Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZC5XP9)

• DOT Name: Sperm-associated antigen 8 (SPAG8)
• Synonyms: HSD-1; Sperm membrane protein 1; SMP-1; Sperm membrane protein BS-84
• Gene Name: SPAG8
• Related Disease:
  Metabolic disorder
  Acromesomelic dysplasia 1, Maroteaux type
  Bone osteosarcoma
  Breast cancer
  Breast carcinoma
  Carcinoma
  Leprosy
  Osteosarcoma
  Tall stature-scoliosis-macrodactyly of the great toes syndrome
  Amyotrophic lateral sclerosis
  Frontotemporal dementia
  Obesity
  Pick disease
  Temporal lobe epilepsy
• UniProt ID: SPAG8_HUMAN
• PDB ID: 7UNG; 8J07
• Sequence:
  METNESTEGSRSRSRSLDIQPSSEGLGPTSEPFPSSDDSPRSALAAATAAAAAAASAAAA
  TAAFTTAKAAALSTKTPAPCSEFMEPSSDPSLLGEPCAGPGFTHNIAHGSLGFEPVYVSC
  IAQDTCTTTDHSSNPGPVPGSSSGPVLGSSSGAGHGSGSGSGPGCGSVPGSGSGPGPGSG
  PGSGPGHGSGSHPGPASGPGPDTGPDSELSPCIPPGFRNLVADRVPNYTSWSQHCPWEPQ
  KQPPWEFLQVLEPGARGLWKPPDIKGKLMVCYETLPRGQCLLYNWEEERATNHLDQVPSM
  QDGSESFFFRHGHRGLLTMQLKSPMPSSTTQKDSYQPPGNVYWPLRGKREAMLEMLLQHQ
  ICKEVQAEQEPTRKLFEVESVTHHDYRMELAQAGTPAPTKPHDYRQEQPETFWIQRAPQL
  PGVSNIRTLDTPFRKNCSFSTPVPLSLGKLLPYEPENYPYQLGEISSLPCPGGRLGGGGG
  RMTPF
• Function: Microtubule inner protein (MIP) part of the dynein-decorated doublet microtubules (DMTs) in cilia axoneme, which is required for motile cilia beating. Plays a role in spermatogenesis by enhancing the binding of CREM isoform tau to its coactivator FHL5 and increasing the FHL5-regulated transcriptional activation of CREM isoform tau. Involved in the acrosome reaction and in binding of sperm to the zona pellucida. Plays a role in regulation of the cell cycle by controlling progression through the G2/M phase, possibly by delaying the activation of CDK1 which is required for entry into mitosis. May play a role in fertility and microtubule formation through interaction with RANBP9.
• Tissue Specificity: Expressed in testis (germ cells), but not in liver, kidney, prostate and small intestine. Expressed in airway epithelial cells .

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Metabolic disorder	DIS71G5H	Definitive	Altered Expression	[1]
Acromesomelic dysplasia 1, Maroteaux type	DISGIJPF	Strong	Genetic Variation	[2]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[4]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[4]
Carcinoma	DISH9F1N	Strong	Altered Expression	[5]
Leprosy	DISAA4UI	Strong	Altered Expression	[6]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[3]
Tall stature-scoliosis-macrodactyly of the great toes syndrome	DISSOGO0	Strong	Genetic Variation	[2]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Genetic Variation	[7]
Frontotemporal dementia	DISKYHXL	Limited	Genetic Variation	[7]
Obesity	DIS47Y1K	Limited	Altered Expression	[8]
Pick disease	DISP6X50	Limited	Genetic Variation	[7]
Temporal lobe epilepsy	DISNOPXX	Limited	Altered Expression	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Sperm-associated antigen 8 (SPAG8).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Sperm-associated antigen 8 (SPAG8).	[11]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of Sperm-associated antigen 8 (SPAG8).	[12]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Sperm-associated antigen 8 (SPAG8).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Sperm-associated antigen 8 (SPAG8).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Sperm-associated antigen 8 (SPAG8).	[14]

References

• [1] Expression of the mRNA coding for 11beta-hydroxysteroid dehydrogenase type 1 in adipose tissue from obese patients: an in situ hybridization study.J Clin Endocrinol Metab. 2002 Jun;87(6):2701-5. doi: 10.1210/jcem.87.6.8614.
• [2] Mutations in the transmembrane natriuretic peptide receptor NPR-B impair skeletal growth and cause acromesomelic dysplasia, type Maroteaux. Am J Hum Genet. 2004 Jul;75(1):27-34. doi: 10.1086/422013. Epub 2004 May 14.
• [3] Characterization of 11beta-hydroxysteroid dehydrogenase activity and corticosteroid receptor expression in human osteosarcoma cell lines.J Endocrinol. 1999 Jun;161(3):455-64. doi: 10.1677/joe.0.1610455.
• [4] Quantitative analysis of aromatase, sulfatase and 17beta-HSD(1) mRNA expression in soft tissue metastases of breast cancer.Cancer Lett. 2006 Nov 8;243(1):23-31. doi: 10.1016/j.canlet.2005.11.010. Epub 2006 Mar 23.
• [5] Estrogen-metabolizing enzymes in breast cancers from women over the age of 80 years.J Clin Endocrinol Metab. 2006 Feb;91(2):607-13. doi: 10.1210/jc.2005-1967. Epub 2005 Nov 22.
• [6] Cortisol and proinflammatory cytokine profiles in type 1 (reversal) reactions of leprosy.Immunol Lett. 2013 Nov-Dec;156(1-2):159-67. doi: 10.1016/j.imlet.2013.10.008. Epub 2013 Nov 1.
• [7] Whole-genome sequencing reveals a coding non-pathogenic variant tagging a non-coding pathogenic hexanucleotide repeat expansion in C9orf72 as cause of amyotrophic lateral sclerosis.Hum Mol Genet. 2012 Jun 1;21(11):2412-9. doi: 10.1093/hmg/dds055. Epub 2012 Feb 17.
• [8] Overexpression of 11beta-hydroxysteroid dehydrogenase-1 in adipose tissue is associated with acquired obesity and features of insulin resistance: studies in young adult monozygotic twins.J Clin Endocrinol Metab. 2004 Sep;89(9):4414-21. doi: 10.1210/jc.2004-0153.
• [9] Expression of mRNAs encoding for 17beta-hydroxisteroid dehydrogenase isozymes 1, 2, 3 and 4 in epileptic human hippocampus.Epilepsy Res. 2000 Aug;41(1):83-91. doi: 10.1016/s0920-1211(00)00130-3.
• [10] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [11] 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.
• [12] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [15] 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.