Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT54OJQF)

• DOT Name: ATP-dependent zinc metalloprotease YME1L1
• Synonyms: EC 3.4.24.-; ATP-dependent metalloprotease FtsH1; Meg-4; Presenilin-associated metalloprotease; PAMP; YME1-like protein 1
• Gene Name: YME1L1
• Related Disease:
  Obsolete autosomal recessive optic atrophy
  Optic atrophy 11
• UniProt ID: YMEL1_HUMAN
• EC Number: 3.4.24.-
• Pfam ID: PF00004 ; PF17862 ; PF01434
• Sequence:
  MFSLSSTVQPQVTVPLSHLINAFHTPKNTSVSLSGVSVSQNQHRDVVPEHEAPSSECMFS
  DFLTKLNIVSIGKGKIFEGYRSMFMEPAKRMKKSLDTTDNWHIRPEPFSLSIPPSLNLRD
  LGLSELKIGQIDQLVENLLPGFCKGKNISSHWHTSHVSAQSFFENKYGNLDIFSTLRSSC
  LYRHHSRALQSICSDLQYWPVFIQSRGFKTLKSRTRRLQSTSERLAETQNIAPSFVKGFL
  LRDRGSDVESLDKLMKTKNIPEAHQDAFKTGFAEGFLKAQALTQKTNDSLRRTRLILFVL
  LLFGIYGLLKNPFLSVRFRTTTGLDSAVDPVQMKNVTFEHVKGVEEAKQELQEVVEFLKN
  PQKFTILGGKLPKGILLVGPPGTGKTLLARAVAGEADVPFYYASGSEFDEMFVGVGASRI
  RNLFREAKANAPCVIFIDELDSVGGKRIESPMHPYSRQTINQLLAEMDGFKPNEGVIIIG
  ATNFPEALDNALIRPGRFDMQVTVPRPDVKGRTEILKWYLNKIKFDQSVDPEIIARGTVG
  FSGAELENLVNQAALKAAVDGKEMVTMKELEFSKDKILMGPERRSVEIDNKNKTITAYHE
  SGHAIIAYYTKDAMPINKATIMPRGPTLGHVSLLPENDRWNETRAQLLAQMDVSMGGRVA
  EELIFGTDHITTGASSDFDNATKIAKRMVTKFGMSEKLGVMTYSDTGKLSPETQSAIEQE
  IRILLRDSYERAKHILKTHAKEHKNLAEALLTYETLDAKEIQIVLEGKKLEVR
• Function: ATP-dependent metalloprotease that catalyzes the degradation of folded and unfolded proteins with a suitable degron sequence in the mitochondrial intermembrane region. Plays an important role in regulating mitochondrial morphology and function by cleaving OPA1 at position S2, giving rise to a form of OPA1 that promotes maintenance of normal mitochondrial structure and mitochondrial protein metabolism. Ensures cell proliferation, maintains normal cristae morphology and complex I respiration activity, promotes antiapoptotic activity and protects mitochondria from the accumulation of oxidatively damaged membrane proteins. Required for normal, constitutive degradation of PRELID1. Catalyzes the degradation of OMA1 in response to membrane depolarization. Required to control the accumulation of nonassembled respiratory chain subunits (NDUFB6, OX4 and ND1).
• Tissue Specificity: High expression in cardiac and skeletal muscle mitochondria.
• Reactome Pathway: Processing of SMDT1 (R-HSA-8949664)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Obsolete autosomal recessive optic atrophy	DISP0XVX	Supportive	Autosomal recessive	[1]
Optic atrophy 11	DISU3ETB	Limited	Unknown	[1]

10 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 ATP-dependent zinc metalloprotease YME1L1.	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of ATP-dependent zinc metalloprotease YME1L1.	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of ATP-dependent zinc metalloprotease YME1L1.	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of ATP-dependent zinc metalloprotease YME1L1.	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of ATP-dependent zinc metalloprotease YME1L1.	[6]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of ATP-dependent zinc metalloprotease YME1L1.	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of ATP-dependent zinc metalloprotease YME1L1.	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of ATP-dependent zinc metalloprotease YME1L1.	[9]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of ATP-dependent zinc metalloprotease YME1L1.	[10]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of ATP-dependent zinc metalloprotease YME1L1.	[11]

References

• [1] Homozygous YME1L1 mutation causes mitochondriopathy with optic atrophy and mitochondrial network fragmentation. Elife. 2016 Aug 6;5:e16078. doi: 10.7554/eLife.16078.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [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] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] 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.
• [7] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [8] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [9] 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.
• [10] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [11] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.