Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTM3QBU8)

• DOT Name: AP-4 complex subunit sigma-1 (AP4S1)
• Synonyms: AP-4 adaptor complex subunit sigma-1; Adaptor-related protein complex 4 subunit sigma-1; Sigma-1 subunit of AP-4; Sigma-4-adaptin; Sigma4-adaptin
• Gene Name: AP4S1
• Related Disease:
  AP-4 deficiency syndrome
  Hereditary spastic paraplegia
  Hereditary spastic paraplegia 51
  Cerebral palsy
  Hereditary spastic paraplegia 52
  Intellectual disability
  Obsolete AP4-related intellectual disability and spastic paraplegia
• UniProt ID: AP4S1_HUMAN
• Pfam ID: PF01217
• Sequence:
  MIKFFLMVNKQGQTRLSKYYEHVDINKRTLLETEVIKSCLSRSNEQCSFIEYKDFKLIYR
  QYAALFIVVGVNDTENEMAIYEFIHNFVEVLDEYFSRVSELDIMFNLDKVHIILDEMVLN
  GCIVETNRARILAPLLILDKMSES
• Function: Component of the adaptor protein complex 4 (AP-4). Adaptor protein complexes are vesicle coat components involved both in vesicle formation and cargo selection. They control the vesicular transport of proteins in different trafficking pathways. AP-4 forms a non clathrin-associated coat on vesicles departing the trans-Golgi network (TGN) and may be involved in the targeting of proteins from the trans-Golgi network (TGN) to the endosomal-lysosomal system. It is also involved in protein sorting to the basolateral membrane in epithelial cells and the proper asymmetric localization of somatodendritic proteins in neurons. AP-4 is involved in the recognition and binding of tyrosine-based sorting signals found in the cytoplasmic part of cargos, but may also recognize other types of sorting signal (Probable).
• Tissue Specificity: Widely expressed.
• KEGG Pathway: Lysosome (hsa04142)
• Reactome Pathway: Lysosome Vesicle Biogenesis (R-HSA-432720)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
AP-4 deficiency syndrome	DISCF43Z	Definitive	Autosomal recessive	[1]
Hereditary spastic paraplegia	DISGZQV1	Definitive	Biomarker	[2]
Hereditary spastic paraplegia 51	DIS3DFPG	Definitive	Biomarker	[2]
Cerebral palsy	DIS82ODL	Strong	Genetic Variation	[3]
Hereditary spastic paraplegia 52	DISQ4O7P	Strong	Autosomal recessive	[4]
Intellectual disability	DISMBNXP	Strong	Biomarker	[5]
Obsolete AP4-related intellectual disability and spastic paraplegia	DISFYNHU	Supportive	Autosomal recessive	[4]

9 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 AP-4 complex subunit sigma-1 (AP4S1).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of AP-4 complex subunit sigma-1 (AP4S1).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of AP-4 complex subunit sigma-1 (AP4S1).	[8]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of AP-4 complex subunit sigma-1 (AP4S1).	[9]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of AP-4 complex subunit sigma-1 (AP4S1).	[10]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of AP-4 complex subunit sigma-1 (AP4S1).	[12]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of AP-4 complex subunit sigma-1 (AP4S1).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of AP-4 complex subunit sigma-1 (AP4S1).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of AP-4 complex subunit sigma-1 (AP4S1).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of AP-4 complex subunit sigma-1 (AP4S1).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of AP-4 complex subunit sigma-1 (AP4S1).	[11]

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] Generation and characterization of six human induced pluripotent stem cell lines (iPSC) from three families with AP4B1-associated hereditary spastic paraplegia (SPG47).Stem Cell Res. 2019 Oct;40:101575. doi: 10.1016/j.scr.2019.101575. Epub 2019 Sep 11.
• [3] Identification of mutations in AP4S1/SPG52 through next generation sequencing in three families.Eur J Neurol. 2016 Oct;23(10):1580-7. doi: 10.1111/ene.13085. Epub 2016 Jul 22.
• [4] Adaptor protein complex 4 deficiency causes severe autosomal-recessive intellectual disability, progressive spastic paraplegia, shy character, and short stature. Am J Hum Genet. 2011 Jun 10;88(6):788-795. doi: 10.1016/j.ajhg.2011.04.019. Epub 2011 May 27.
• [5] Autosomal recessive spastic tetraplegia caused by AP4M1 and AP4B1 gene mutation: expansion of the facial and neuroimaging features. Am J Med Genet A. 2014 Jul;164A(7):1677-85. doi: 10.1002/ajmg.a.36514. Epub 2014 Apr 3.
• [6] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [7] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [8] 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.
• [9] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [10] Pharmacogenomic identification of novel determinants of response to chemotherapy in colon cancer. Cancer Res. 2006 Mar 1;66(5):2765-77.
• [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 testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [13] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [14] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [15] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.