Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTK3EJFD)

• DOT Name: Sterol-4-alpha-carboxylate 3-dehydrogenase, decarboxylating (NSDHL)
• Synonyms: EC 1.1.1.170; Protein H105e3
• Gene Name: NSDHL
• Related Disease:
  CHILD syndrome
  CK syndrome
  Chondrodysplasia punctata
  Head-neck squamous cell carcinoma
  Incontinentia pigmenti
  X-linked chondrodysplasia punctata
  X-linked chondrodysplasia punctata 2
  Intellectual disability
  Melanocytic nevus
• UniProt ID: NSDHL_HUMAN
• PDB ID: 6JKG; 6JKH
• EC Number: 1.1.1.170
• Pfam ID: PF01073
• Sequence:
  MEPAVSEPMRDQVARTHLTEDTPKVNADIEKVNQNQAKRCTVIGGSGFLGQHMVEQLLAR
  GYAVNVFDIQQGFDNPQVRFFLGDLCSRQDLYPALKGVNTVFHCASPPPSSNNKELFYRV
  NYIGTKNVIETCKEAGVQKLILTSSASVIFEGVDIKNGTEDLPYAMKPIDYYTETKILQE
  RAVLGANDPEKNFLTTAIRPHGIFGPRDPQLVPILIEAARNGKMKFVIGNGKNLVDFTFV
  ENVVHGHILAAEQLSRDSTLGGKAFHITNDEPIPFWTFLSRILTGLNYEAPKYHIPYWVA
  YYLALLLSLLVMVISPVIQLQPTFTPMRVALAGTFHYYSCERAKKAMGYQPLVTMDDAME
  RTVQSFRHLRRVK
• Function: Catalyzes the NAD(P)(+)-dependent oxidative decarboxylation of the C4 methyl groups of 4-alpha-carboxysterols in post-squalene cholesterol biosynthesis. Also plays a role in the regulation of the endocytic trafficking of EGFR.
• Tissue Specificity: Brain, heart, liver, lung, kidney, skin and placenta.
• KEGG Pathway:
  Steroid biosynthesis (hsa00100)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Cholesterol biosynthesis (R-HSA-191273)
• BioCyc Pathway: MetaCyc:HS07423-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
CHILD syndrome	DIS9F5U7	Definitive	X-linked	[1]
CK syndrome	DISN95GO	Definitive	X-linked	[2]
Chondrodysplasia punctata	DISERVGO	Strong	Biomarker	[3]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Biomarker	[4]
Incontinentia pigmenti	DIS0ALLE	Strong	Biomarker	[5]
X-linked chondrodysplasia punctata	DISU9RLP	Strong	Biomarker	[3]
X-linked chondrodysplasia punctata 2	DISI20G2	Strong	Genetic Variation	[6]
Intellectual disability	DISMBNXP	moderate	Genetic Variation	[7]
Melanocytic nevus	DISYS32D	Disputed	Genetic Variation	[1]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Dasatinib	DMJV2EK	Approved	Sterol-4-alpha-carboxylate 3-dehydrogenase, decarboxylating (NSDHL) decreases the response to substance of Dasatinib.	[4]
LY294002	DMY1AFS	Phase 1	Sterol-4-alpha-carboxylate 3-dehydrogenase, decarboxylating (NSDHL) decreases the response to substance of LY294002.	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Sterol-4-alpha-carboxylate 3-dehydrogenase, decarboxylating (NSDHL).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Sterol-4-alpha-carboxylate 3-dehydrogenase, decarboxylating (NSDHL).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Sterol-4-alpha-carboxylate 3-dehydrogenase, decarboxylating (NSDHL).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Sterol-4-alpha-carboxylate 3-dehydrogenase, decarboxylating (NSDHL).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Sterol-4-alpha-carboxylate 3-dehydrogenase, decarboxylating (NSDHL).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Sterol-4-alpha-carboxylate 3-dehydrogenase, decarboxylating (NSDHL).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Sterol-4-alpha-carboxylate 3-dehydrogenase, decarboxylating (NSDHL).	[14]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Sterol-4-alpha-carboxylate 3-dehydrogenase, decarboxylating (NSDHL).	[15]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Sterol-4-alpha-carboxylate 3-dehydrogenase, decarboxylating (NSDHL).	[16]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Sterol-4-alpha-carboxylate 3-dehydrogenase, decarboxylating (NSDHL).	[17]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Sterol-4-alpha-carboxylate 3-dehydrogenase, decarboxylating (NSDHL).	[18]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Sterol-4-alpha-carboxylate 3-dehydrogenase, decarboxylating (NSDHL).	[19]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Sterol-4-alpha-carboxylate 3-dehydrogenase, decarboxylating (NSDHL).	[20]
Fluoxetine	DM3PD2C	Approved	Fluoxetine increases the expression of Sterol-4-alpha-carboxylate 3-dehydrogenase, decarboxylating (NSDHL).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Sterol-4-alpha-carboxylate 3-dehydrogenase, decarboxylating (NSDHL).	[23]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Sterol-4-alpha-carboxylate 3-dehydrogenase, decarboxylating (NSDHL).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Sterol-4-alpha-carboxylate 3-dehydrogenase, decarboxylating (NSDHL).	[25]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Sterol-4-alpha-carboxylate 3-dehydrogenase, decarboxylating (NSDHL).	[26]
PP-242	DM2348V	Investigative	PP-242 decreases the expression of Sterol-4-alpha-carboxylate 3-dehydrogenase, decarboxylating (NSDHL).	[27]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Sterol-4-alpha-carboxylate 3-dehydrogenase, decarboxylating (NSDHL).	[22]

References

• [1] Mutations in the NSDHL gene, encoding a 3beta-hydroxysteroid dehydrogenase, cause CHILD syndrome. Am J Med Genet. 2000 Feb 14;90(4):339-46.
• [2] Characterization of a new X-linked mental retardation syndrome with microcephaly, cortical malformation, and thin habitus. Am J Med Genet A. 2009 Nov;149A(11):2469-78. doi: 10.1002/ajmg.a.33071.
• [3] Placental defects are associated with male lethality in bare patches and striated embryos deficient in the NAD(P)H Steroid Dehydrogenase-like (NSDHL) Enzyme.Mol Genet Metab. 2005 Jan;84(1):48-60. doi: 10.1016/j.ymgme.2004.08.007.
• [4] Targeting C4-demethylating genes in the cholesterol pathway sensitizes cancer cells to EGF receptor inhibitors via increased EGF receptor degradation. Cancer Discov. 2013 Jan;3(1):96-111. doi: 10.1158/2159-8290.CD-12-0031. Epub 2012 Nov 2.
• [5] The Str mouse as a model for incontinentia pigmenti.Pflugers Arch. 2000;440(5 Suppl):R53-4.
• [6] Male CDPX2 patient with EBP mosaicism and asymmetrically lateralized skin lesions with strict midline demarcation.Am J Med Genet A. 2019 Jul;179(7):1315-1318. doi: 10.1002/ajmg.a.61159. Epub 2019 Apr 29.
• [7] Hypomorphic temperature-sensitive alleles of NSDHL cause CK syndrome. Am J Hum Genet. 2010 Dec 10;87(6):905-14. doi: 10.1016/j.ajhg.2010.11.004.
• [8] 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.
• [9] 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.
• [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] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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] Proteomics-based identification of differentially abundant proteins from human keratinocytes exposed to arsenic trioxide. J Proteomics Bioinform. 2014 Jul;7(7):166-178.
• [16] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [17] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [18] Coordinate up-regulation of TMEM97 and cholesterol biosynthesis genes in normal ovarian surface epithelial cells treated with progesterone: implications for pathogenesis of ovarian cancer. BMC Cancer. 2007 Dec 11;7:223.
• [19] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [20] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [21] Screening autism-associated environmental factors in differentiating human neural progenitors with fractional factorial design-based transcriptomics. Sci Rep. 2023 Jun 29;13(1):10519. doi: 10.1038/s41598-023-37488-0.
• [22] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [23] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [24] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [25] 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.
• [26] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [27] Marine biogenics in sea spray aerosols interact with the mTOR signaling pathway. Sci Rep. 2019 Jan 24;9(1):675.
• [28] Targeting C4-demethylating genes in the cholesterol pathway sensitizes cancer cells to EGF receptor inhibitors via increased EGF receptor degradation. Cancer Discov. 2013 Jan;3(1):96-111. doi: 10.1158/2159-8290.CD-12-0031. Epub 2012 Nov 2.