Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9IJLX7)

• DOT Name: Polyprenol reductase (SRD5A3)
• Synonyms: EC 1.3.1.94; 3-oxo-5-alpha-steroid 4-dehydrogenase 3; EC 1.3.1.22; Steroid 5-alpha-reductase 2-like; Steroid 5-alpha-reductase 3; S5AR 3; SR type 3
• Gene Name: SRD5A3
• Related Disease: SRD5A3-congenital disorder of glycosylation
• UniProt ID: PORED_HUMAN
• EC Number: 1.3.1.22; 1.3.1.94
• Pfam ID: PF02544
• Sequence:
  MAPWAEAEHSALNPLRAVWLTLTAAFLLTLLLQLLPPGLLPGCAIFQDLIRYGKTKCGEP
  SRPAACRAFDVPKRYFSHFYIISVLWNGFLLWCLTQSLFLGAPFPSWLHGLLRILGAAQF
  QGGELALSAFLVLVFLWLHSLRRLFECLYVSVFSNVMIHVVQYCFGLVYYVLVGLTVLSQ
  VPMDGRNAYITGKNLLMQARWFHILGMMMFIWSSAHQYKCHVILGNLRKNKAGVVIHCNH
  RIPFGDWFEYVSSPNYLAELMIYVSMAVTFGFHNLTWWLVVTNVFFNQALSAFLSHQFYK
  SKFVSYPKHRKAFLPFLF
• Function: Plays a key role in early steps of protein N-linked glycosylation by being required for the conversion of polyprenol into dolichol. Dolichols are required for the synthesis of dolichol-linked monosaccharides and the oligosaccharide precursor used for N-glycosylation. Acts as a polyprenol reductase that promotes the reduction of the alpha-isoprene unit of polyprenols into dolichols in a NADP-dependent mechanism. Also able to convert testosterone (T) into 5-alpha-dihydrotestosterone (DHT).
• Tissue Specificity: Expressed in preadipocytes (at protein level) . Overexpressed in hormone-refractory prostate cancers (HRPC). Almost no or little expression in normal adult organs.
• KEGG Pathway:
  Steroid hormone biosynthesis (hsa00140)
  N-Glycan biosynthesis (hsa00510)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Synthesis of Dolichyl-phosphate (R-HSA-446199)
  Defective SRD5A3 causes SRD5A3-CDG, KHRZ (R-HSA-4755579)
  Androgen biosynthesis (R-HSA-193048)
• BioCyc Pathway: MetaCyc:HS13249-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
SRD5A3-congenital disorder of glycosylation	DISGHPPC	Definitive	Autosomal recessive	[1]

21 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 Polyprenol reductase (SRD5A3).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Polyprenol reductase (SRD5A3).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Polyprenol reductase (SRD5A3).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Polyprenol reductase (SRD5A3).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Polyprenol reductase (SRD5A3).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Polyprenol reductase (SRD5A3).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Polyprenol reductase (SRD5A3).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Polyprenol reductase (SRD5A3).	[9]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Polyprenol reductase (SRD5A3).	[10]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Polyprenol reductase (SRD5A3).	[8]
Cidofovir	DMA13GD	Approved	Cidofovir decreases the expression of Polyprenol reductase (SRD5A3).	[8]
Ifosfamide	DMCT3I8	Approved	Ifosfamide decreases the expression of Polyprenol reductase (SRD5A3).	[8]
Clodronate	DM9Y6X7	Approved	Clodronate decreases the expression of Polyprenol reductase (SRD5A3).	[8]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Polyprenol reductase (SRD5A3).	[11]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Polyprenol reductase (SRD5A3).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Polyprenol reductase (SRD5A3).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Polyprenol reductase (SRD5A3).	[14]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Polyprenol reductase (SRD5A3).	[15]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Polyprenol reductase (SRD5A3).	[16]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN increases the expression of Polyprenol reductase (SRD5A3).	[17]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE decreases the expression of Polyprenol reductase (SRD5A3).	[18]

References

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• [9] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [10] 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.
• [11] Identification of a group of brominated flame retardants as novel androgen receptor antagonists and potential neuronal and endocrine disrupters. Environ Int. 2015 Jan;74:60-70.
• [12] Quantitative proteomics and transcriptomics addressing the estrogen receptor subtype-mediated effects in T47D breast cancer cells exposed to the phytoestrogen genistein. Mol Cell Proteomics. 2011 Jan;10(1):M110.002170.
• [13] 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.
• [14] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [15] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [16] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.
• [17] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.
• [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.