Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUP0WHF)

• DOT Name: Phospholipase DDHD2 (DDHD2)
• Synonyms: EC 3.1.1.-; DDHD domain-containing protein 2; KIAA0725p; SAM, WWE and DDHD domain-containing protein 1
• Gene Name: DDHD2
• Related Disease:
  GM1 gangliosidosis
  Hereditary spastic paraplegia 54
  Nervous system disease
  Breast cancer
  Breast carcinoma
  Intellectual disability
  Obesity
  Spastic ataxia
  Vascular purpura
  Hereditary spastic paraplegia
• UniProt ID: DDHD2_HUMAN
• EC Number: 3.1.1.-
• Pfam ID: PF02862 ; PF00536 ; PF02825
• Sequence:
  MSSVQSQQEQLSQSDPSPSPNSCSSFELIDMDAGSLYEPVSPHWFYCKIIDSKETWIPFN
  SEDSQQLEEAYSSGKGCNGRVVPTDGGRYDVHLGERMRYAVYWDELASEVRRCTWFYKGD
  KDNKYVPYSESFSQVLEETYMLAVTLDEWKKKLESPNREIIILHNPKLMVHYQPVAGSDD
  WGSTPTEQGRPRTVKRGVENISVDIHCGEPLQIDHLVFVVHGIGPACDLRFRSIVQCVND
  FRSVSLNLLQTHFKKAQENQQIGRVEFLPVNWHSPLHSTGVDVDLQRITLPSINRLRHFT
  NDTILDVFFYNSPTYCQTIVDTVASEMNRIYTLFLQRNPDFKGGVSIAGHSLGSLILFDI
  LTNQKDSLGDIDSEKDSLNIVMDQGDTPTLEEDLKKLQLSEFFDIFEKEKVDKEALALCT
  DRDLQEIGIPLGPRKKILNYFSTRKNSMGIKRPAPQPASGANIPKESEFCSSSNTRNGDY
  LDVGIGQVSVKYPRLIYKPEIFFAFGSPIGMFLTVRGLKRIDPNYRFPTCKGFFNIYHPF
  DPVAYRIEPMVVPGVEFEPMLIPHHKGRKRMHLELREGLTRMSMDLKNNLLGSLRMAWKS
  FTRAPYPALQASETPEETEAEPESTSEKPSDVNTEETSVAVKEEVLPINVGMLNGGQRID
  YVLQEKPIESFNEYLFALQSHLCYWESEDTVLLVLKEIYQTQGIFLDQPLQ
• Function: Phospholipase that hydrolyzes preferentially phosphatidic acid, including 1,2-dioleoyl-sn-phosphatidic acid, and phosphatidylethanolamine. Specifically binds to phosphatidylinositol 3-phosphate (PI(3)P), phosphatidylinositol 4-phosphate (PI(4)P), phosphatidylinositol 5-phosphate (PI(5)P) and possibly phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2). May be involved in the maintenance of the endoplasmic reticulum and/or Golgi structures. May regulate the transport between Golgi apparatus and plasma membrane.
• Tissue Specificity: Widely expressed (at protein level).
• Reactome Pathway: Synthesis of PA (R-HSA-1483166)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
GM1 gangliosidosis	DISN3L2M	Definitive	Genetic Variation	[1]
Hereditary spastic paraplegia 54	DIS2AY6F	Definitive	Autosomal recessive	[2]
Nervous system disease	DISJ7GGT	Definitive	Genetic Variation	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[5]
Obesity	DIS47Y1K	Strong	CausalMutation	[5]
Spastic ataxia	DISIRRA9	Strong	Biomarker	[5]
Vascular purpura	DIS6ZZMF	Strong	Biomarker	[6]
Hereditary spastic paraplegia	DISGZQV1	moderate	Genetic Variation	[6]

1 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 Phospholipase DDHD2 (DDHD2).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Phospholipase DDHD2 (DDHD2).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Phospholipase DDHD2 (DDHD2).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Phospholipase DDHD2 (DDHD2).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Phospholipase DDHD2 (DDHD2).	[11]

References

• [1] Defining the genetic basis of early onset hereditary spastic paraplegia using whole genome sequencing.Neurogenetics. 2016 Oct;17(4):265-270. doi: 10.1007/s10048-016-0495-z. Epub 2016 Sep 28.
• [2] Mutations in DDHD2, encoding an intracellular phospholipase A(1), cause a recessive form of complex hereditary spastic paraplegia. Am J Hum Genet. 2012 Dec 7;91(6):1073-81. doi: 10.1016/j.ajhg.2012.10.017. Epub 2012 Nov 21.
• [3] Loss of DDHD2, whose mutation causes spastic paraplegia, promotes reactive oxygen species generation and apoptosis.Cell Death Dis. 2018 Jul 23;9(8):797. doi: 10.1038/s41419-018-0815-3.
• [4] miR-503 represses human cell proliferation and directly targets the oncogene DDHD2 by non-canonical target pairing.BMC Genomics. 2015 Feb 5;16(1):40. doi: 10.1186/s12864-015-1279-9.
• [5] Late-onset spastic ataxia phenotype in a patient with a homozygous DDHD2 mutation.Sci Rep. 2014 Nov 24;4:7132. doi: 10.1038/srep07132.
• [6] Defining the clinical-genetic and neuroradiological features in SPG54: description of eight additional cases and nine novel DDHD2 variants.J Neurol. 2019 Nov;266(11):2657-2664. doi: 10.1007/s00415-019-09466-y. Epub 2019 Jul 13.
• [7] 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.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.