Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT912R2E)

• DOT Name: Gasdermin-A (GSDMA)
• Synonyms: Gasdermin-1
• Gene Name: GSDMA
• Related Disease:
  Advanced cancer
  Crohn disease
  Gastric cancer
  Inflammatory bowel disease
  Systemic sclerosis
  Autoimmune disease
  Seasonal allergic rhinitis
  Type-1 diabetes
• UniProt ID: GSDMA_HUMAN
• Pfam ID: PF04598 ; PF17708
• Sequence:
  MTMFENVTRALARQLNPRGDLTPLDSLIDFKRFHPFCLVLRKRKSTLFWGARYVRTDYTL
  LDVLEPGSSPSDPTDTGNFGFKNMLDTRVEGDVDVPKTVKVKGTAGLSQNSTLEVQTLSV
  APKALETVQERKLAADHPFLKEMQDQGENLYVVMEVVETVQEVTLERAGKAEACFSLPFF
  APLGLQGSINHKEAVTIPKGCVLAFRVRQLMVKGKDEWDIPHICNDNMQTFPPGEKSGEE
  KVILIQASDVGDVHEGFRTLKEEVQRETQQVEKLSRVGQSSLLSSLSKLLGKKKELQDLE
  LALEGALDKGHEVTLEALPKDVLLSKEAVGAILYFVGALTELSEAQQKLLVKSMEKKILP
  VQLKLVESTMEQNFLLDKEGVFPLQPELLSSLGDEELTLTEALVGLSGLEVQRSGPQYMW
  DPDTLPRLCALYAGLSLLQQLTKAS
• Function: [Gasdermin-A]: This form constitutes the precursor of the pore-forming protein and acts as a sensor of infection: upon infection by S.pyogenes, specifically cleaved by S.pyogenes effector protein SpeB in epithelial cells, releasing the N-terminal moiety (Gasdermin-A, N-terminal) that binds to membranes and forms pores, triggering pyroptosis; [Gasdermin-A, N-terminal]: Pore-forming protein that causes membrane permeabilization and pyroptosis. Released upon cleavage by S.pyogenes effector protein SpeB, and binds to membrane inner leaflet lipids. Homooligomerizes within the membrane and forms pores of 10-15 nanometers (nm) of inner diameter, triggering pyroptosis. Pyroptosis triggers the elimination of the infected skin cell, depriving the pathogen of its protective niche, while inducing an inflammatory response. This ultimately prevents bacterial penetration of the epithelial barrier and a subsequent systemic dissemination of the pathogen. Binds to cardiolipin and other acidic phospholipids, such as phosphatidylserine, which mediate its targeting to the inner leaflet membrane.
• Tissue Specificity: Expressed predominantly in the gastrointestinal tract and, at a lower level, in the skin. Also detected in mammary gland. In the gastrointestinal tract, mainly expressed in differentiated cells, including the differentiated cell layer of esophagus and mucus-secreting pit cells of the gastric epithelium. Down-regulated in gastric cancer cells.

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Crohn disease	DIS2C5Q8	Strong	Altered Expression	[2]
Gastric cancer	DISXGOUK	Strong	Biomarker	[3]
Inflammatory bowel disease	DISGN23E	Strong	Altered Expression	[2]
Systemic sclerosis	DISF44L6	Strong	Genetic Variation	[4]
Autoimmune disease	DISORMTM	moderate	Biomarker	[5]
Seasonal allergic rhinitis	DIS58KQX	Limited	Genetic Variation	[6]
Type-1 diabetes	DIS7HLUB	Limited	Biomarker	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Gasdermin-A (GSDMA).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Gasdermin-A (GSDMA).	[9]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Gasdermin-A (GSDMA).	[10]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Gasdermin-A (GSDMA).	[11]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Gasdermin-A (GSDMA).	[13]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of Gasdermin-A (GSDMA).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Gasdermin-A (GSDMA).	[12]

References

• [1] Integrative analysis of somatic mutations altering microRNA targeting in cancer genomes.PLoS One. 2012;7(10):e47137. doi: 10.1371/journal.pone.0047137. Epub 2012 Oct 16.
• [2] Gene Expression-Genotype Analysis Implicates GSDMA, GSDMB, and LRRC3C as Contributors to Inflammatory Bowel Disease Susceptibility.Biomed Res Int. 2015;2015:834805. doi: 10.1155/2015/834805. Epub 2015 Sep 21.
• [3] Distinctive expression and function of four GSDM family genes (GSDMA-D) in normal and malignant upper gastrointestinal epithelium.Genes Chromosomes Cancer. 2009 Mar;48(3):261-71. doi: 10.1002/gcc.20636.
• [4] Transethnic meta-analysis identifies GSDMA and PRDM1 as susceptibility genes to systemic sclerosis.Ann Rheum Dis. 2017 Jun;76(6):1150-1158. doi: 10.1136/annrheumdis-2016-210645. Epub 2017 Mar 17.
• [5] Gasdermins and their role in immunity and inflammation.J Exp Med. 2019 Nov 4;216(11):2453-2465. doi: 10.1084/jem.20190545. Epub 2019 Sep 23.
• [6] Genome-wide association analysis identifies 11 risk variants associated with the asthma with hay fever phenotype.J Allergy Clin Immunol. 2014 Jun;133(6):1564-71. doi: 10.1016/j.jaci.2013.10.030. Epub 2013 Dec 31.
• [7] Genetic association analyses of atopic illness and proinflammatory cytokine genes with type 1 diabetes.Diabetes Metab Res Rev. 2011 Nov;27(8):838-43. doi: 10.1002/dmrr.1259.
• [8] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [9] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [10] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [11] Characterizing the genetic basis for nicotine induced cancer development: a transcriptome sequencing study. PLoS One. 2013 Jun 18;8(6):e67252.
• [12] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [13] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [14] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.