Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2PNKOP)

• DOT Name: Serine palmitoyltransferase small subunit A (SPTSSA)
• Synonyms: Small subunit of serine palmitoyltransferase A; ssSPTa
• Gene Name: SPTSSA
• Related Disease:
  Spastic paraplegia 90A, autosomal dominant
  Spastic paraplegia 90B, autosomal recessive
• UniProt ID: SPTSA_HUMAN
• PDB ID: 6M4N; 6M4O; 7CQI; 7CQK; 7K0I; 7K0J; 7K0K; 7K0L; 7K0M; 7K0N; 7K0O; 7K0P; 7K0Q; 7YIU; 7YIY; 7YJ1; 7YJ2
• Pfam ID: PF11779
• Sequence:
  MAGMALARAWKQMSWFYYQYLLVTALYMLEPWERTVFNSMLVSIVGMALYTGYVFMPQHI
  MAILHYFEIVQ
• Function: Component of the serine palmitoyltransferase multisubunit enzyme (SPT) that catalyzes the initial and rate-limiting step in sphingolipid biosynthesis by condensing L-serine and activated acyl-CoA (most commonly palmitoyl-CoA) to form long-chain bases. The SPT complex is composed of SPTLC1, SPTLC2 or SPTLC3 and SPTSSA or SPTSSB. Within this complex, the heterodimer consisting of SPTLC1 and SPTLC2/SPTLC3 forms the catalytic core. Within the SPT complex, SPTSSA stimulates the catalytic activity and plays a role in substrate specificity, which depends upon the overall complex composition. The SPTLC1-SPTLC2-SPTSSA complex shows a strong preference for C16-CoA substrate, while the SPTLC1-SPTLC3-SPTSSA isozyme uses both C14-CoA and C16-CoA as substrates, with a slight preference for C14-CoA. Independently of its action as a SPT component, may be involved in MBOAT7 localization to mitochondria-associated membranes, a membrane bridge between the endoplasmic reticulum and mitochondria, may hence affect MBOAT7-catalyzed incorporation of arachidonic acid into phosphatidylinositol.
• KEGG Pathway: Sphingolipid sig.ling pathway (hsa04071)
• Reactome Pathway: Sphingolipid de novo biosynthesis (R-HSA-1660661)
• BioCyc Pathway: MetaCyc:MONOMER66-34371

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Spastic paraplegia 90A, autosomal dominant	DISDYPQP	Strong	Autosomal dominant	[1]
Spastic paraplegia 90B, autosomal recessive	DISV2XDB	Limited	Unknown	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Etoposide	DMNH3PG	Approved	Serine palmitoyltransferase small subunit A (SPTSSA) affects the response to substance of Etoposide.	[15]

13 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 Serine palmitoyltransferase small subunit A (SPTSSA).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Serine palmitoyltransferase small subunit A (SPTSSA).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Serine palmitoyltransferase small subunit A (SPTSSA).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Serine palmitoyltransferase small subunit A (SPTSSA).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Serine palmitoyltransferase small subunit A (SPTSSA).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Serine palmitoyltransferase small subunit A (SPTSSA).	[7]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Serine palmitoyltransferase small subunit A (SPTSSA).	[8]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Serine palmitoyltransferase small subunit A (SPTSSA).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Serine palmitoyltransferase small subunit A (SPTSSA).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Serine palmitoyltransferase small subunit A (SPTSSA).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Serine palmitoyltransferase small subunit A (SPTSSA).	[12]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Serine palmitoyltransferase small subunit A (SPTSSA).	[13]
Resorcinol	DMM37C0	Investigative	Resorcinol increases the expression of Serine palmitoyltransferase small subunit A (SPTSSA).	[14]

References

• [1] SPTSSA variants alter sphingolipid synthesis and cause a complex hereditary spastic paraplegia. Brain. 2023 Apr 19;146(4):1420-1435. doi: 10.1093/brain/awac460.
• [2] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [3] 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.
• [4] 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.
• [5] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] 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.
• [9] Unique transcriptome, pathways, and networks in the human endometrial fibroblast response to progesterone in endometriosis. Biol Reprod. 2011 Apr;84(4):801-15.
• [10] 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.
• [11] 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.
• [12] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [13] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [14] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [15] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.