Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCIES3H)

• DOT Name: 3-ketodihydrosphingosine reductase (KDSR)
• Synonyms: KDS reductase; EC 1.1.1.102; 3-dehydrosphinganine reductase; Follicular variant translocation protein 1; FVT-1; Short chain dehydrogenase/reductase family 35C member 1
• Gene Name: KDSR
• Related Disease:
  Erythrokeratodermia variabilis et progressiva 4
  Advanced cancer
  B-cell lymphoma
  B-cell neoplasm
  Classic Hodgkin lymphoma
  Erythrokeratoderma
  Fatty liver disease
  Inherited bleeding disorder, platelet-type
  Skin disease
  Spinal muscular atrophy
  Thrombocytopenia
  Follicular lymphoma
  Erythrokeratodermia variabilis
  Clear cell renal carcinoma
• UniProt ID: KDSR_HUMAN
• EC Number: 1.1.1.102
• Pfam ID: PF00106
• Sequence:
  MLLLAAAFLVAFVLLLYMVSPLISPKPLALPGAHVVVTGGSSGIGKCIAIECYKQGAFIT
  LVARNEDKLLQAKKEIEMHSINDKQVVLCISVDVSQDYNQVENVIKQAQEKLGPVDMLVN
  CAGMAVSGKFEDLEVSTFERLMSINYLGSVYPSRAVITTMKERRVGRIVFVSSQAGQLGL
  FGFTAYSASKFAIRGLAEALQMEVKPYNVYITVAYPPDTDTPGFAEENRTKPLETRLISE
  TTSVCKPEQVAKQIVKDAIQGNFNSSLGSDGYMLSALTCGMAPVTSITEGLQQVVTMGLF
  RTIALFYLGSFDSIVRRCMMQREKSENADKTA
• Function: Catalyzes the reduction of 3-ketodihydrosphingosine (KDS) to dihydrosphingosine (DHS).
• Tissue Specificity: Expressed in all tissues examined. Highest expression in placenta. High expression in lung, kidney, stomach and small intestine, low expression in heart, spleen and skeletal muscle. Weakly expressed in normal hematopoietic tissues. Higher expression in some T-cell malignancies and PHA-stimulated lymphocytes.
• KEGG Pathway:
  Sphingolipid metabolism (hsa00600)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Sphingolipid de novo biosynthesis (R-HSA-1660661)
• BioCyc Pathway: MetaCyc:HS04306-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Erythrokeratodermia variabilis et progressiva 4	DISOWXAN	Definitive	Autosomal recessive	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
B-cell lymphoma	DISIH1YQ	Strong	Altered Expression	[3]
B-cell neoplasm	DISVY326	Strong	Altered Expression	[3]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Biomarker	[3]
Erythrokeratoderma	DISQGG08	Strong	Genetic Variation	[4]
Fatty liver disease	DIS485QZ	Strong	Genetic Variation	[5]
Inherited bleeding disorder, platelet-type	DISIUNXT	Strong	Biomarker	[4]
Skin disease	DISDW8R6	Strong	Genetic Variation	[6]
Spinal muscular atrophy	DISTLKOB	Strong	Genetic Variation	[7]
Thrombocytopenia	DISU61YW	Strong	Genetic Variation	[6]
Follicular lymphoma	DISVEUR6	moderate	Biomarker	[8]
Erythrokeratodermia variabilis	DIS4BMUQ	Supportive	Autosomal dominant	[4]
Clear cell renal carcinoma	DISBXRFJ	Limited	Biomarker	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	3-ketodihydrosphingosine reductase (KDSR) increases the response to substance of Doxorubicin.	[23]

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 3-ketodihydrosphingosine reductase (KDSR).	[10]

12 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 3-ketodihydrosphingosine reductase (KDSR).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of 3-ketodihydrosphingosine reductase (KDSR).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of 3-ketodihydrosphingosine reductase (KDSR).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of 3-ketodihydrosphingosine reductase (KDSR).	[14]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of 3-ketodihydrosphingosine reductase (KDSR).	[15]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of 3-ketodihydrosphingosine reductase (KDSR).	[16]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of 3-ketodihydrosphingosine reductase (KDSR).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of 3-ketodihydrosphingosine reductase (KDSR).	[18]
SB-431542	DM0YOXQ	Preclinical	SB-431542 increases the expression of 3-ketodihydrosphingosine reductase (KDSR).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of 3-ketodihydrosphingosine reductase (KDSR).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of 3-ketodihydrosphingosine reductase (KDSR).	[21]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of 3-ketodihydrosphingosine reductase (KDSR).	[22]

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] FVT-1, a novel human transcription unit affected by variant translocation t(2;18)(p11;q21) of follicular lymphoma.Blood. 1993 Jan 1;81(1):136-42.
• [3] Expression of the follicular lymphoma variant translocation 1 gene in diffuse large B-cell lymphoma correlates with subtype and clinical outcome.Am J Clin Pathol. 2008 Dec;130(6):957-62. doi: 10.1309/AJCP12HIRWSRQLAN.
• [4] Mutations in KDSR Cause Recessive Progressive Symmetric Erythrokeratoderma. Am J Hum Genet. 2017 Jun 1;100(6):978-984. doi: 10.1016/j.ajhg.2017.05.003.
• [5] 3-ketodihydrosphingosine reductase mutation induces steatosis and hepatic injury in zebrafish.Sci Rep. 2019 Feb 4;9(1):1138. doi: 10.1038/s41598-018-37946-0.
• [6] Sphingolipid dysregulation due to lack of functional KDSR impairs proplatelet formation causing thrombocytopenia.Haematologica. 2019 May;104(5):1036-1045. doi: 10.3324/haematol.2018.204784. Epub 2018 Nov 22.
• [7] A missense mutation in the 3-ketodihydrosphingosine reductase FVT1 as candidate causal mutation for bovine spinal muscular atrophy.Proc Natl Acad Sci U S A. 2007 Apr 17;104(16):6746-51. doi: 10.1073/pnas.0607721104. Epub 2007 Apr 9.
• [8] Towards a systematic analysis of human short-chain dehydrogenases/reductases (SDR): Ligand identification and structure-activity relationships. Chem Biol Interact. 2015 Jun 5;234:114-25.
• [9] Decreased SPTLC1 expression predicts worse outcomes in ccRCC patients.J Cell Biochem. 2020 Feb;121(2):1552-1562. doi: 10.1002/jcb.29390. Epub 2019 Sep 12.
• [10] 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.
• [11] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [12] 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.
• [13] 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.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [16] 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.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] 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.
• [19] Activin/nodal signaling switches the terminal fate of human embryonic stem cell-derived trophoblasts. J Biol Chem. 2015 Apr 3;290(14):8834-48.
• [20] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [21] 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.
• [22] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
• [23] cDNA microarray analysis of isogenic paclitaxel- and doxorubicin-resistant breast tumor cell lines reveals distinct drug-specific genetic signatures of resistance. Breast Cancer Res Treat. 2006 Mar;96(1):17-39. doi: 10.1007/s10549-005-9026-6. Epub 2005 Dec 2.