Details of Drug Off-Target (DOT)

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

• DOT Name: Endoplasmic reticulum protein SC65 (P3H4)
• Synonyms: Leprecan-like protein 4; Nucleolar autoantigen No55; Prolyl 3-hydroxylase family member 4; Synaptonemal complex protein SC65
• Gene Name: P3H4
• Related Disease:
  Advanced cancer
  Bladder cancer
  Cerebral infarction
  Ehlers-Danlos syndrome, kyphoscoliotic type 1
  High blood pressure
  Interstitial cystitis
  Prostate cancer
  Prostate carcinoma
  Renal carcinoma
  Renal cell carcinoma
  Urinary bladder cancer
  Urinary bladder neoplasm
  Membranous glomerulonephritis
  Neoplasm
• UniProt ID: SC65_HUMAN
• Sequence:
  MARVAWGLLWLLLGSAGAQYEKYSFRGFPPEDLMPLAAAYGHALEQYEGESWRESARYLE
  AALRLHRLLRDSEAFCHANCSGPAPAAKPDPDGGRADEWACELRLFGRVLERAACLRRCK
  RTLPAFQVPYPPRQLLRDFQSRLPYQYLHYALFKANRLEKAVAAAYTFLQRNPKHELTAK
  YLNYYQGMLDVADESLTDLEAQPYEAVFLRAVKLYNSGDFRSSTEDMERALSEYLAVFAR
  CLAGCEGAHEQVDFKDFYPAIADLFAESLQCKVDCEANLTPNVGGYFVDKFVATMYHYLQ
  FAYYKLNDVRQAARSAASYMLFDPKDSVMQQNLVYYRFHRARWGLEEEDFQPREEAMLYH
  NQTAELRELLEFTHMYLQSDDEMELEETEPPLEPEDALSDAEFEGEGDYEEGMYADWWQE
  PDAKGDEAEAEPEPELA
• Function: Part of a complex composed of PLOD1, P3H3 and P3H4 that catalyzes hydroxylation of lysine residues in collagen alpha chains and is required for normal assembly and cross-linking of collagen fibrils. Required for normal bone density and normal skin stability via its role in hydroxylation of lysine residues in collagen alpha chains and in collagen fibril assembly.
• Tissue Specificity: Detected in fibroblasts (at protein level) . Detected in spleen, prostate, testis, ovary, colon, pancreas, kidney, placenta and heart .

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[1]
Cerebral infarction	DISR1WNP	Strong	Biomarker	[2]
Ehlers-Danlos syndrome, kyphoscoliotic type 1	DISVE04H	Strong	Biomarker	[3]
High blood pressure	DISY2OHH	Strong	Biomarker	[2]
Interstitial cystitis	DIS7CAJA	Strong	Biomarker	[4]
Prostate cancer	DISF190Y	Strong	Biomarker	[5]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[5]
Renal carcinoma	DISER9XT	Strong	Biomarker	[2]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[2]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[1]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[1]
Membranous glomerulonephritis	DISFSUKQ	Limited	Biomarker	[6]
Neoplasm	DISZKGEW	Limited	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Endoplasmic reticulum protein SC65 (P3H4).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Endoplasmic reticulum protein SC65 (P3H4).	[15]

8 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 Endoplasmic reticulum protein SC65 (P3H4).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Endoplasmic reticulum protein SC65 (P3H4).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Endoplasmic reticulum protein SC65 (P3H4).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Endoplasmic reticulum protein SC65 (P3H4).	[11]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Endoplasmic reticulum protein SC65 (P3H4).	[12]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Endoplasmic reticulum protein SC65 (P3H4).	[13]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Endoplasmic reticulum protein SC65 (P3H4).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Endoplasmic reticulum protein SC65 (P3H4).	[16]

References

• [1] P3H4 is correlated with clinicopathological features and prognosis in bladder cancer.World J Surg Oncol. 2018 Oct 15;16(1):206. doi: 10.1186/s12957-018-1507-2.
• [2] P3H4 affects renal carcinoma through up-regulating miR-1/133a.Eur Rev Med Pharmacol Sci. 2018 Aug;22(16):5180-5186. doi: 10.26355/eurrev_201808_15714.
• [3] P3h3-null and Sc65-null Mice Phenocopy the Collagen Lysine Under-hydroxylation and Cross-linking Abnormality of Ehlers-Danlos Syndrome Type VIA.J Biol Chem. 2017 Mar 3;292(9):3877-3887. doi: 10.1074/jbc.M116.762245. Epub 2017 Jan 23.
• [4] cDNA cloning and characterization of a novel nucleolar protein.Mol Biol Cell. 1996 Jul;7(7):1015-24. doi: 10.1091/mbc.7.7.1015.
• [5] Identification of nucleolar protein No55 as a tumour-associated autoantigen in patients with prostate cancer.Br J Cancer. 2000 Sep;83(6):743-9. doi: 10.1054/bjoc.2000.1365.
• [6] Identification and characterization of a new autoimmune protein in membranous nephropathy by immunoscreening of a renal cDNA library.PLoS One. 2012;7(11):e48845. doi: 10.1371/journal.pone.0048845. Epub 2012 Nov 8.
• [7] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [8] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] 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.
• [11] 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.
• [12] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [13] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] 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.
• [16] Cultured human peripheral blood mononuclear cells alter their gene expression when challenged with endocrine-disrupting chemicals. Toxicology. 2013 Jan 7;303:17-24.