Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUI609X)

• DOT Name: Omega-hydroxyceramide transacylase (PNPLA1)
• Synonyms: EC 2.3.1.296; Patatin-like phospholipase domain-containing protein 1
• Gene Name: PNPLA1
• Related Disease:
  Cervical cancer
  Cervical carcinoma
  Autosomal recessive congenital ichthyosis 10
  Dorfman-Chanarin disease
  Obesity
  Congenital ichthyosiform erythroderma
• UniProt ID: PLPL1_HUMAN
• EC Number: 2.3.1.296
• Pfam ID: PF01734
• Sequence:
  MEEQVFKGDPDTPHSISFSGSGFLSFYQAGAVDALRDLAPRMLETAHRFAGTSAGAVIAA
  LAICGIEMDEYLRVLNVGVAEVKKSFLGPLSPSCKMVQMMRQFLYRVLPEDSYKVTTGKL
  HVSLTRLTDGENVVVSEFTSKEELIEALYCSCFVPVYCGLIPPTYRGVRYIDGGFTGMQP
  CAFWTDAITISTFSGQQDICPRDCPAIFHDFRMFNCSFQFSLENIARMTHALFPPDLVIL
  HDYYYRGYEDAVLYLRRLNAVYLNSSSKRVIFPRVEVYCQIELALGNECPERSQPSLRAR
  QASLEGATQPHKEWVPKGDGRGSHGPPVSQPVQTLEFTCESPVSAPVSPLEQPPAQPLAS
  STPLSLSGMPPVSFPAVHKPPSSTPGSSLPTPPPGLSPLSPQQQVQPSGSPARSLHSQAP
  TSPRPSLGPSTVGAPQTLPRSSLSAFPAQPPVEELGQEQPQAVALLVSSKPKSAVPLVHV
  KETVSKPYVTESPAEDSNWVNKVFKKNKQKTSGTRKGFPRHSGSKKPSSKVQ
• Function: Omega-hydroxyceramide transacylase involved in the synthesis of omega-O-acylceramides (esterified omega-hydroxyacyl-sphingosine; EOS), which are extremely hydrophobic lipids involved in skin barrier formation. Catalyzes the last step of the synthesis of omega-O-acylceramides by transferring linoleic acid from triglycerides to an omega-hydroxyceramide. Omega-O-acylceramides, are required for the biogenesis of lipid lamellae in the stratum corneum and the formation of the cornified lipid envelope which are essential for the epidermis barrier function. These lipids also play a role in keratinocyte differentiation. May also act on omega-hydroxylated ultra-long chain fatty acids (omega-OH ULCFA) and acylglucosylceramides (GlcEOS).
• Tissue Specificity: Expressed in the digestive system. Expressed in the epidermis of skin keratinocytes. Strongly expressed in the granular layer. Expressed in the upper epidermis and eccrine sweat glands of the dermis and in the region of keratin filament bundles, which is more pronounced in upper epidermal layers and in the lower cornified layers.
• BioCyc Pathway: MetaCyc:ENSG00000180316-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cervical cancer	DISFSHPF	Definitive	Biomarker	[1]
Cervical carcinoma	DIST4S00	Definitive	Biomarker	[1]
Autosomal recessive congenital ichthyosis 10	DIS0IG0Y	Strong	Autosomal recessive	[2]
Dorfman-Chanarin disease	DISKKT3R	Strong	Biomarker	[3]
Obesity	DIS47Y1K	Strong	Genetic Variation	[4]
Congenital ichthyosiform erythroderma	DISV8HQX	Supportive	Autosomal recessive	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Omega-hydroxyceramide transacylase (PNPLA1).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Omega-hydroxyceramide transacylase (PNPLA1).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Omega-hydroxyceramide transacylase (PNPLA1).	[7]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Omega-hydroxyceramide transacylase (PNPLA1).	[9]

References

• [1] Identification of human patatin-like phospholipase domain-containing protein 1 and a mutant in human cervical cancer HeLa cells.Mol Biol Rep. 2013 Oct;40(10):5597-605. doi: 10.1007/s11033-013-2661-9. Epub 2013 Sep 22.
• [2] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [3] Molecular mechanism of the ichthyosis pathology of Chanarin-Dorfman syndrome: Stimulation of PNPLA1-catalyzed -O-acylceramide production by ABHD5.J Dermatol Sci. 2018 Dec;92(3):245-253. doi: 10.1016/j.jdermsci.2018.11.005. Epub 2018 Nov 20.
• [4] Genetic variance in the adiponutrin gene family and childhood obesity.PLoS One. 2009;4(4):e5327. doi: 10.1371/journal.pone.0005327. Epub 2009 Apr 24.
• [5] PNPLA1 mutations cause autosomal recessive congenital ichthyosis in golden retriever dogs and humans. Nat Genet. 2012 Jan 15;44(2):140-7. doi: 10.1038/ng.1056.
• [6] 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.
• [7] 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.
• [8] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [9] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.