Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTH4ZLJP)

• DOT Name: Trimethyllysine dioxygenase, mitochondrial (TMLHE)
• Synonyms: EC 1.14.11.8; Epsilon-trimethyllysine 2-oxoglutarate dioxygenase; Epsilon-trimethyllysine hydroxylase; TML hydroxylase; TML-alpha-ketoglutarate dioxygenase; TML dioxygenase; TMLD
• Gene Name: TMLHE
• Related Disease:
  Venous thromboembolism
  Autism spectrum disorder
  Intellectual disability
  Autism
  Epsilon-trimethyllysine hydroxylase deficiency
  Systemic primary carnitine deficiency disease
• UniProt ID: TMLH_HUMAN
• EC Number: 1.14.11.8
• Pfam ID: PF06155 ; PF02668
• Sequence:
  MWYHRLSHLHSRLQDLLKGGVIYPALPQPNFKSLLPLAVHWHHTASKSLTCAWQQHEDHF
  ELKYANTVMRFDYVWLRDHCRSASCYNSKTHQRSLDTASVDLCIKPKTIRLDETTLFFTW
  PDGHVTKYDLNWLVKNSYEGQKQKVIQPRILWNAEIYQQAQVPSVDCQSFLETNEGLKKF
  LQNFLLYGIAFVENVPPTQEHTEKLAERISLIRETIYGRMWYFTSDFSRGDTAYTKLALD
  RHTDTTYFQEPCGIQVFHCLKHEGTGGRTLLVDGFYAAEQVLQKAPEEFELLSKVPLKHE
  YIEDVGECHNHMIGIGPVLNIYPWNKELYLIRYNNYDRAVINTVPYDVVHRWYTAHRTLT
  IELRRPENEFWVKLKPGRVLFIDNWRVLHGRECFTGYRQLCGCYLTRDDVLNTARLLGLQ
  A
• Function: Converts trimethyllysine (TML) into hydroxytrimethyllysine (HTML).
• Tissue Specificity: All isoforms, but isoform 8, are widely expressed in adult and fetal tissues. Isoform 8 is restricted to heart and skeletal muscle.
• KEGG Pathway:
  Lysine degradation (hsa00310)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Carnitine synthesis (R-HSA-71262)
• BioCyc Pathway: MetaCyc:HS08089-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Venous thromboembolism	DISUR7CR	Strong	Genetic Variation	[1]
Autism spectrum disorder	DISXK8NV	Disputed	X-linked	[2]
Intellectual disability	DISMBNXP	Disputed	Genetic Variation	[3]
Autism	DISV4V1Z	Limited	Biomarker	[4]
Epsilon-trimethyllysine hydroxylase deficiency	DIS6SM2M	Limited	Unknown	[5]
Systemic primary carnitine deficiency disease	DIS9OPZ4	Limited	Biomarker	[4]

7 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 Trimethyllysine dioxygenase, mitochondrial (TMLHE).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Trimethyllysine dioxygenase, mitochondrial (TMLHE).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Trimethyllysine dioxygenase, mitochondrial (TMLHE).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Trimethyllysine dioxygenase, mitochondrial (TMLHE).	[9]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Trimethyllysine dioxygenase, mitochondrial (TMLHE).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Trimethyllysine dioxygenase, mitochondrial (TMLHE).	[12]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Trimethyllysine dioxygenase, mitochondrial (TMLHE).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Trimethyllysine dioxygenase, mitochondrial (TMLHE).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Trimethyllysine dioxygenase, mitochondrial (TMLHE).	[13]

References

• [1] Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism.Blood. 2019 Nov 7;134(19):1645-1657. doi: 10.1182/blood.2019000435.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] Analysis of the chromosome X exome in patients with autism spectrum disorders identified novel candidate genes, including TMLHE.Transl Psychiatry. 2012 Oct 23;2(10):e179. doi: 10.1038/tp.2012.102.
• [4] Brain carnitine deficiency causes nonsyndromic autism with an extreme male bias: A hypothesis.Bioessays. 2017 Aug;39(8):10.1002/bies.201700012. doi: 10.1002/bies.201700012. Epub 2017 Jul 13.
• [5] Use of array CGH to detect exonic copy number variants throughout the genome in autism families detects a novel deletion in TMLHE. Hum Mol Genet. 2011 Nov 15;20(22):4360-70. doi: 10.1093/hmg/ddr363. Epub 2011 Aug 24.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [10] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [11] 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.
• [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] Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol. 2012 Jul;41(1):369-77.
• [14] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.