Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6QTX7R)

• DOT Name: Low density lipoprotein receptor adapter protein 1 (LDLRAP1)
• Synonyms: Autosomal recessive hypercholesterolemia protein
• Gene Name: LDLRAP1
• Related Disease:
  Hypercholesterolemia, familial, 4
  Plasma cell neoplasm
  Severe combined immunodeficiency
  Advanced cancer
  Arteriosclerosis
  Atherosclerosis
  Epithelial ovarian cancer
  Familial hypercholesterolemia
  Hepatitis C virus infection
  Hypercholesterolemia, familial, 1
  Lipid metabolism disorder
  Myocardial infarction
  Neoplasm
  Plasma cell myeloma
  Vibrio cholerae infection
  Homozygous familial hypercholesterolemia
  Colorectal carcinoma
  Cardiomyopathy
• UniProt ID: ARH_HUMAN
• PDB ID: 2G30
• Pfam ID: PF00640
• Sequence:
  MDALKSAGRALIRSPSLAKQSWGGGGRHRKLPENWTDTRETLLEGMLFSLKYLGMTLVEQ
  PKGEELSAAAIKRIVATAKASGKKLQKVTLKVSPRGIILTDNLTNQLIENVSIYRISYCT
  ADKMHDKVFAYIAQSQHNQSLECHAFLCTKRKMAQAVTLTVAQAFKVAFEFWQVSKEEKE
  KRDKASQEGGDVLGARQDCTPSLKSLVATGNLLDLEETAKAPLSTVSANTTNMDEVPRPQ
  ALSGSSVVWELDDGLDEAFSRLAQSRTNPQVLDTGLTAQDMHYAQCLSPVDWDKPDSSGT
  EQDDLFSF
• Function: Adapter protein (clathrin-associated sorting protein (CLASP)) required for efficient endocytosis of the LDL receptor (LDLR) in polarized cells such as hepatocytes and lymphocytes, but not in non-polarized cells (fibroblasts). May be required for LDL binding and internalization but not for receptor clustering in coated pits. May facilitate the endocytosis of LDLR and LDLR-LDL complexes from coated pits by stabilizing the interaction between the receptor and the structural components of the pits. May also be involved in the internalization of other LDLR family members. Binds to phosphoinositides, which regulate clathrin bud assembly at the cell surface. Required for trafficking of LRP2 to the endocytic recycling compartment which is necessary for LRP2 proteolysis, releasing a tail fragment which translocates to the nucleus and mediates transcriptional repression.
• Tissue Specificity: Expressed at high levels in the kidney, liver, and placenta, with lower levels detectable in brain, heart, muscle, colon, spleen, intestine, lung, and leukocytes.
• KEGG Pathway:
  Endocytosis (hsa04144)
  Cholesterol metabolism (hsa04979)
• Reactome Pathway:
  Cargo recognition for clathrin-mediated endocytosis (R-HSA-8856825)
  Clathrin-mediated endocytosis (R-HSA-8856828)
  Chylomicron clearance (R-HSA-8964026)
  LDL clearance (R-HSA-8964038)
  Transport of RCbl within the body (R-HSA-9758890)
  Vitamin D (calciferol) metabolism (R-HSA-196791)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hypercholesterolemia, familial, 4	DISFLNLI	Definitive	Autosomal recessive	[1]
Plasma cell neoplasm	DIS2PJJM	Definitive	Biomarker	[2]
Severe combined immunodeficiency	DIS6MF4Q	Definitive	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[3]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[4]
Atherosclerosis	DISMN9J3	Strong	Genetic Variation	[5]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[6]
Familial hypercholesterolemia	DISC06IX	Strong	Genetic Variation	[7]
Hepatitis C virus infection	DISQ0M8R	Strong	Genetic Variation	[8]
Hypercholesterolemia, familial, 1	DISU411W	Strong	Genetic Variation	[7]
Lipid metabolism disorder	DISEOA7S	Strong	Genetic Variation	[9]
Myocardial infarction	DIS655KI	Strong	Genetic Variation	[10]
Neoplasm	DISZKGEW	Strong	Biomarker	[11]
Plasma cell myeloma	DIS0DFZ0	Strong	Altered Expression	[11]
Vibrio cholerae infection	DISW7E3U	Strong	Biomarker	[12]
Homozygous familial hypercholesterolemia	DISRCNCF	Supportive	Autosomal recessive	[13]
Colorectal carcinoma	DIS5PYL0	Disputed	Biomarker	[14]
Cardiomyopathy	DISUPZRG	Limited	Biomarker	[15]

13 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 Low density lipoprotein receptor adapter protein 1 (LDLRAP1).	[16]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Low density lipoprotein receptor adapter protein 1 (LDLRAP1).	[17]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Low density lipoprotein receptor adapter protein 1 (LDLRAP1).	[18]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Low density lipoprotein receptor adapter protein 1 (LDLRAP1).	[19]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Low density lipoprotein receptor adapter protein 1 (LDLRAP1).	[20]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Low density lipoprotein receptor adapter protein 1 (LDLRAP1).	[22]
Marinol	DM70IK5	Approved	Marinol increases the expression of Low density lipoprotein receptor adapter protein 1 (LDLRAP1).	[23]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Low density lipoprotein receptor adapter protein 1 (LDLRAP1).	[24]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Low density lipoprotein receptor adapter protein 1 (LDLRAP1).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Low density lipoprotein receptor adapter protein 1 (LDLRAP1).	[27]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Low density lipoprotein receptor adapter protein 1 (LDLRAP1).	[28]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Low density lipoprotein receptor adapter protein 1 (LDLRAP1).	[24]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Low density lipoprotein receptor adapter protein 1 (LDLRAP1).	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Low density lipoprotein receptor adapter protein 1 (LDLRAP1).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Low density lipoprotein receptor adapter protein 1 (LDLRAP1).	[26]

References

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• [17] 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.
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• [19] 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.
• [20] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
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• [22] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [23] Single-cell Transcriptome Mapping Identifies Common and Cell-type Specific Genes Affected by Acute Delta9-tetrahydrocannabinol in Humans. Sci Rep. 2020 Feb 26;10(1):3450. doi: 10.1038/s41598-020-59827-1.
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