Details of Drug Off-Target (DOT)

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

• DOT Name: Bifunctional 3'-phosphoadenosine 5'-phosphosulfate synthase 2 (PAPSS2)
• Synonyms: PAPS synthase 2; PAPSS 2; Sulfurylase kinase 2; SK 2; SK2
• Gene Name: PAPSS2
• Related Disease:
  Non-insulin dependent diabetes
  Spondyloepimetaphyseal dysplasia, PAPSS2 type
  Brachyolmia
  Diastrophic dysplasia
  Knee osteoarthritis
  Osteoarthritis
  Polycystic ovarian syndrome
  Pyle disease
  Spondyloepimetaphyseal dysplasia
  Autosomal recessive brachyolmia
  Intellectual disability
  Osteochondrodysplasia
• UniProt ID: PAPS2_HUMAN
• PDB ID: 2AX4; 7FH3; 7FHA; 8I1N; 8I1O
• EC Number: 2.7.1.25; 2.7.7.4
• Pfam ID: PF01583 ; PF01747 ; PF14306
• Sequence:
  MSGIKKQKTENQQKSTNVVYQAHHVSRNKRGQVVGTRGGFRGCTVWLTGLSGAGKTTISF
  ALEEYLVSHAIPCYSLDGDNVRHGLNRNLGFSPGDREENIRRIAEVAKLFADAGLVCITS
  FISPFAKDRENARKIHESAGLPFFEIFVDAPLNICESRDVKGLYKRARAGEIKGFTGIDS
  DYEKPETPERVLKTNLSTVSDCVHQVVELLQEQNIVPYTIIKDIHELFVPENKLDHVRAE
  AETLPSLSITKLDLQWVQVLSEGWATPLKGFMREKEYLQVMHFDTLLDDGVINMSIPIVL
  PVSAEDKTRLEGCSKFVLAHGGRRVAILRDAEFYEHRKEERCSRVWGTTCTKHPHIKMVM
  ESGDWLVGGDLQVLEKIRWNDGLDQYRLTPLELKQKCKEMNADAVFAFQLRNPVHNGHAL
  LMQDTRRRLLERGYKHPVLLLHPLGGWTKDDDVPLDWRMKQHAAVLEEGVLDPKSTIVAI
  FPSPMLYAGPTEVQWHCRSRMIAGANFYIVGRDPAGMPHPETKKDLYEPTHGGKVLSMAP
  GLTSVEIIPFRVAAYNKAKKAMDFYDPARHNEFDFISGTRMRKLAREGENPPDGFMAPKA
  WKVLTDYYRSLEKN
• Function: Bifunctional enzyme with both ATP sulfurylase and APS kinase activity, which mediates two steps in the sulfate activation pathway. The first step is the transfer of a sulfate group to ATP to yield adenosine 5'-phosphosulfate (APS), and the second step is the transfer of a phosphate group from ATP to APS yielding 3'-phosphoadenylylsulfate/PAPS, the activated sulfate donor used by sulfotransferases. In mammals, PAPS is the sole source of sulfate while APS appears to only be an intermediate in the sulfate-activation pathway. Plays indirectly an important role in skeletogenesis during postnatal growth.
• Tissue Specificity: Expressed in cartilage and adrenal gland.
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Selenocompound metabolism (hsa00450)
  Sulfur metabolism (hsa00920)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Metabolism of ingested H2SeO4 and H2SeO3 into H2Se (R-HSA-2408550)
  Defective PAPSS2 causes SEMD-PA (R-HSA-3560796)
  Transport and synthesis of PAPS (R-HSA-174362)
• BioCyc Pathway: MetaCyc:HS07544-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Altered Expression	[1]
Spondyloepimetaphyseal dysplasia, PAPSS2 type	DIS3GE3I	Definitive	Autosomal recessive	[2]
Brachyolmia	DISK6FWF	Strong	Biomarker	[3]
Diastrophic dysplasia	DISNTGP7	Strong	Genetic Variation	[4]
Knee osteoarthritis	DISLSNBJ	Strong	Genetic Variation	[4]
Osteoarthritis	DIS05URM	Strong	Genetic Variation	[5]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Genetic Variation	[6]
Pyle disease	DISJ2YQ3	Strong	Genetic Variation	[2]
Spondyloepimetaphyseal dysplasia	DISO4L5A	Strong	Genetic Variation	[7]
Autosomal recessive brachyolmia	DISCS189	Supportive	Autosomal recessive	[2]
Intellectual disability	DISMBNXP	Limited	Biomarker	[7]
Osteochondrodysplasia	DIS9SPWW	Limited	Biomarker	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Bifunctional 3'-phosphoadenosine 5'-phosphosulfate synthase 2 (PAPSS2).	[9]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Bifunctional 3'-phosphoadenosine 5'-phosphosulfate synthase 2 (PAPSS2).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Bifunctional 3'-phosphoadenosine 5'-phosphosulfate synthase 2 (PAPSS2).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Bifunctional 3'-phosphoadenosine 5'-phosphosulfate synthase 2 (PAPSS2).	[12]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Bifunctional 3'-phosphoadenosine 5'-phosphosulfate synthase 2 (PAPSS2).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Bifunctional 3'-phosphoadenosine 5'-phosphosulfate synthase 2 (PAPSS2).	[14]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Bifunctional 3'-phosphoadenosine 5'-phosphosulfate synthase 2 (PAPSS2).	[15]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Bifunctional 3'-phosphoadenosine 5'-phosphosulfate synthase 2 (PAPSS2).	[16]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of Bifunctional 3'-phosphoadenosine 5'-phosphosulfate synthase 2 (PAPSS2).	[17]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Bifunctional 3'-phosphoadenosine 5'-phosphosulfate synthase 2 (PAPSS2).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Bifunctional 3'-phosphoadenosine 5'-phosphosulfate synthase 2 (PAPSS2).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Bifunctional 3'-phosphoadenosine 5'-phosphosulfate synthase 2 (PAPSS2).	[20]
PMID27336223-Compound-5	DM6E50A	Patented	PMID27336223-Compound-5 increases the expression of Bifunctional 3'-phosphoadenosine 5'-phosphosulfate synthase 2 (PAPSS2).	[17]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Bifunctional 3'-phosphoadenosine 5'-phosphosulfate synthase 2 (PAPSS2).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Bifunctional 3'-phosphoadenosine 5'-phosphosulfate synthase 2 (PAPSS2).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Bifunctional 3'-phosphoadenosine 5'-phosphosulfate synthase 2 (PAPSS2).	[23]

References

• [1] Metformin regulates atrial SK2 and SK3 expression through inhibiting the PKC/ERK signaling pathway in type 2 diabetic rats.BMC Cardiovasc Disord. 2018 Dec 13;18(1):236. doi: 10.1186/s12872-018-0950-x.
• [2] PAPSS2 mutations cause autosomal recessive brachyolmia. J Med Genet. 2012 Aug;49(8):533-8. doi: 10.1136/jmedgenet-2012-101039. Epub 2012 Jul 11.
• [3] PAPSS2-related brachyolmia: Clinical and radiological phenotype in 18 new cases.Am J Med Genet A. 2019 Sep;179(9):1884-1894. doi: 10.1002/ajmg.a.61282. Epub 2019 Jul 16.
• [4] Identification of sequence polymorphisms in two sulfation-related genes, PAPSS2 and SLC26A2, and an association analysis with knee osteoarthritis.J Hum Genet. 2001;46(9):538-43. doi: 10.1007/s100380170036.
• [5] The osteoarthritis-associated gene PAPSS2 promotes differentiation and matrix formation in ATDC5 chondrogenic cells.Exp Ther Med. 2018 Dec;16(6):5190-5200. doi: 10.3892/etm.2018.6843. Epub 2018 Oct 11.
• [6] PAPSS2 deficiency causes androgen excess via impaired DHEA sulfation--in vitro and in vivo studies in a family harboring two novel PAPSS2 mutations.J Clin Endocrinol Metab. 2015 Apr;100(4):E672-80. doi: 10.1210/jc.2014-3556. Epub 2015 Jan 16.
• [7] Exclusion of the dymeclin and PAPSS2 genes in a novel form of spondyloepimetaphyseal dysplasia and mental retardation.Eur J Hum Genet. 2005 May;13(5):541-6. doi: 10.1038/sj.ejhg.5201339.
• [8] Human 3'-phosphoadenosine 5'-phosphosulfate (PAPS) synthase: biochemistry, molecular biology and genetic deficiency.IUBMB Life. 2003 Jan;55(1):1-11. doi: 10.1080/1521654031000072148.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [11] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [12] 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.
• [13] Epidermal growth factor receptor signalling in human breast cancer cells operates parallel to estrogen receptor alpha signalling and results in tamoxifen insensitive proliferation. BMC Cancer. 2014 Apr 23;14:283.
• [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] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [16] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [17] 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.
• [18] A high concentration of genistein down-regulates activin A, Smad3 and other TGF-beta pathway genes in human uterine leiomyoma cells. Exp Mol Med. 2012 Apr 30;44(4):281-92.
• [19] 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.
• [20] 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.
• [21] Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides. J Biol Chem. 2018 Apr 13;293(15):5600-5612.
• [22] Comparison of transcriptome expression alterations by chronic exposure to low-dose bisphenol A in different subtypes of breast cancer cells. Toxicol Appl Pharmacol. 2019 Dec 15;385:114814. doi: 10.1016/j.taap.2019.114814. Epub 2019 Nov 9.
• [23] 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.