Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVLWW9T)

• DOT Name: Glycerol-3-phosphate dehydrogenase 1-like protein (GPD1L)
• Synonyms: GPD1-L; EC 1.1.1.8
• Gene Name: GPD1L
• Related Disease:
  Arrhythmia
  Atrial fibrillation
  Cardiac failure
  Congestive heart failure
  Fatty liver disease
  Head-neck squamous cell carcinoma
  Obesity
  Osteoarthritis
  Brugada syndrome 1
  Conduction system disorder
  Sinoatrial node disorder
  Brugada syndrome 2
  Coronary atherosclerosis
  Coronary heart disease
• UniProt ID: GPD1L_HUMAN
• PDB ID: 2PLA
• EC Number: 1.1.1.8
• Pfam ID: PF07479 ; PF01210
• Sequence:
  MAAAPLKVCIVGSGNWGSAVAKIIGNNVKKLQKFASTVKMWVFEETVNGRKLTDIINNDH
  ENVKYLPGHKLPENVVAMSNLSEAVQDADLLVFVIPHQFIHRICDEITGRVPKKALGITL
  IKGIDEGPEGLKLISDIIREKMGIDISVLMGANIANEVAAEKFCETTIGSKVMENGLLFK
  ELLQTPNFRITVVDDADTVELCGALKNIVAVGAGFCDGLRCGDNTKAAVIRLGLMEMIAF
  ARIFCKGQVSTATFLESCGVADLITTCYGGRNRRVAEAFARTGKTIEELEKEMLNGQKLQ
  GPQTSAEVYRILKQKGLLDKFPLFTAVYQICYESRPVQEMLSCLQSHPEHT
• Function: Plays a role in regulating cardiac sodium current; decreased enzymatic activity with resulting increased levels of glycerol 3-phosphate activating the DPD1L-dependent SCN5A phosphorylation pathway, may ultimately lead to decreased sodium current; cardiac sodium current may also be reduced due to alterations of NAD(H) balance induced by DPD1L.
• Tissue Specificity: Most highly expressed in heart tissue, with lower levels in the skeletal muscle, kidney, lung and other organs.
• KEGG Pathway: Glycerophospholipid metabolism (hsa00564)
• Reactome Pathway: Synthesis of PA (R-HSA-1483166)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arrhythmia	DISFF2NI	Strong	Altered Expression	[1]
Atrial fibrillation	DIS15W6U	Strong	Genetic Variation	[2]
Cardiac failure	DISDC067	Strong	Biomarker	[3]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[3]
Fatty liver disease	DIS485QZ	Strong	Biomarker	[4]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Altered Expression	[5]
Obesity	DIS47Y1K	Strong	Biomarker	[6]
Osteoarthritis	DIS05URM	moderate	Biomarker	[7]
Brugada syndrome 1	DISKBA7V	Disputed	Autosomal dominant	[8]
Conduction system disorder	DISED5HG	Disputed	Biomarker	[3]
Sinoatrial node disorder	DISYJI6J	Disputed	Biomarker	[3]
Brugada syndrome 2	DIS21MGL	Limited	Unknown	[9]
Coronary atherosclerosis	DISKNDYU	Limited	Genetic Variation	[10]
Coronary heart disease	DIS5OIP1	Limited	Biomarker	[10]

17 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 Glycerol-3-phosphate dehydrogenase 1-like protein (GPD1L).	[11]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Glycerol-3-phosphate dehydrogenase 1-like protein (GPD1L).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Glycerol-3-phosphate dehydrogenase 1-like protein (GPD1L).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Glycerol-3-phosphate dehydrogenase 1-like protein (GPD1L).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Glycerol-3-phosphate dehydrogenase 1-like protein (GPD1L).	[15]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Glycerol-3-phosphate dehydrogenase 1-like protein (GPD1L).	[16]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Glycerol-3-phosphate dehydrogenase 1-like protein (GPD1L).	[17]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Glycerol-3-phosphate dehydrogenase 1-like protein (GPD1L).	[18]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Glycerol-3-phosphate dehydrogenase 1-like protein (GPD1L).	[19]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Glycerol-3-phosphate dehydrogenase 1-like protein (GPD1L).	[19]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Glycerol-3-phosphate dehydrogenase 1-like protein (GPD1L).	[20]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Glycerol-3-phosphate dehydrogenase 1-like protein (GPD1L).	[21]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Glycerol-3-phosphate dehydrogenase 1-like protein (GPD1L).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Glycerol-3-phosphate dehydrogenase 1-like protein (GPD1L).	[22]
PMID27336223-Compound-5	DM6E50A	Patented	PMID27336223-Compound-5 decreases the expression of Glycerol-3-phosphate dehydrogenase 1-like protein (GPD1L).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Glycerol-3-phosphate dehydrogenase 1-like protein (GPD1L).	[23]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Glycerol-3-phosphate dehydrogenase 1-like protein (GPD1L).	[24]

References

• [1] Whole-exome sequencing identifies a novel mutation of GPD1L (R189X) associated with familial conduction disease and sudden death.J Cell Mol Med. 2018 Feb;22(2):1350-1354. doi: 10.1111/jcmm.13409. Epub 2017 Oct 27.
• [2] Functional consequences of genetic variation in sodium channel modifiers in early onset lone atrial fibrillation.Per Med. 2018 Mar;15(2):93-102. doi: 10.2217/pme-2017-0076. Epub 2018 Jan 31.
• [3] GPD1L links redox state to cardiac excitability by PKC-dependent phosphorylation of the sodium channel SCN5A.Am J Physiol Heart Circ Physiol. 2009 Oct;297(4):H1446-52. doi: 10.1152/ajpheart.00513.2009. Epub 2009 Aug 7.
• [4] Characterization of chemically induced liver injuries using gene co-expression modules.PLoS One. 2014 Sep 16;9(9):e107230. doi: 10.1371/journal.pone.0107230. eCollection 2014.
• [5] The prognostic value of glycerol-3-phosphate dehydrogenase 1-like expression in head and neck squamous cell carcinoma.Histopathology. 2014 Feb;64(3):348-55. doi: 10.1111/his.12258. Epub 2013 Nov 26.
• [6] A Systems Genetics Approach Identified GPD1L and its Molecular Mechanism for Obesity in Human Adipose Tissue.Sci Rep. 2017 May 11;7(1):1799. doi: 10.1038/s41598-017-01517-6.
• [7] miR-181a Modulates Chondrocyte Apoptosis by Targeting Glycerol-3-Phosphate Dehydrogenase 1-Like Protein (GPD1L) in Osteoarthritis.Med Sci Monit. 2017 Mar 10;23:1224-1231. doi: 10.12659/msm.899228.
• [8] 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.
• [9] 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.
• [10] Common variants in CASQ2, GPD1L, and NOS1AP are significantly associated with risk of sudden death in patients with coronary artery disease.Circ Cardiovasc Genet. 2011 Aug 1;4(4):397-402. doi: 10.1161/CIRCGENETICS.111.959916. Epub 2011 Jun 17.
• [11] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [12] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [13] 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.
• [14] 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.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [17] 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.
• [18] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [19] 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.
• [20] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [21] PPARgamma controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells. J Exp Med. 2006 Oct 2;203(10):2351-62.
• [22] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [23] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [24] 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.