Details of Drug Off-Target (DOT)

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

• DOT Name: Sorting and assembly machinery component 50 homolog (SAMM50)
• Synonyms: Transformation-related gene 3 protein; TRG-3
• Gene Name: SAMM50
• Related Disease:
  Cardiovascular disease
  Fatty liver disease
  Hepatocellular carcinoma
  HIV infectious disease
  Myocardial ischemia
  Neoplasm
  Non-alcoholic fatty liver disease
  Non-alcoholic steatohepatitis
  Non-insulin dependent diabetes
  Bacterial meningitis
  Meningitis
• UniProt ID: SAM50_HUMAN
• PDB ID: 6YOO; 6YOP
• Pfam ID: PF01103
• Sequence:
  MGTVHARSLEPLPSSGPDFGGLGEEAEFVEVEPEAKQEILENKDVVVQHVHFDGLGRTKD
  DIIICEIGDVFKAKNLIEVMRKSHEAREKLLRLGIFRQVDVLIDTCQGDDALPNGLDVTF
  EVTELRRLTGSYNTMVGNNEGSMVLGLKLPNLLGRAEKVTFQFSYGTKETSYGLSFFKPR
  PGNFERNFSVNLYKVTGQFPWSSLRETDRGMSAEYSFPIWKTSHTVKWEGVWRELGCLSR
  TASFAVRKESGHSLKSSLSHAMVIDSRNSSILPRRGALLKVNQELAGYTGGDVSFIKEDF
  ELQLNKQLIFDSVFSASFWGGMLVPIGDKPSSIADRFYLGGPTSIRGFSMHSIGPQSEGD
  YLGGEAYWAGGLHLYTPLPFRPGQGGFGELFRTHFFLNAGNLCNLNYGEGPKAHIRKLAE
  CIRWSYGAGIVLRLGNIARLELNYCVPMGVQTGDRICDGVQFGAGIRFL
• Function: Plays a crucial role in the maintenance of the structure of mitochondrial cristae and the proper assembly of the mitochondrial respiratory chain complexes. Required for the assembly of TOMM40 into the TOM complex.
• KEGG Pathway: Mitophagy - animal (hsa04137)
• Reactome Pathway:
  Cristae formation (R-HSA-8949613)
  RAC2 GTPase cycle (R-HSA-9013404)
  Mitochondrial protein import (R-HSA-1268020)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[1]
Fatty liver disease	DIS485QZ	Strong	Genetic Variation	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[2]
HIV infectious disease	DISO97HC	Strong	Genetic Variation	[3]
Myocardial ischemia	DISFTVXF	Strong	Genetic Variation	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Genetic Variation	[2]
Non-alcoholic steatohepatitis	DIST4788	Strong	Genetic Variation	[2]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[5]
Bacterial meningitis	DISRP9SL	Limited	Biomarker	[6]
Meningitis	DISQABAA	Limited	Biomarker	[6]

2 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 Sorting and assembly machinery component 50 homolog (SAMM50).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Sorting and assembly machinery component 50 homolog (SAMM50).	[17]

12 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 Sorting and assembly machinery component 50 homolog (SAMM50).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Sorting and assembly machinery component 50 homolog (SAMM50).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Sorting and assembly machinery component 50 homolog (SAMM50).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Sorting and assembly machinery component 50 homolog (SAMM50).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Sorting and assembly machinery component 50 homolog (SAMM50).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Sorting and assembly machinery component 50 homolog (SAMM50).	[13]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Sorting and assembly machinery component 50 homolog (SAMM50).	[14]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Sorting and assembly machinery component 50 homolog (SAMM50).	[15]
Permethrin	DMZ0Q1G	Approved	Permethrin increases the expression of Sorting and assembly machinery component 50 homolog (SAMM50).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Sorting and assembly machinery component 50 homolog (SAMM50).	[18]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Sorting and assembly machinery component 50 homolog (SAMM50).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Sorting and assembly machinery component 50 homolog (SAMM50).	[20]

References

• [1] Mendelian randomization estimates of alanine aminotransferase with cardiovascular disease: Guangzhou Biobank Cohort study.Hum Mol Genet. 2017 Jan 15;26(2):430-437. doi: 10.1093/hmg/ddw396.
• [2] Risk estimation model for nonalcoholic fatty liver disease in the Japanese using multiple genetic markers.PLoS One. 2018 Jan 31;13(1):e0185490. doi: 10.1371/journal.pone.0185490. eCollection 2018.
• [3] The PNPLA3 Genetic Variant rs738409 Influences the Progression to Cirrhosis in HIV/Hepatitis C Virus Coinfected Patients.PLoS One. 2016 Dec 14;11(12):e0168265. doi: 10.1371/journal.pone.0168265. eCollection 2016.
• [4] Towards an Organ-Sparing Approach for Locally Advanced Esophageal Cancer.Dig Surg. 2019;36(6):462-469. doi: 10.1159/000493435. Epub 2018 Sep 18.
• [5] Genome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes.Nat Commun. 2018 Jul 27;9(1):2941. doi: 10.1038/s41467-018-04951-w.
• [6] Omp85 genosensor for detection of human brain bacterial meningitis.Biotechnol Lett. 2013 Jun;35(6):929-35. doi: 10.1007/s10529-013-1161-2. Epub 2013 Mar 8.
• [7] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [13] 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.
• [14] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [15] 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.
• [16] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [17] 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.
• [18] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [19] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [20] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.