Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3ZIANF)

• DOT Name: Procollagen-lysine,2-oxoglutarate 5-dioxygenase 1 (PLOD1)
• Synonyms: EC 1.14.11.4; Lysyl hydroxylase 1; LH1
• Gene Name: PLOD1
• Related Disease: Ehlers-Danlos syndrome, kyphoscoliotic type 1
• UniProt ID: PLOD1_HUMAN
• EC Number: 1.14.11.4
• Pfam ID: PF03171
• Sequence:
  MRPLLLLALLGWLLLAEAKGDAKPEDNLLVLTVATKETEGFRRFKRSAQFFNYKIQALGL
  GEDWNVEKGTSAGGGQKVRLLKKALEKHADKEDLVILFADSYDVLFASGPRELLKKFRQA
  RSQVVFSAEELIYPDRRLETKYPVVSDGKRFLGSGGFIGYAPNLSKLVAEWEGQDSDSDQ
  LFYTKIFLDPEKREQINITLDHRCRIFQNLDGALDEVVLKFEMGHVRARNLAYDTLPVLI
  HGNGPTKLQLNYLGNYIPRFWTFETGCTVCDEGLRSLKGIGDEALPTVLVGVFIEQPTPF
  VSLFFQRLLRLHYPQKHMRLFIHNHEQHHKAQVEEFLAQHGSEYQSVKLVGPEVRMANAD
  ARNMGADLCRQDRSCTYYFSVDADVALTEPNSLRLLIQQNKNVIAPLMTRHGRLWSNFWG
  ALSADGYYARSEDYVDIVQGRRVGVWNVPYISNIYLIKGSALRGELQSSDLFHHSKLDPD
  MAFCANIRQQDVFMFLTNRHTLGHLLSLDSYRTTHLHNDLWEVFSNPEDWKEKYIHQNYT
  KALAGKLVETPCPDVYWFPIFTEVACDELVEEMEHFGQWSLGNNKDNRIQGGYENVPTID
  IHMNQIGFEREWHKFLLEYIAPMTEKLYPGYYTRAQFDLAFVVRYKPDEQPSLMPHHDAS
  TFTINIALNRVGVDYEGGGCRFLRYNCSIRAPRKGWTLMHPGRLTHYHEGLPTTRGTRYI
  AVSFVDP
• 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-linkling of collagen fibrils. Forms hydroxylysine residues in -Xaa-Lys-Gly- sequences in collagens. These hydroxylysines serve as sites of attachment for carbohydrate units and are essential for the stability of the intermolecular collagen cross-links (Probable).
• KEGG Pathway:
  Lysine degradation (hsa00310)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Collagen biosynthesis and modifying enzymes (R-HSA-1650814)
• BioCyc Pathway: MetaCyc:HS01440-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ehlers-Danlos syndrome, kyphoscoliotic type 1	DISVE04H	Definitive	Autosomal recessive	[1]

5 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 Procollagen-lysine,2-oxoglutarate 5-dioxygenase 1 (PLOD1).	[2]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Procollagen-lysine,2-oxoglutarate 5-dioxygenase 1 (PLOD1).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Procollagen-lysine,2-oxoglutarate 5-dioxygenase 1 (PLOD1).	[14]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Procollagen-lysine,2-oxoglutarate 5-dioxygenase 1 (PLOD1).	[15]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Procollagen-lysine,2-oxoglutarate 5-dioxygenase 1 (PLOD1).	[16]

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 Procollagen-lysine,2-oxoglutarate 5-dioxygenase 1 (PLOD1).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Procollagen-lysine,2-oxoglutarate 5-dioxygenase 1 (PLOD1).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Procollagen-lysine,2-oxoglutarate 5-dioxygenase 1 (PLOD1).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Procollagen-lysine,2-oxoglutarate 5-dioxygenase 1 (PLOD1).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Procollagen-lysine,2-oxoglutarate 5-dioxygenase 1 (PLOD1).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Procollagen-lysine,2-oxoglutarate 5-dioxygenase 1 (PLOD1).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Procollagen-lysine,2-oxoglutarate 5-dioxygenase 1 (PLOD1).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Procollagen-lysine,2-oxoglutarate 5-dioxygenase 1 (PLOD1).	[11]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Procollagen-lysine,2-oxoglutarate 5-dioxygenase 1 (PLOD1).	[12]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Procollagen-lysine,2-oxoglutarate 5-dioxygenase 1 (PLOD1).	[13]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Procollagen-lysine,2-oxoglutarate 5-dioxygenase 1 (PLOD1).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Procollagen-lysine,2-oxoglutarate 5-dioxygenase 1 (PLOD1).	[8]

References

• [1] A patient with Ehlers-Danlos syndrome type VI is a compound heterozygote for mutations in the lysyl hydroxylase gene. J Clin Invest. 1994 Apr;93(4):1716-21. doi: 10.1172/JCI117155.
• [2] 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.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [8] Convergent transcriptional profiles induced by endogenous estrogen and distinct xenoestrogens in breast cancer cells. Carcinogenesis. 2006 Aug;27(8):1567-78.
• [9] 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.
• [10] 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.
• [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] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [13] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [14] 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.
• [15] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [16] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.