Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWT4HAF)

• DOT Name: Long-chain fatty acid transport protein 4 (SLC27A4)
• Synonyms: FATP-4; Fatty acid transport protein 4; Arachidonate--CoA ligase; EC 6.2.1.15; Long-chain-fatty-acid--CoA ligase; EC 6.2.1.3; Solute carrier family 27 member 4; Very long-chain acyl-CoA synthetase 4; ACSVL4; EC 6.2.1.-
• Gene Name: SLC27A4
• Related Disease: Ichthyosis prematurity syndrome
• UniProt ID: S27A4_HUMAN
• EC Number: 6.2.1.-; 6.2.1.15; 6.2.1.3
• Pfam ID: PF00501 ; PF13193
• Sequence:
  MLLGASLVGVLLFSKLVLKLPWTQVGFSLLFLYLGSGGWRFIRVFIKTIRRDIFGGLVLL
  KVKAKVRQCLQERRTVPILFASTVRRHPDKTALIFEGTDTHWTFRQLDEYSSSVANFLQA
  RGLASGDVAAIFMENRNEFVGLWLGMAKLGVEAALINTNLRRDALLHCLTTSRARALVFG
  SEMASAICEVHASLDPSLSLFCSGSWEPGAVPPSTEHLDPLLKDAPKHLPSCPDKGFTDK
  LFYIYTSGTTGLPKAAIVVHSRYYRMAALVYYGFRMRPNDIVYDCLPLYHSAGNIVGIGQ
  CLLHGMTVVIRKKFSASRFWDDCIKYNCTIVQYIGELCRYLLNQPPREAENQHQVRMALG
  NGLRQSIWTNFSSRFHIPQVAEFYGATECNCSLGNFDSQVGACGFNSRILSFVYPIRLVR
  VNEDTMELIRGPDGVCIPCQPGEPGQLVGRIIQKDPLRRFDGYLNQGANNKKIAKDVFKK
  GDQAYLTGDVLVMDELGYLYFRDRTGDTFRWKGENVSTTEVEGTLSRLLDMADVAVYGVE
  VPGTEGRAGMAAVASPTGNCDLERFAQVLEKELPLYARPIFLRLLPELHKTGTYKFQKTE
  LRKEGFDPAIVKDPLFYLDAQKGRYVPLDQEAYSRIQAGEEKL
• Function: Mediates the levels of long-chain fatty acids (LCFA) in the cell by facilitating their transport across cell membranes. Appears to be the principal fatty acid transporter in small intestinal enterocytes. Also functions as an acyl-CoA ligase catalyzing the ATP-dependent formation of fatty acyl-CoA using LCFA and very-long-chain fatty acids (VLCFA) as substrates, which prevents fatty acid efflux from cells and might drive more fatty acid uptake. Plays a role in the formation of the epidermal barrier. Required for fat absorption in early embryogenesis. Probably involved in fatty acid transport across the blood barrier. Indirectly inhibits RPE65 via substrate competition and via production of VLCFA derivatives like lignoceroyl-CoA. Prevents light-induced degeneration of rods and cones.
• Tissue Specificity: Expressed at highest levels in brain, testis, colon and kidney. Expressed at medium levels in heart and liver, small intestine and stomach. Expressed at low levels in peripheral leukocytes, bone marrow, skeletal muscle and aorta. Expressed in adipose tissue . Expressed in brain gray matter .
• KEGG Pathway:
  PPAR sig.ling pathway (hsa03320)
  Insulin resistance (hsa04931)
  Fat digestion and absorption (hsa04975)
• Reactome Pathway:
  Transport of fatty acids (R-HSA-804914)
  Defective SLC27A4 causes ichthyosis prematurity syndrome (IPS) (R-HSA-5619108)
• BioCyc Pathway: MetaCyc:ENSG00000167114-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ichthyosis prematurity syndrome	DISYD4IG	Definitive	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Long-chain fatty acid transport protein 4 (SLC27A4).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Long-chain fatty acid transport protein 4 (SLC27A4).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Long-chain fatty acid transport protein 4 (SLC27A4).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Long-chain fatty acid transport protein 4 (SLC27A4).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Long-chain fatty acid transport protein 4 (SLC27A4).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Long-chain fatty acid transport protein 4 (SLC27A4).	[7]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of Long-chain fatty acid transport protein 4 (SLC27A4).	[8]
Vitamin B3	DMQVRZH	Approved	Vitamin B3 increases the expression of Long-chain fatty acid transport protein 4 (SLC27A4).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Long-chain fatty acid transport protein 4 (SLC27A4).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Long-chain fatty acid transport protein 4 (SLC27A4).	[11]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Long-chain fatty acid transport protein 4 (SLC27A4).	[12]
Linalool	DMGZQ5P	Investigative	Linalool increases the expression of Long-chain fatty acid transport protein 4 (SLC27A4).	[8]

References

• [1] 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.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] 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.
• [4] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [5] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [6] 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.
• [7] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [8] Linalool is a PPARalpha ligand that reduces plasma TG levels and rewires the hepatic transcriptome and plasma metabolome. J Lipid Res. 2014 Jun;55(6):1098-110.
• [9] Structure-dependent effects of pyridine derivatives on mechanisms of intestinal fatty acid uptake: regulation of nicotinic acid receptor and fatty acid transporter expression. J Nutr Biochem. 2014 Jul;25(7):750-7. doi: 10.1016/j.jnutbio.2014.03.002. Epub 2014 Mar 22.
• [10] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [11] Exposure to environmental bisphenol A inhibits HTR-8/SVneo cell migration and invasion. J Biomed Res. 2020 Jun 30;34(5):369-378. doi: 10.7555/JBR.34.20200013.
• [12] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.