Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT29JZKW)

• DOT Name: Sperm-associated antigen 1 (SPAG1)
• Synonyms: HSD-3.8; Infertility-related sperm protein Spag-1
• Gene Name: SPAG1
• Related Disease:
  Primary ciliary dyskinesia 28
  Neoplasm
  Pancreatic adenocarcinoma
  Primary ciliary dyskinesia 1
  Visceral leishmaniasis
  Primary ciliary dyskinesia
• UniProt ID: SPAG1_HUMAN
• PDB ID: 6I57; 7BEV
• Pfam ID: PF13877 ; PF00515 ; PF13181
• Sequence:
  MTTKDYPSLWGFGTTKTFKIPIEHLDFKYIEKCSDVKHLEKILCVLRSGEEGYYPELTEF
  CEKHLQALAPESRALRKDKPAATAASFTAEEWEKIDGDIKSWVSEIKKEEDKMHFHETET
  FPAMKDNLPPVRGSNSCLHVGKEKYSKRPTKKKTPRDYAEWDKFDVEKECLKIDEDYKEK
  TVIDKSHLSKIETRIDTAGLTEKEKDFLATREKEKGNEAFNSGDYEEAVMYYTRSISALP
  TVVAYNNRAQAEIKLQNWNSAFQDCEKVLELEPGNVKALLRRATTYKHQNKLREATEDLS
  KVLDVEPDNDLAKKTLSEVERDLKNSEAASETQTKGKRMVIQEIENSEDEEGKSGRKHED
  GGGDKKPAEPAGAARAAQPCVMGNIQKKLTGKAEGGKRPARGAPQRGQTPEAGADKRSPR
  RASAAAAAGGGATGHPGGGQGAENPAGLKSQGNELFRSGQFAEAAGKYSAAIALLEPAGS
  EIADDLSILYSNRAACYLKEGNCSGCIQDCNRALELHPFSMKPLLRRAMAYETLEQYGKA
  YVDYKTVLQIDCGLQLANDSVNRLSRILMELDGPNWREKLSPIPAVPASVPLQAWHPAKE
  MISKQAGDSSSHRQQGITDEKTFKALKEEGNQCVNDKNYKDALSKYSECLKINNKECAIY
  TNRALCYLKLCQFEEAKQDCDQALQLADGNVKAFYRRALAHKGLKNYQKSLIDLNKVILL
  DPSIIEAKMELEEVTRLLNLKDKTAPFNKEKERRKIEIQEVNEGKEEPGRPAGEVSMGCL
  ASEKGGKSSRSPEDPEKLPIAKPNNAYEFGQIINALSTRKDKEACAHLLAITAPKDLPMF
  LSNKLEGDTFLLLIQSLKNNLIEKDPSLVYQHLLYLSKAERFKMMLTLISKGQKELIEQL
  FEDLSDTPNNHFTLEDIQALKRQYEL
• Function: May play a role in the cytoplasmic assembly of the ciliary dynein arms. May play a role in fertilization. Binds GTP and has GTPase activity.
• Tissue Specificity: Present in most tissues, including lung, with the strongest expression in brain, colon, kidney, and testis. In sperm and testis, detected in particular in pachytene primary spermatocytes. Up-regulated in pancreatic tumor tissues and not in normal pancreatic tissue.

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Primary ciliary dyskinesia 28	DIS5SGZ9	Definitive	Autosomal recessive	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Pancreatic adenocarcinoma	DISKHX7S	Strong	Biomarker	[2]
Primary ciliary dyskinesia 1	DISPGX6H	Strong	GermlineCausalMutation	[3]
Visceral leishmaniasis	DISTKEYK	Strong	Biomarker	[4]
Primary ciliary dyskinesia	DISOBC7V	Supportive	Autosomal dominant	[3]

15 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 Sperm-associated antigen 1 (SPAG1).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Sperm-associated antigen 1 (SPAG1).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Sperm-associated antigen 1 (SPAG1).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Sperm-associated antigen 1 (SPAG1).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Sperm-associated antigen 1 (SPAG1).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Sperm-associated antigen 1 (SPAG1).	[10]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Sperm-associated antigen 1 (SPAG1).	[11]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Sperm-associated antigen 1 (SPAG1).	[12]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Sperm-associated antigen 1 (SPAG1).	[13]
Mifepristone	DMGZQEF	Approved	Mifepristone increases the expression of Sperm-associated antigen 1 (SPAG1).	[14]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Sperm-associated antigen 1 (SPAG1).	[15]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Sperm-associated antigen 1 (SPAG1).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Sperm-associated antigen 1 (SPAG1).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Sperm-associated antigen 1 (SPAG1).	[19]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Sperm-associated antigen 1 (SPAG1).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Sperm-associated antigen 1 (SPAG1).	[18]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid decreases the phosphorylation of Sperm-associated antigen 1 (SPAG1).	[21]

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] Sperm-associated antigen 1 is expressed early in pancreatic tumorigenesis and promotes motility of cancer cells.Oncogene. 2007 Mar 8;26(11):1533-45. doi: 10.1038/sj.onc.1209961. Epub 2006 Sep 18.
• [3] Mutations in SPAG1 cause primary ciliary dyskinesia associated with defective outer and inner dynein arms. Am J Hum Genet. 2013 Oct 3;93(4):711-20. doi: 10.1016/j.ajhg.2013.07.025. Epub 2013 Sep 19.
• [4] Recombinant small glutamine-rich tetratricopeptide repeat-containing protein of Leishmania infantum: Potential vaccine and diagnostic application against visceral leishmaniasis.Mol Immunol. 2017 Nov;91:272-281. doi: 10.1016/j.molimm.2017.09.017. Epub 2017 Oct 5.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] 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.
• [7] 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.
• [8] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [9] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [10] 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.
• [11] 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.
• [12] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [13] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [14] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [15] 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.
• [16] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [17] 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.
• [18] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [19] 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.
• [20] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [21] Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.