Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6CVN45)

• DOT Name: Plasma protease C1 inhibitor (SERPING1)
• Synonyms: C1 Inh; C1Inh; C1 esterase inhibitor; C1-inhibiting factor; Serpin G1
• Gene Name: SERPING1
• Related Disease:
  Hereditary angioedema with C1Inh deficiency
  C1 inhibitor deficiency
  Hereditary angioedema type 1
  Hereditary angioedema type 2
• UniProt ID: IC1_HUMAN
• PDB ID: 2OAY; 5DU3; 5DUQ; 7AKV
• Pfam ID: PF00079
• Sequence:
  MASRLTLLTLLLLLLAGDRASSNPNATSSSSQDPESLQDRGEGKVATTVISKMLFVEPIL
  EVSSLPTTNSTTNSATKITANTTDEPTTQPTTEPTTQPTIQPTQPTTQLPTDSPTQPTTG
  SFCPGPVTLCSDLESHSTEAVLGDALVDFSLKLYHAFSAMKKVETNMAFSPFSIASLLTQ
  VLLGAGENTKTNLESILSYPKDFTCVHQALKGFTTKGVTSVSQIFHSPDLAIRDTFVNAS
  RTLYSSSPRVLSNNSDANLELINTWVAKNTNNKISRLLDSLPSDTRLVLLNAIYLSAKWK
  TTFDPKKTRMEPFHFKNSVIKVPMMNSKKYPVAHFIDQTLKAKVGQLQLSHNLSLVILVP
  QNLKHRLEDMEQALSPSVFKAIMEKLEMSKFQPTLLTLPRIKVTTSQDMLSIMEKLEFFD
  FSYDLNLCGLTEDPDLQVSAMQHQTVLELTETGVEAAAASAISVARTLLVFEVQQPFLFV
  LWDQQHKFPVFMGRVYDPRA
• Function: Activation of the C1 complex is under control of the C1-inhibitor. It forms a proteolytically inactive stoichiometric complex with the C1r or C1s proteases. May play a potentially crucial role in regulating important physiological pathways including complement activation, blood coagulation, fibrinolysis and the generation of kinins. Very efficient inhibitor of FXIIa. Inhibits chymotrypsin and kallikrein.
• KEGG Pathway:
  Complement and coagulation cascades (hsa04610)
  Pertussis (hsa05133)
• Reactome Pathway:
  Intrinsic Pathway of Fibrin Clot Formation (R-HSA-140837)
  Defective SERPING1 causes hereditary angioedema (R-HSA-9657689)
  Regulation of Complement cascade (R-HSA-977606)
  Platelet degranulation (R-HSA-114608)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hereditary angioedema with C1Inh deficiency	DISDL0QL	Definitive	Autosomal dominant	[1]
C1 inhibitor deficiency	DISCFU40	Supportive	Autosomal dominant	[2]
Hereditary angioedema type 1	DISZ0BWT	Supportive	Autosomal dominant	[3]
Hereditary angioedema type 2	DIS1YDSQ	Supportive	Autosomal dominant	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Sulforaphane	DMQY3L0	Investigative	Plasma protease C1 inhibitor (SERPING1) affects the binding of Sulforaphane.	[21]

14 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 Plasma protease C1 inhibitor (SERPING1).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Plasma protease C1 inhibitor (SERPING1).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Plasma protease C1 inhibitor (SERPING1).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Plasma protease C1 inhibitor (SERPING1).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Plasma protease C1 inhibitor (SERPING1).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Plasma protease C1 inhibitor (SERPING1).	[9]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Plasma protease C1 inhibitor (SERPING1).	[10]
Marinol	DM70IK5	Approved	Marinol increases the expression of Plasma protease C1 inhibitor (SERPING1).	[11]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Plasma protease C1 inhibitor (SERPING1).	[12]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Plasma protease C1 inhibitor (SERPING1).	[13]
Danazol	DML8KTN	Approved	Danazol increases the expression of Plasma protease C1 inhibitor (SERPING1).	[15]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Plasma protease C1 inhibitor (SERPING1).	[16]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Plasma protease C1 inhibitor (SERPING1).	[17]
Butanoic acid	DMTAJP7	Investigative	Butanoic acid increases the expression of Plasma protease C1 inhibitor (SERPING1).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Olanzapine	DMPFN6Y	Approved	Olanzapine affects the phosphorylation of Plasma protease C1 inhibitor (SERPING1).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Plasma protease C1 inhibitor (SERPING1).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Plasma protease C1 inhibitor (SERPING1).	[19]

References

• [1] 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.
• [2] Unique C1 inhibitor dysfunction in a kindred without angioedema. II. Identification of an Ala443-->Val substitution and functional analysis of the recombinant mutant protein. J Clin Invest. 1995 Mar;95(3):1299-305. doi: 10.1172/JCI117780.
• [3] Mutational spectrum of the c1 inhibitor gene in a cohort of Italian patients with hereditary angioedema: description of nine novel mutations. Ann Hum Genet. 2014 Mar;78(2):73-82. doi: 10.1111/ahg.12052. Epub 2014 Jan 24.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] 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.
• [6] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [7] Gene expression data from acetaminophen-induced toxicity in human hepatic in vitro systems and clinical liver samples. Data Brief. 2016 Mar 26;7:1052-1057. doi: 10.1016/j.dib.2016.03.069. eCollection 2016 Jun.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Fetal-sex dependent genomic responses in the circulating lymphocytes of arsenic-exposed pregnant women in New Hampshire. Reprod Toxicol. 2017 Oct;73:184-195. doi: 10.1016/j.reprotox.2017.07.023. Epub 2017 Aug 6.
• [11] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [12] Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis. Hum Reprod. 2011 Jul;26(7):1813-25.
• [13] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [14] Effects of olanzapine on serum protein phosphorylation patterns in patients with schizophrenia. Proteomics Clin Appl. 2015 Oct;9(9-10):907-16. doi: 10.1002/prca.201400148. Epub 2015 May 15.
• [15] Guillain-Barr syndrome following danazol and corticosteroid therapy for hereditary angioedema. Am J Med. 1985 Jul;79(1):111-4. doi: 10.1016/0002-9343(85)90553-4.
• [16] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [17] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [18] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [19] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [20] MS4A3-HSP27 target pathway reveals potential for haematopoietic disorder treatment in alimentary toxic aleukia. Cell Biol Toxicol. 2023 Feb;39(1):201-216. doi: 10.1007/s10565-021-09639-4. Epub 2021 Sep 28.
• [21] Identification of potential protein targets of isothiocyanates by proteomics. Chem Res Toxicol. 2011 Oct 17;24(10):1735-43. doi: 10.1021/tx2002806. Epub 2011 Aug 26.