Details of Drug Off-Target (DOT)

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

• DOT Name: Probable D-lactate dehydrogenase, mitochondrial (LDHD)
• Synonyms: DLD; Lactate dehydrogenase D; EC 1.1.2.4
• Gene Name: LDHD
• Related Disease: Clear cell renal carcinoma
• UniProt ID: LDHD_HUMAN
• EC Number: 1.1.2.4
• Pfam ID: PF02913 ; PF01565
• Sequence:
  MARLLRSATWELFPWRGYCSQKAKGELCRDFVEALKAVVGGSHVSTAAVVREQHGRDESV
  HRCEPPDAVVWPQNVEQVSRLAALCYRQGVPIIPFGTGTGLEGGVCAVQGGVCVNLTHMD
  RILELNQEDFSVVVEPGVTRKALNAHLRDSGLWFPVDPGADASLCGMAATGASGTNAVRY
  GTMRDNVLNLEVVLPDGRLLHTAGRGRHFRFGFWPEIPHHTAWYSPCVSLGRRKSAAGYN
  LTGLFVGSEGTLGLITATTLRLHPAPEATVAATCAFPSVQAAVDSTVHILQAAVPVARIE
  FLDEVMMDACNRYSKLNCLVAPTLFLEFHGSQQALEEQLQRTEEIVQQNGASDFSWAKEA
  EERSRLWTARHNAWYAALATRPGCKGYSTDVCVPISRLPEIVVQTKEDLNASGLTGSIVG
  HVGDGNFHCILLVNPDDAEELGRVKAFAEQLGRRALALHGTCTGEHGIGMGKRQLLQEEV
  GAVGVETMRQLKAVLDPQGLMNPGKVL
• Function: Involved in D-lactate, but not L-lactate catabolic process.
• Tissue Specificity: Expressed moderately in heart and liver and at lower levels in skeletal muscle and kidney.
• KEGG Pathway:
  Pyruvate metabolism (hsa00620)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Mitochondrial protein import (R-HSA-1268020)
• BioCyc Pathway: MetaCyc:HS15490-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
Clear cell renal carcinoma	DISBXRFJ	moderate	Biomarker	[1]

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 Probable D-lactate dehydrogenase, mitochondrial (LDHD).	[2]
OXYBENZONE	DMMZYX6	Investigative	OXYBENZONE increases the methylation of Probable D-lactate dehydrogenase, mitochondrial (LDHD).	[15]

16 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 Probable D-lactate dehydrogenase, mitochondrial (LDHD).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Probable D-lactate dehydrogenase, mitochondrial (LDHD).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Probable D-lactate dehydrogenase, mitochondrial (LDHD).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Probable D-lactate dehydrogenase, mitochondrial (LDHD).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Probable D-lactate dehydrogenase, mitochondrial (LDHD).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Probable D-lactate dehydrogenase, mitochondrial (LDHD).	[8]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Probable D-lactate dehydrogenase, mitochondrial (LDHD).	[7]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Probable D-lactate dehydrogenase, mitochondrial (LDHD).	[8]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Probable D-lactate dehydrogenase, mitochondrial (LDHD).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Probable D-lactate dehydrogenase, mitochondrial (LDHD).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Probable D-lactate dehydrogenase, mitochondrial (LDHD).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Probable D-lactate dehydrogenase, mitochondrial (LDHD).	[3]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Probable D-lactate dehydrogenase, mitochondrial (LDHD).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Probable D-lactate dehydrogenase, mitochondrial (LDHD).	[12]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Probable D-lactate dehydrogenase, mitochondrial (LDHD).	[13]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Probable D-lactate dehydrogenase, mitochondrial (LDHD).	[14]

References

• [1] Prognostic value of D-lactate dehydrogenase in patients with clear cell renal cell carcinoma.Oncol Lett. 2018 Jul;16(1):866-874. doi: 10.3892/ol.2018.8782. Epub 2018 May 22.
• [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] 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] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [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] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [8] 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.
• [9] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [12] 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.
• [13] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [14] Evaluation of an in vitro model of androgen ablation and identification of the androgen responsive proteome in LNCaP cells. Proteomics. 2007 Jan;7(1):47-63.
• [15] Pregnancy exposure to synthetic phenols and placental DNA methylation - An epigenome-wide association study in male infants from the EDEN cohort. Environ Pollut. 2021 Dec 1;290:118024. doi: 10.1016/j.envpol.2021.118024. Epub 2021 Aug 21.