Details of Drug Off-Target (DOT)

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

• DOT Name: Phospholipase DDHD1 (DDHD1)
• Synonyms: EC 3.1.1.111; EC 3.1.1.32; DDHD domain-containing protein 1; Phosphatidic acid-preferring phospholipase A1 homolog; PA-PLA1; EC 3.1.1.118; Phospholipid sn-1 acylhydrolase
• Gene Name: DDHD1
• Related Disease:
  Hereditary spastic paraplegia
  Hereditary spastic paraplegia 56
  Autism spectrum disorder
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Hereditary spastic paraplegia 28
  Hypercholesterolemia, familial, 4
  Inherited retinal dystrophy
  Neurodegeneration with brain iron accumulation
  Pure hereditary spastic paraplegia
  Retinopathy
  Vascular purpura
• UniProt ID: DDHD1_HUMAN
• EC Number: 3.1.1.111; 3.1.1.118; 3.1.1.32
• Pfam ID: PF02862
• Sequence:
  MNYPGRGSPRSPEHNGRGGGGGAWELGSDARPAFGGGVCCFEHLPGGDPDDGDVPLALLR
  GEPGLHLAPGTDDHNHHLALDPCLSDENYDFSSAESGSSLRYYSEGESGGGGSSLSLHPP
  QQPPLVPTNSGGGGATGGSPGERKRTRLGGPAARHRYEVVTELGPEEVRWFYKEDKKTWK
  PFIGYDSLRIELAFRTLLQTTGARPQGGDRDGDHVCSPTGPASSSGEDDDEDRACGFCQS
  TTGHEPEMVELVNIEPVCVRGGLYEVDVTQGECYPVYWNQADKIPVMRGQWFIDGTWQPL
  EEEESNLIEQEHLNCFRGQQMQENFDIEVSKSIDGKDAVHSFKLSRNHVDWHSVDEVYLY
  SDATTSKIARTVTQKLGFSKASSSGTRLHRGYVEEATLEDKPSQTTHIVFVVHGIGQKMD
  QGRIIKNTAMMREAARKIEERHFSNHATHVEFLPVEWRSKLTLDGDTVDSITPDKVRGLR
  DMLNSSAMDIMYYTSPLYRDELVKGLQQELNRLYSLFCSRNPDFEEKGGKVSIVSHSLGC
  VITYDIMTGWNPVRLYEQLLQKEEELPDERWMSYEERHLLDELYITKRRLKEIEERLHGL
  KASSMTQTPALKFKVENFFCMGSPLAVFLALRGIRPGNTGSQDHILPREICNRLLNIFHP
  TDPVAYRLEPLILKHYSNISPVQIHWYNTSNPLPYEHMKPSFLNPAKEPTSVSENEGIST
  IPSPVTSPVLSRRHYGESITNIGKASILGAASIGKGLGGMLFSRFGRSSTTQSSETSKDS
  MEDEKKPVASPSATTVGTQTLPHSSSGFLDSAYFRLQESFFNLPQLLFPENVMQNKDNAL
  VELDHRIDFELREGLVESRYWSAVTSHTAYWSSLDVALFLLTFMYKHEHDDDAKPNLDPI
• Function: Phospholipase A1 (PLA1) that hydrolyzes ester bonds at the sn-1 position of glycerophospholipids producing a free fatty acid and a lysophospholipid (Probable). Prefers phosphatidate (1,2-diacyl-sn-glycero-3-phosphate, PA) as substrate in vitro, but can efficiently hydrolyze phosphatidylinositol (1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol), PI), as well as a range of other glycerophospholipid substrates such as phosphatidylcholine (1,2-diacyl-sn-glycero-3-phosphocholine, PC), phosphatidylethanolamine (1,2-diacyl-sn-glycero-3-phosphoethanolamine, PE), phosphatidylserine (1,2-diacyl-sn-glycero-3-phospho-L-serine, PS) and phosphatidylglycerol (1,2-diacyl-sn-glycero-3-phospho-(1'-sn-glycerol), PG) (Probable). Involved in the regulation of the endogenous content of polyunsaturated PI and PS lipids in the nervous system. Changes in these lipids extend to downstream metabolic products like PI phosphates PIP and PIP2, which play fundamental roles in cell biology. Regulates mitochondrial morphology. These dynamic changes may be due to PA hydrolysis at the mitochondrial surface. May play a regulatory role in spermatogenesis or sperm function.
• Tissue Specificity: Highly expressed in testis. Also expressed in brain, spleen and lung. Only expressed in cerebellum in fetal brain.
• Reactome Pathway: Synthesis of PA (R-HSA-1483166)
• BioCyc Pathway: MetaCyc:ENSG00000100523-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hereditary spastic paraplegia	DISGZQV1	Definitive	Autosomal recessive	[1]
Hereditary spastic paraplegia 56	DISJLW1T	Definitive	Autosomal recessive	[2]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[3]
Colon cancer	DISVC52G	Strong	Biomarker	[4]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[4]
Hereditary spastic paraplegia 28	DISABM1Q	Strong	Autosomal recessive	[5]
Hypercholesterolemia, familial, 4	DISFLNLI	Strong	Genetic Variation	[6]
Inherited retinal dystrophy	DISGGL77	Strong	Genetic Variation	[7]
Neurodegeneration with brain iron accumulation	DISRK4DZ	Strong	Biomarker	[7]
Pure hereditary spastic paraplegia	DIS8X71E	Strong	Genetic Variation	[7]
Retinopathy	DISB4B0F	Strong	Biomarker	[7]
Vascular purpura	DIS6ZZMF	Strong	Biomarker	[8]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Warfarin	DMJYCVW	Approved	Phospholipase DDHD1 (DDHD1) affects the response to substance of Warfarin.	[19]

10 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 Phospholipase DDHD1 (DDHD1).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Phospholipase DDHD1 (DDHD1).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Phospholipase DDHD1 (DDHD1).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Phospholipase DDHD1 (DDHD1).	[12]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Phospholipase DDHD1 (DDHD1).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Phospholipase DDHD1 (DDHD1).	[14]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Phospholipase DDHD1 (DDHD1).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Phospholipase DDHD1 (DDHD1).	[16]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Phospholipase DDHD1 (DDHD1).	[17]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Phospholipase DDHD1 (DDHD1).	[18]

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] Mapping of a new form of pure autosomal recessive spastic paraplegia (SPG28). Ann Neurol. 2005 Apr;57(4):567-71. doi: 10.1002/ana.20416.
• [3] Recessive gene disruptions in autism spectrum disorder.Nat Genet. 2019 Jul;51(7):1092-1098. doi: 10.1038/s41588-019-0433-8. Epub 2019 Jun 17.
• [4] The phospholipase DDHD1 as a new target in colorectal cancer therapy.J Exp Clin Cancer Res. 2018 Apr 13;37(1):82. doi: 10.1186/s13046-018-0753-z.
• [5] Alteration of fatty-acid-metabolizing enzymes affects mitochondrial form and function in hereditary spastic paraplegia. Am J Hum Genet. 2012 Dec 7;91(6):1051-64. doi: 10.1016/j.ajhg.2012.11.001. Epub 2012 Nov 21.
• [6] Prevalent LIPH founder mutations lead to loss of P2Y5 activation ability of PA-PLA1alpha in autosomal recessive hypotrichosis.Hum Mutat. 2010 May;31(5):602-10. doi: 10.1002/humu.21235.
• [7] Mutations in DDHD1, encoding a phospholipase A1, is a novel cause of retinopathy and neurodegeneration with brain iron accumulation.Eur J Med Genet. 2017 Dec;60(12):639-642. doi: 10.1016/j.ejmg.2017.08.015. Epub 2017 Aug 14.
• [8] The Spastic Paraplegia-Associated Phospholipase DDHD1 Is a Primary Brain Phosphatidylinositol Lipase.Biochemistry. 2018 Oct 2;57(39):5759-5767. doi: 10.1021/acs.biochem.8b00810. Epub 2018 Sep 17.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] 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.
• [11] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [16] 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.
• [17] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [18] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [19] Genetic determinants of warfarin maintenance dose and time in therapeutic treatment range: a RE-LY genomics substudy. Pharmacogenomics. 2016 Aug;17(13):1425-39. doi: 10.2217/pgs-2016-0061. Epub 2016 Aug 4.