Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTT00T7Q)

• DOT Name: Multifunctional procollagen lysine hydroxylase and glycosyltransferase LH3 (PLOD3)
• Gene Name: PLOD3
• Related Disease:
  Bone fragility with contractures, arterial rupture, and deafness
  Bronchopulmonary dysplasia
  Esophageal cancer
  Glioblastoma multiforme
  Glioma
  Hepatocellular carcinoma
  Hypothyroidism
  Lung cancer
  Lung carcinoma
  Neoplasm
  Advanced cancer
  Cataract
  Connective tissue disorder
  Epidermolysis bullosa
  Epidermolysis bullosa simplex
  Gamma-glutamyl transpeptidase deficiency
  Lymphoma
  Metastatic malignant neoplasm
• UniProt ID: PLOD3_HUMAN
• PDB ID: 6FXK; 6FXM; 6FXR; 6FXT; 6FXX; 6FXY; 6TE3; 6TEC; 6TES; 6TEU; 6TEX; 6TEZ; 6WFV; 8ONE
• EC Number: 1.14.11.4; 2.4.1.50; 2.4.1.66
• Pfam ID: PF03171
• Sequence:
  MTSSGPGPRFLLLLPLLLPPAASASDRPRGRDPVNPEKLLVITVATAETEGYLRFLRSAE
  FFNYTVRTLGLGEEWRGGDVARTVGGGQKVRWLKKEMEKYADREDMIIMFVDSYDVILAG
  SPTELLKKFVQSGSRLLFSAESFCWPEWGLAEQYPEVGTGKRFLNSGGFIGFATTIHQIV
  RQWKYKDDDDDQLFYTRLYLDPGLREKLSLNLDHKSRIFQNLNGALDEVVLKFDRNRVRI
  RNVAYDTLPIVVHGNGPTKLQLNYLGNYVPNGWTPEGGCGFCNQDRRTLPGGQPPPRVFL
  AVFVEQPTPFLPRFLQRLLLLDYPPDRVTLFLHNNEVFHEPHIADSWPQLQDHFSAVKLV
  GPEEALSPGEARDMAMDLCRQDPECEFYFSLDADAVLTNLQTLRILIEENRKVIAPMLSR
  HGKLWSNFWGALSPDEYYARSEDYVELVQRKRVGVWNVPYISQAYVIRGDTLRMELPQRD
  VFSGSDTDPDMAFCKSFRDKGIFLHLSNQHEFGRLLATSRYDTEHLHPDLWQIFDNPVDW
  KEQYIHENYSRALEGEGIVEQPCPDVYWFPLLSEQMCDELVAEMEHYGQWSGGRHEDSRL
  AGGYENVPTVDIHMKQVGYEDQWLQLLRTYVGPMTESLFPGYHTKARAVMNFVVRYRPDE
  QPSLRPHHDSSTFTLNVALNHKGLDYEGGGCRFLRYDCVISSPRKGWALLHPGRLTHYHE
  GLPTTWGTRYIMVSFVDP
• Function: Multifunctional enzyme that catalyzes a series of essential post-translational modifications on Lys residues in procollagen. Plays a redundant role in catalyzing the formation of hydroxylysine residues in -Xaa-Lys-Gly- sequences in collagens. Plays a redundant role in catalyzing the transfer of galactose onto hydroxylysine groups, giving rise to galactosyl 5-hydroxylysine. Has an essential role by catalyzing the subsequent transfer of glucose moieties, giving rise to 1,2-glucosylgalactosyl-5-hydroxylysine residues. Catalyzes hydroxylation and glycosylation of Lys residues in the MBL1 collagen-like domain, giving rise to hydroxylysine and 1,2-glucosylgalactosyl-5-hydroxylysine residues. Essential for normal biosynthesis and secretion of type IV collagens (Probable). Essential for normal formation of basement membranes.
• Tissue Specificity: Ubiquitous . Detected in heart, placenta and pancreas and at lower levels in lung, liver and skeletal muscle .
• KEGG Pathway:
  Lysine degradation (hsa00310)
  Other types of O-glycan biosynthesis (hsa00514)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Collagen biosynthesis and modifying enzymes (R-HSA-1650814)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bone fragility with contractures, arterial rupture, and deafness	DISAY31A	Strong	Autosomal recessive	[1]
Bronchopulmonary dysplasia	DISO0BY5	Strong	Altered Expression	[2]
Esophageal cancer	DISGB2VN	Strong	Genetic Variation	[3]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[4]
Glioma	DIS5RPEH	Strong	Biomarker	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[5]
Hypothyroidism	DISR0H6D	Strong	Biomarker	[6]
Lung cancer	DISCM4YA	Strong	Biomarker	[7]
Lung carcinoma	DISTR26C	Strong	Biomarker	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[7]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[8]
Cataract	DISUD7SL	Limited	Biomarker	[9]
Connective tissue disorder	DISKXBS3	Limited	Genetic Variation	[10]
Epidermolysis bullosa	DISVOTZQ	Limited	Genetic Variation	[10]
Epidermolysis bullosa simplex	DIS2CZ6X	Limited	Genetic Variation	[11]
Gamma-glutamyl transpeptidase deficiency	DIS4VHAI	Limited	Genetic Variation	[11]
Lymphoma	DISN6V4S	Limited	Biomarker	[12]
Metastatic malignant neoplasm	DIS86UK6	Limited	Biomarker	[8]

3 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 Multifunctional procollagen lysine hydroxylase and glycosyltransferase LH3 (PLOD3).	[13]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Multifunctional procollagen lysine hydroxylase and glycosyltransferase LH3 (PLOD3).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Multifunctional procollagen lysine hydroxylase and glycosyltransferase LH3 (PLOD3).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Multifunctional procollagen lysine hydroxylase and glycosyltransferase LH3 (PLOD3).	[14]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Multifunctional procollagen lysine hydroxylase and glycosyltransferase LH3 (PLOD3).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Multifunctional procollagen lysine hydroxylase and glycosyltransferase LH3 (PLOD3).	[16]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Multifunctional procollagen lysine hydroxylase and glycosyltransferase LH3 (PLOD3).	[17]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Multifunctional procollagen lysine hydroxylase and glycosyltransferase LH3 (PLOD3).	[19]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the expression of Multifunctional procollagen lysine hydroxylase and glycosyltransferase LH3 (PLOD3).	[19]
Guaiacol	DMN4E7T	Phase 3	Guaiacol increases the expression of Multifunctional procollagen lysine hydroxylase and glycosyltransferase LH3 (PLOD3).	[19]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Multifunctional procollagen lysine hydroxylase and glycosyltransferase LH3 (PLOD3).	[19]
Puerarin	DMJIMXH	Phase 2	Puerarin increases the expression of Multifunctional procollagen lysine hydroxylase and glycosyltransferase LH3 (PLOD3).	[19]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Multifunctional procollagen lysine hydroxylase and glycosyltransferase LH3 (PLOD3).	[20]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Multifunctional procollagen lysine hydroxylase and glycosyltransferase LH3 (PLOD3).	[21]
MG-132	DMKA2YS	Preclinical	MG-132 decreases the expression of Multifunctional procollagen lysine hydroxylase and glycosyltransferase LH3 (PLOD3).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Multifunctional procollagen lysine hydroxylase and glycosyltransferase LH3 (PLOD3).	[23]
Chlorogenic acid	DM2Y3P4	Investigative	Chlorogenic acid increases the expression of Multifunctional procollagen lysine hydroxylase and glycosyltransferase LH3 (PLOD3).	[19]
1,4-Dithiothreitol	DMIFOXE	Investigative	1,4-Dithiothreitol increases the expression of Multifunctional procollagen lysine hydroxylase and glycosyltransferase LH3 (PLOD3).	[21]

References

• [1] A connective tissue disorder caused by mutations of the lysyl hydroxylase 3 gene. Am J Hum Genet. 2008 Oct;83(4):495-503. doi: 10.1016/j.ajhg.2008.09.004. Epub 2008 Oct 2.
• [2] Deregulation of the lysyl hydroxylase matrix cross-linking system in experimental and clinical bronchopulmonary dysplasia.Am J Physiol Lung Cell Mol Physiol. 2014 Feb;306(3):L246-59. doi: 10.1152/ajplung.00109.2013. Epub 2013 Nov 27.
• [3] Genome-wide association study identifies three new susceptibility loci for esophageal squamous-cell carcinoma in Chinese populations.Nat Genet. 2011 Jun 5;43(7):679-84. doi: 10.1038/ng.849.
• [4] Overexpression of PLOD3 promotes tumor progression and poor prognosis in gliomas.Oncotarget. 2018 Feb 28;9(21):15705-15720. doi: 10.18632/oncotarget.24594. eCollection 2018 Mar 20.
• [5] Systems biology analysis of hepatitis C virus infection reveals the role of copy number increases in regions of chromosome 1q in hepatocellular carcinoma metabolism.Mol Biosyst. 2016 Apr 26;12(5):1496-506. doi: 10.1039/c5mb00827a.
• [6] Differential expression of procollagen lysine 2-oxoglutarate 5-deoxygenase and matrix metalloproteinase isoforms in hypothyroid rat ovary and disintegration of extracellular matrix.Endocrinology. 2005 Jul;146(7):2963-75. doi: 10.1210/en.2004-1440. Epub 2005 Apr 7.
• [7] PLOD3 suppression exerts an anti-tumor effect on human lung cancer cells by modulating the PKC-delta signaling pathway.Cell Death Dis. 2019 Feb 15;10(3):156. doi: 10.1038/s41419-019-1405-8.
• [8] PLOD3 promotes lung metastasis via regulation of STAT3.Cell Death Dis. 2018 Nov 15;9(12):1138. doi: 10.1038/s41419-018-1186-5.
• [9] Lysyl hydroxylase 3 is required for normal lens capsule formation and maintenance of lens epithelium integrity and fate.Dev Biol. 2020 Feb 15;458(2):177-188. doi: 10.1016/j.ydbio.2019.10.020. Epub 2019 Oct 24.
• [10] Mutations in PLOD3, encoding lysyl hydroxylase 3, cause a complex connective tissue disorder including recessive dystrophic epidermolysis bullosa-like blistering phenotype with abnormal anchoring fibrils and type VII collagen deficiency.Matrix Biol. 2019 Aug;81:91-106. doi: 10.1016/j.matbio.2018.11.006. Epub 2018 Nov 18.
• [11] Reduction of lysyl hydroxylase 3 causes deleterious changes in the deposition and organization of extracellular matrix.J Biol Chem. 2009 Oct 9;284(41):28204-28211. doi: 10.1074/jbc.M109.038190. Epub 2009 Aug 20.
• [12] Localization of collagen modifying enzymes on fibroblastic reticular cells and follicular dendritic cells in non-neoplastic and neoplastic lymphoid tissues.Leuk Lymphoma. 2016 Jul;57(7):1687-96. doi: 10.3109/10428194.2015.1107907. Epub 2015 Dec 24.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [17] 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.
• [18] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [19] Examining the genomic influence of skin antioxidants in vitro. Mediators Inflamm. 2010;2010.
• [20] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [21] Proteomic signatures in thapsigargin-treated hepatoma cells. Chem Res Toxicol. 2011 Aug 15;24(8):1215-22. doi: 10.1021/tx200109y. Epub 2011 Jul 1.
• [22] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [23] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.