Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9SOV66)

• DOT Name: Leucine-rich repeat-containing protein 49 (LRRC49)
• Synonyms: Centriolar satellite-associated tubulin polyglutamylase complex regulator 2; Tubulin polyglutamylase complex subunit 4; PGs4
• Gene Name: LRRC49
• Related Disease:
  Breast cancer
  Breast carcinoma
  Breast neoplasm
• UniProt ID: LRC49_HUMAN
• Pfam ID: PF12799 ; PF14580
• Sequence:
  MIPGKYRSVSGRAANNVNCGLHLVIQTSSLPEKNKVEFKLNKDTSSFPGRLLQHDLERNY
  SSRQGDHINLVSSSLSSFPILQRSSEEKILYSDRLSLERQKLTVCPIINGEDHLRLLNFQ
  HNFITRIQNISNLQKLISLDLYDNQIEEISGLSTLRCLRVLLLGKNRIKKISNLENLKSL
  DVLDLHGNQITKIENINHLCELRVLNLARNFLSHVDNLNGLDSLTELNLRHNQITFVRDV
  DNLPCLQHLFLSFNNISSFDSVSCLADSSSLSDITFDGNPIAQESWYKHTVLQNMMQLRQ
  LDMKRITEEERRMASVLAKKEEEKKRESHKQSLLKEKKRLTINNVARQWDLQQQRVANIA
  TNEDRKDSDSPQDPCQIDGSTLSAFPEETGPLDSGLNNALQGLSVIDTYLVEVDGDTLSL
  YGSGALESLDRNWSVQTAGMITTVSFTFIEFDEIVQVLPKLKIKFPNSLHLKFKETNLVM
  LQQFNALAQLRRIDQLTIDPQGNPVVNFTLWKYYVLFRLSHFSMQKINGTEVTQNDMIMA
  ERLFGILAHVASSELPQYRLISILGDARKKQFRYLLESKGKKPGIINEENNDSKRLVGEN
  TNRATLNYTTRDFYNEKLEEIKEKKKFCKTYIEDLVKEATEINMKNEALQKLWPQMFIEL
  VRDAVIEIRNKNSYMKLCLQQITDQK
• Function: Subunit of the tubulin polyglutamylase complex (TPGC). The complex mediates cilia and flagella polyglutamylation which is essential for their biogenesis and motility.
• Reactome Pathway: Carboxyterminal post-translational modifications of tubulin (R-HSA-8955332)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Posttranslational Modification	[1]
Breast carcinoma	DIS2UE88	Strong	Posttranslational Modification	[1]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[1]

9 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 Leucine-rich repeat-containing protein 49 (LRRC49).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Leucine-rich repeat-containing protein 49 (LRRC49).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Leucine-rich repeat-containing protein 49 (LRRC49).	[4]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Leucine-rich repeat-containing protein 49 (LRRC49).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Leucine-rich repeat-containing protein 49 (LRRC49).	[3]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Leucine-rich repeat-containing protein 49 (LRRC49).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Leucine-rich repeat-containing protein 49 (LRRC49).	[7]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Leucine-rich repeat-containing protein 49 (LRRC49).	[8]
9-hydroxyoctadecadienoic acid	DM0FWNJ	Investigative	9-hydroxyoctadecadienoic acid increases the expression of Leucine-rich repeat-containing protein 49 (LRRC49).	[9]

References

• [1] Silencing of LRRC49 and THAP10 genes by bidirectional promoter hypermethylation is a frequent event in breast cancer.Int J Oncol. 2008 Jul;33(1):25-31.
• [2] Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.
• [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] 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.
• [5] Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [6] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [7] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [8] 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.
• [9] A proteomic analysis of acute leukemia cells treated with 9-hydroxyoctadecadienoic acid. Lipids Health Dis. 2016 Nov 10;15(1):192. doi: 10.1186/s12944-016-0359-4.