Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTP0UPL2)

• DOT Name: Cobalamin trafficking protein CblD (MMADHC)
• Synonyms: CblD; Methylmalonic aciduria and homocystinuria type D protein, mitochondrial
• Gene Name: MMADHC
• Related Disease:
  Inborn disorder of cobalamin metabolism and transport
  Methylmalonic aciduria and homocystinuria type cblD
  Homocystinuria
  Methylmalonic acidemia
• UniProt ID: MMAD_HUMAN
• PDB ID: 5CUZ; 5CV0; 6X8Z
• Pfam ID: PF10229
• Sequence:
  MANVLCNRARLVSYLPGFCSLVKRVVNPKAFSTAGSSGSDESHVAAAPPDICSRTVWPDE
  TMGPFGPQDQRFQLPGNIGFDCHLNGTASQKKSLVHKTLPDVLAEPLSSERHEFVMAQYV
  NEFQGNDAPVEQEINSAETYFESARVECAIQTCPELLRKDFESLFPEVANGKLMILTVTQ
  KTKNDMTVWSEEVEIEREVLLEKFINGAKEICYALRAEGYWADFIDPSSGLAFFGPYTNN
  TLFETDERYRHLGFSVDDLGCCKVIRHSLWGTHVVVGSIFTNATPDSHIMKKLSGN
• Function: Involved in cobalamin metabolism and trafficking. Plays a role in regulating the biosynthesis and the proportion of two coenzymes, methylcob(III)alamin (MeCbl) and 5'-deoxyadenosylcobalamin (AdoCbl). Promotes oxidation of cob(II)alamin bound to MMACHC. The processing of cobalamin in the cytosol occurs in a multiprotein complex composed of at least MMACHC, MMADHC, MTRR (methionine synthase reductase) and MTR (methionine synthase) which may contribute to shuttle safely and efficiently cobalamin towards MTR in order to produce methionine.
• Tissue Specificity: Widely expressed at high levels.
• KEGG Pathway: Cobalamin transport and metabolism (hsa04980)
• Reactome Pathway:
  Cobalamin (Cbl) metabolism (R-HSA-9759218)
  Defective MMADHC causes MMAHCD (R-HSA-3359473)
• BioCyc Pathway: MetaCyc:ENSG00000168288-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 disorder of cobalamin metabolism and transport	DISTUC4M	Definitive	Autosomal recessive	[1]
Methylmalonic aciduria and homocystinuria type cblD	DISUIMO9	Definitive	Autosomal recessive	[2]
Homocystinuria	DISK3N1S	Disputed	Genetic Variation	[3]
Methylmalonic acidemia	DISHY8VB	Disputed	Genetic Variation	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Cobalamin trafficking protein CblD (MMADHC).	[4]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Cobalamin trafficking protein CblD (MMADHC).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Cobalamin trafficking protein CblD (MMADHC).	[8]

4 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cobalamin trafficking protein CblD (MMADHC).	[5]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Cobalamin trafficking protein CblD (MMADHC).	[7]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Cobalamin trafficking protein CblD (MMADHC).	[9]
chloropicrin	DMSGBQA	Investigative	chloropicrin affects the expression of Cobalamin trafficking protein CblD (MMADHC).	[10]

References

• [1] 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.
• [2] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [3] Clinical and molecular heterogeneity in patients with the cblD inborn error of cobalamin metabolism.J Pediatr. 2009 Apr;154(4):551-6. doi: 10.1016/j.jpeds.2008.10.043. Epub 2008 Dec 5.
• [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] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [6] 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.
• [7] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [8] 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.
• [9] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [10] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.