Details of Drug Off-Target (DOT)

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

• DOT Name: Lysosomal cobalamin transporter ABCD4 (ABCD4)
• Synonyms: EC 7.6.2.8; ATP-binding cassette sub-family D member 4; PMP70-related protein; P70R; Peroxisomal membrane protein 1-like; PXMP1-L; Peroxisomal membrane protein 69; PMP69
• Gene Name: ABCD4
• Related Disease: Methylmalonic acidemia with homocystinuria, type cblJ
• UniProt ID: ABCD4_HUMAN
• PDB ID: 6JBJ
• EC Number: 7.6.2.8
• Pfam ID: PF06472 ; PF00005
• Sequence:
  MAVAGPAPGAGARPRLDLQFLQRFLQILKVLFPSWSSQNALMFLTLLCLTLLEQFVIYQV
  GLIPSQYYGVLGNKDLEGFKTLTFLAVMLIVLNSTLKSFDQFTCNLLYVSWRKDLTEHLH
  RLYFRGRAYYTLNVLRDDIDNPDQRISQDVERFCRQLSSMASKLIISPFTLVYYTYQCFQ
  STGWLGPVSIFGYFILGTVVNKTLMGPIVMKLVHQEKLEGDFRFKHMQIRVNAEPAAFYR
  AGHVEHMRTDRRLQRLLQTQRELMSKELWLYIGINTFDYLGSILSYVVIAIPIFSGVYGD
  LSPAELSTLVSKNAFVCIYLISCFTQLIDLSTTLSDVAGYTHRIGQLRETLLDMSLKSQD
  CEILGESEWGLDTPPGWPAAEPADTAFLLERVSISAPSSDKPLIKDLSLKISEGQSLLIT
  GNTGTGKTSLLRVLGGLWTSTRGSVQMLTDFGPHGVLFLPQKPFFTDGTLREQVIYPLKE
  VYPDSGSADDERILRFLELAGLSNLVARTEGLDQQVDWNWYDVLSPGEMQRLSFARLFYL
  QPKYAVLDEATSALTEEVESELYRIGQQLGMTFISVGHRQSLEKFHSLVLKLCGGGRWEL
  MRIKVE
• Function: Lysosomal membrane protein that transports cobalamin (Vitamin B12) from the lysosomal lumen to the cytosol in an ATP-dependent manner. Targeted by LMBRD1 lysosomal chaperone from the endoplasmic reticulum to the lysosomal membrane. Then forms a complex with lysosomal chaperone LMBRD1 and cytosolic MMACHC to transport cobalamin across the lysosomal membrane.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway:
  ABC transporters (hsa02010)
  Peroxisome (hsa04146)
  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 acidemia with homocystinuria, type cblJ	DISEQ2LP	Strong	Autosomal recessive	[1]

5 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 Lysosomal cobalamin transporter ABCD4 (ABCD4).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Lysosomal cobalamin transporter ABCD4 (ABCD4).	[3]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Lysosomal cobalamin transporter ABCD4 (ABCD4).	[4]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Lysosomal cobalamin transporter ABCD4 (ABCD4).	[5]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Lysosomal cobalamin transporter ABCD4 (ABCD4).	[6]

References

• [1] Mutations in ABCD4 cause a new inborn error of vitamin B12 metabolism. Nat Genet. 2012 Oct;44(10):1152-5. doi: 10.1038/ng.2386. Epub 2012 Aug 26.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [5] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [6] 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.