Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZCIZH0)

• DOT Name: Lysosomal cobalamin transport escort protein LMBD1 (LMBRD1)
• Synonyms: LMBD1; HDAg-L-interacting protein NESI; LMBR1 domain-containing protein 1; Nuclear export signal-interacting protein
• Gene Name: LMBRD1
• Related Disease: Methylmalonic aciduria and homocystinuria type cblF
• UniProt ID: LMBD1_HUMAN
• Pfam ID: PF04791
• Sequence:
  MATSGAASAELVIGWCIFGLLLLAILAFCWIYVRKYQSRRESEVVSTITAIFSLAIALIT
  SALLPVDIFLVSYMKNQNGTFKDWANANVSRQIEDTVLYGYYTLYSVILFCVFFWIPFVY
  FYYEEKDDDDTSKCTQIKTALKYTLGFVVICALLLLVGAFVPLNVPNNKNSTEWEKVKSL
  FEELGSSHGLAALSFSISSLTLIGMLAAITYTAYGMSALPLNLIKGTRSAAYERLENTED
  IEEVEQHIQTIKSKSKDGRPLPARDKRALKQFEERLRTLKKRERHLEFIENSWWTKFCGA
  LRPLKIVWGIFFILVALLFVISLFLSNLDKALHSAGIDSGFIIFGANLSNPLNMLLPLLQ
  TVFPLDYILITIIIMYFIFTSMAGIRNIGIWFFWIRLYKIRRGRTRPQALLFLCMILLLI
  VLHTSYMIYSLAPQYVMYGSQNYLIETNITSDNHKGNSTLSVPKRCDADAPEDQCTVTRT
  YLFLHKFWFFSAAYYFGNWAFLGVFLIGLIVSCCKGKKSVIEGVDEDSDISDDEPSVYSA
• Function: Lysosomal membrane chaperone required to export cobalamin (vitamin B12) from the lysosome to the cytosol, allowing its conversion to cofactors. Targets ABCD4 transporter from the endoplasmic reticulum to the lysosome. Then forms a complex with lysosomal ABCD4 and cytoplasmic MMACHC to transport cobalamin across the lysosomal membrane. Acts as an adapter protein which plays an important role in mediating and regulating the internalization of the insulin receptor (INSR). Involved in clathrin-mediated endocytosis of INSR via its interaction with adapter protein complex 2. Essential for the initiation of gastrulation and early formation of mesoderm structures during embryogenesis; [Isoform 3]: (Microbial infection) May play a role in the assembly of hepatitis delta virus (HDV).
• Tissue Specificity: Isoform 3 is expressed in liver.
• KEGG Pathway:
  Vitamin digestion and absorption (hsa04977)
  Cobalamin transport and metabolism (hsa04980)
• Reactome Pathway:
  Uptake of dietary cobalamins into enterocytes (R-HSA-9758881)
  Transport of RCbl within the body (R-HSA-9758890)
  Defective ABCD4 causes MAHCJ (R-HSA-5683329)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Methylmalonic aciduria and homocystinuria type cblF	DISAPKM7	Definitive	Autosomal recessive	[1]

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 Lysosomal cobalamin transport escort protein LMBD1 (LMBRD1).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Lysosomal cobalamin transport escort protein LMBD1 (LMBRD1).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Lysosomal cobalamin transport escort protein LMBD1 (LMBRD1).	[11]

8 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 Lysosomal cobalamin transport escort protein LMBD1 (LMBRD1).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Lysosomal cobalamin transport escort protein LMBD1 (LMBRD1).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Lysosomal cobalamin transport escort protein LMBD1 (LMBRD1).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Lysosomal cobalamin transport escort protein LMBD1 (LMBRD1).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Lysosomal cobalamin transport escort protein LMBD1 (LMBRD1).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Lysosomal cobalamin transport escort protein LMBD1 (LMBRD1).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Lysosomal cobalamin transport escort protein LMBD1 (LMBRD1).	[10]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Lysosomal cobalamin transport escort protein LMBD1 (LMBRD1).	[12]

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] 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] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [5] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [6] 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.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [9] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [10] 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.
• [11] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [12] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.