Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPJEWQ8)

• DOT Name: Dimethylglycine dehydrogenase, mitochondrial (DMGDH)
• Synonyms: EC 1.5.8.4; ME2GLYDH
• Gene Name: DMGDH
• Related Disease:
  Inborn error of metabolism
  Non-alcoholic fatty liver disease
  Acute myelogenous leukaemia
  Dimethylglycine dehydrogenase deficiency
• UniProt ID: M2GD_HUMAN
• PDB ID: 5L46
• EC Number: 1.5.8.4
• Pfam ID: PF01266 ; PF16350 ; PF01571 ; PF08669
• Sequence:
  MLRPGAQLLRGLLLRSCPLQGSPGRPRSVCGREGEEKPPLSAETQWKDRAETVIIGGGCV
  GVSLAYHLAKAGMKDVVLLEKSELTAGSTWHAAGLTTYFHPGINLKKIHYDSIKLYEKLE
  EETGQVVGFHQPGSIRLATTPVRVDEFKYQMTRTGWHATEQYLIEPEKIQEMFPLLNMNK
  VLAGLYNPGDGHIDPYSLTMALAAGARKCGALLKYPAPVTSLKARSDGTWDVETPQGSMR
  ANRIVNAAGFWAREVGKMIGLEHPLIPVQHQYVVTSTISEVKALKRELPVLRDLEGSYYL
  RQERDGLLFGPYESQEKMKVQDSWVTNGVPPGFGKELFESDLDRIMEHIKAAMEMVPVLK
  KADIINVVNGPITYSPDILPMVGPHQGVRNYWVAIGFGYGIIHAGGVGKYLSDWILHGEP
  PFDLIELDPNRYGKWTTTQYTEAKARESYGFNNIVGYPKEERFAGRPTQRVSGLYQRLES
  KCSMGFHAGWEQPHWFYKPGQDTQYRPSFRRTNWFEPVGSEYKQVMQRVAVTDLSPFGKF
  NIKGQDSIRLLDHLFANVIPKVGFTNISHMLTPKGRVYAELTVSHQSPGEFLLITGSGSE
  LHDLRWIEEEAVKGGYDVEIKNITDELGVLGVAGPQARKVLQKLTSEDLSDDVFKFLQTK
  SLKVSNIPVTAIRISYTGELGWELYHRREDSVALYDAIMNAGQEEGIDNFGTYAMNALRL
  EKAFRAWGLEMNCDTNPLEAGLEYFVKLNKPADFIGKQALKQIKAKGLKRRLVCLTLATD
  DVDPEGNESIWYNGKVVGNTTSGSYSYSIQKSLAFAYVPVQLSEVGQQVEVELLGKNYPA
  VIIQEPLVLTEPTRNRLQKKGGKDKT
• Function: Catalyzes the demethylation of N,N-dimethylglycine to sarcosine. Also has activity with sarcosine in vitro.
• KEGG Pathway:
  Glycine, serine and threonine metabolism (hsa00260)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Choline catabolism (R-HSA-6798163)
• BioCyc Pathway: MetaCyc:HS05695-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Inborn error of metabolism	DISO5FAY	Strong	Biomarker	[1]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Genetic Variation	[2]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[3]
Dimethylglycine dehydrogenase deficiency	DISNZOJ0	Supportive	Autosomal recessive	[1]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Selenium	DM25CGV	Approved	Dimethylglycine dehydrogenase, mitochondrial (DMGDH) affects the abundance of Selenium.	[14]

11 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 Dimethylglycine dehydrogenase, mitochondrial (DMGDH).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Dimethylglycine dehydrogenase, mitochondrial (DMGDH).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Dimethylglycine dehydrogenase, mitochondrial (DMGDH).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Dimethylglycine dehydrogenase, mitochondrial (DMGDH).	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Dimethylglycine dehydrogenase, mitochondrial (DMGDH).	[8]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Dimethylglycine dehydrogenase, mitochondrial (DMGDH).	[8]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Dimethylglycine dehydrogenase, mitochondrial (DMGDH).	[9]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Dimethylglycine dehydrogenase, mitochondrial (DMGDH).	[10]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Dimethylglycine dehydrogenase, mitochondrial (DMGDH).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Dimethylglycine dehydrogenase, mitochondrial (DMGDH).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Dimethylglycine dehydrogenase, mitochondrial (DMGDH).	[13]

References

• [1] Cloning of dimethylglycine dehydrogenase and a new human inborn error of metabolism, dimethylglycine dehydrogenase deficiency. Am J Hum Genet. 2001 Apr;68(4):839-47. doi: 10.1086/319520. Epub 2001 Feb 28.
• [2] Nonalcoholic steatohepatitis is associated with a state of betaine-insufficiency.Liver Int. 2017 Apr;37(4):611-619. doi: 10.1111/liv.13249. Epub 2016 Oct 4.
• [3] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [4] 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.
• [5] 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.
• [6] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [7] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [8] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [9] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [10] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [13] 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.
• [14] Genome-wide association study identifies loci affecting blood copper, selenium and zinc. Hum Mol Genet. 2013 Oct 1;22(19):3998-4006. doi: 10.1093/hmg/ddt239. Epub 2013 May 29.