Details of Drug Off-Target (DOT)

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

• DOT Name: CAAX prenyl protease 1 homolog
• Synonyms: EC 3.4.24.84; Farnesylated proteins-converting enzyme 1; FACE-1; Prenyl protein-specific endoprotease 1; Zinc metalloproteinase Ste24 homolog
• Gene Name: ZMPSTE24
• Related Disease:
  Mandibuloacral dysplasia with type B lipodystrophy
  Obsolete lethal restrictive dermopathy
  Restrictive dermopathy 1
  Hutchinson-Gilford progeria syndrome
• UniProt ID: FACE1_HUMAN
• PDB ID: 2YPT; 4AW6; 5SYT; 6BH8
• EC Number: 3.4.24.84
• Pfam ID: PF01435 ; PF16491
• Sequence:
  MGMWASLDALWEMPAEKRIFGAVLLFSWTVYLWETFLAQRQRRIYKTTTHVPPELGQIMD
  SETFEKSRLYQLDKSTFSFWSGLYSETEGTLILLFGGIPYLWRLSGRFCGYAGFGPEYEI
  TQSLVFLLLATLFSALTGLPWSLYNTFVIEEKHGFNQQTLGFFMKDAIKKFVVTQCILLP
  VSSLLLYIIKIGGDYFFIYAWLFTLVVSLVLVTIYADYIAPLFDKFTPLPEGKLKEEIEV
  MAKSIDFPLTKVYVVEGSKRSSHSNAYFYGFFKNKRIVLFDTLLEEYSVLNKDIQEDSGM
  EPRNEEEGNSEEIKAKVKNKKQGCKNEEVLAVLGHELGHWKLGHTVKNIIISQMNSFLCF
  FLFAVLIGRKELFAAFGFYDSQPTLIGLLIIFQFIFSPYNEVLSFCLTVLSRRFEFQADA
  FAKKLGKAKDLYSALIKLNKDNLGFPVSDWLFSMWHYSHPPLLERLQALKTMKQH
• Function: Transmembrane metalloprotease whose catalytic activity is critical for processing lamin A/LMNA on the inner nuclear membrane and clearing clogged translocons on the endoplasmic reticulum. Proteolytically removes the C-terminal three residues of farnesylated proteins. Plays also an antiviral role independently of its protease activity by restricting enveloped RNA and DNA viruses, including influenza A, Zika, Ebola, Sindbis, vesicular stomatitis, cowpox, and vaccinia. Mechanistically, controls IFITM antiviral pathway to hinder viruses from breaching the endosomal barrier by modulating membrane fluidity.
• Tissue Specificity: Widely expressed. High levels in kidney, prostate, testis and ovary.
• KEGG Pathway: Terpenoid backbone biosynthesis (hsa00900)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mandibuloacral dysplasia with type B lipodystrophy	DISRUZBR	Definitive	Autosomal recessive	[1]
Obsolete lethal restrictive dermopathy	DISI414T	Definitive	Autosomal recessive	[1]
Restrictive dermopathy 1	DISBCVN8	Strong	Autosomal recessive	[2]
Hutchinson-Gilford progeria syndrome	DISY55BU	Supportive	Autosomal dominant	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of CAAX prenyl protease 1 homolog.	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of CAAX prenyl protease 1 homolog.	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of CAAX prenyl protease 1 homolog.	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of CAAX prenyl protease 1 homolog.	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of CAAX prenyl protease 1 homolog.	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of CAAX prenyl protease 1 homolog.	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of CAAX prenyl protease 1 homolog.	[10]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of CAAX prenyl protease 1 homolog.	[11]
Ritonavir	DMU764S	Approved	Ritonavir decreases the activity of CAAX prenyl protease 1 homolog.	[12]
Lopinavir	DMITQS0	Approved	Lopinavir decreases the activity of CAAX prenyl protease 1 homolog.	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of CAAX prenyl protease 1 homolog.	[13]

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] Defective prelamin A processing and muscular and adipocyte alterations in Zmpste24 metalloproteinase-deficient mice. Nat Genet. 2002 May;31(1):94-9. doi: 10.1038/ng871. Epub 2002 Apr 1.
• [3] A homozygous ZMPSTE24 null mutation in combination with a heterozygous mutation in the LMNA gene causes Hutchinson-Gilford progeria syndrome (HGPS): insights into the pathophysiology of HGPS. Hum Mutat. 2006 Jun;27(6):524-31. doi: 10.1002/humu.20315.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [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] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [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] 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.
• [11] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [12] A potent HIV protease inhibitor, darunavir, does not inhibit ZMPSTE24 or lead to an accumulation of farnesyl-prelamin A in cells. J Biol Chem. 2008 Apr 11;283(15):9797-804. doi: 10.1074/jbc.M709629200. Epub 2008 Jan 28.
• [13] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.