May 15.
• [3] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [4] 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.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] 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.
• [8] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [9] Direct involvement of sigma-1 receptors in the dopamine D1 receptor-mediated effects of cocaine. Proc Natl Acad Sci U S A. 2010 Oct 26;107(43):18676-81. doi: 10.1073/pnas.1008911107. Epub 2010 Oct 18.
• [10] Lonp1 and Sig-1R contribute to the counteraction of ursolic acid against ochratoxin A-induced mitochondrial apoptosis. Food Chem Toxicol. 2023 Feb;172:113592. doi: 10.1016/j.fct.2022.113592. Epub 2022 Dec 29.