Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMEF544)

• DOT Name: NAD-dependent protein deacetylase sirtuin-3, mitochondrial (SIRT3)
• Synonyms: hSIRT3; EC 2.3.1.286; Regulatory protein SIR2 homolog 3; SIR2-like protein 3
• Gene Name: SIRT3
• UniProt ID: SIR3_HUMAN
• PDB ID: 3GLR ; 3GLS ; 3GLT ; 3GLU ; 4BN4 ; 4BN5 ; 4BV3 ; 4BVB ; 4BVE ; 4BVF ; 4BVG ; 4BVH ; 4C78 ; 4C7B ; 4FVT ; 4FZ3 ; 4HD8 ; 4JSR ; 4JT8 ; 4JT9 ; 4O8Z ; 5BWN ; 5BWO ; 5D7N ; 5H4D ; 5Y4H ; 5YTK ; 5Z93 ; 5Z94 ; 5ZGC ; 6ISO ; 8ANC ; 8BBK ; 8CCW ; 8CCZ ; 8HLW ; 8HLY ; 8HN9 ; 8V15 ; 8V2N
• EC Number: 2.3.1.286
• Pfam ID: PF02146
• Sequence:
  MAFWGWRAAAALRLWGRVVERVEAGGGVGPFQACGCRLVLGGRDDVSAGLRGSHGARGEP
  LDPARPLQRPPRPEVPRAFRRQPRAAAPSFFFSSIKGGRRSISFSVGASSVVGSGGSSDK
  GKLSLQDVAELIRARACQRVVVMVGAGISTPSGIPDFRSPGSGLYSNLQQYDLPYPEAIF
  ELPFFFHNPKPFFTLAKELYPGNYKPNVTHYFLRLLHDKGLLLRLYTQNIDGLERVSGIP
  ASKLVEAHGTFASATCTVCQRPFPGEDIRADVMADRVPRCPVCTGVVKPDIVFFGEPLPQ
  RFLLHVVDFPMADLLLILGTSLEVEPFASLTEAVRSSVPRLLINRDLVGPLAWHPRSRDV
  AQLGDVVHGVESLVELLGWTEEMRDLVQRETGKLDGPDK
• Function: NAD-dependent protein deacetylase. Activates or deactivates mitochondrial target proteins by deacetylating key lysine residues. Known targets include ACSS1, IDH, GDH, SOD2, PDHA1, LCAD, SDHA and the ATP synthase subunit ATP5PO. Contributes to the regulation of the cellular energy metabolism. Important for regulating tissue-specific ATP levels. In response to metabolic stress, deacetylates transcription factor FOXO3 and recruits FOXO3 and mitochondrial RNA polymerase POLRMT to mtDNA to promote mtDNA transcription. Acts as a regulator of ceramide metabolism by mediating deacetylation of ceramide synthases CERS1, CERS2 and CERS6, thereby increasing their activity and promoting mitochondrial ceramide accumulation. Regulates hepatic lipogenesis. Uses NAD(+) substrate imported by SLC25A47, triggering downstream activation of PRKAA1/AMPK-alpha signaling cascade that ultimately downregulates sterol regulatory element-binding protein (SREBP) transcriptional activities and ATP-consuming lipogenesis to restore cellular energy balance.
• Tissue Specificity: Widely expressed.
• KEGG Pathway:
  Nicoti.te and nicoti.mide metabolism (hsa00760)
  Metabolic pathways (hsa01100)
  Central carbon metabolism in cancer (hsa05230)
• Reactome Pathway:
  FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes (R-HSA-9615017)
  Regulation of FOXO transcriptional activity by acetylation (R-HSA-9617629)
  Transcriptional activation of mitochondrial biogenesis (R-HSA-2151201)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	NAD-dependent protein deacetylase sirtuin-3, mitochondrial (SIRT3) decreases the response to substance of Cisplatin.	[20]
PJ34	DMXO6YH	Preclinical	NAD-dependent protein deacetylase sirtuin-3, mitochondrial (SIRT3) increases the response to substance of PJ34.	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of NAD-dependent protein deacetylase sirtuin-3, mitochondrial (SIRT3).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of NAD-dependent protein deacetylase sirtuin-3, mitochondrial (SIRT3).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of NAD-dependent protein deacetylase sirtuin-3, mitochondrial (SIRT3).	[2]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of NAD-dependent protein deacetylase sirtuin-3, mitochondrial (SIRT3).	[3]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of NAD-dependent protein deacetylase sirtuin-3, mitochondrial (SIRT3).	[4]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of NAD-dependent protein deacetylase sirtuin-3, mitochondrial (SIRT3).	[5]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of NAD-dependent protein deacetylase sirtuin-3, mitochondrial (SIRT3).	[6]
Stavudine	DM6DEK9	Approved	Stavudine increases the expression of NAD-dependent protein deacetylase sirtuin-3, mitochondrial (SIRT3).	[6]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of NAD-dependent protein deacetylase sirtuin-3, mitochondrial (SIRT3).	[8]
Berberine	DMC5Q8X	Phase 4	Berberine decreases the expression of NAD-dependent protein deacetylase sirtuin-3, mitochondrial (SIRT3).	[9]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of NAD-dependent protein deacetylase sirtuin-3, mitochondrial (SIRT3).	[10]
SEN-196	DMLDBQ5	Phase 2	SEN-196 decreases the activity of NAD-dependent protein deacetylase sirtuin-3, mitochondrial (SIRT3).	[11]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of NAD-dependent protein deacetylase sirtuin-3, mitochondrial (SIRT3).	[13]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of NAD-dependent protein deacetylase sirtuin-3, mitochondrial (SIRT3).	[14]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid decreases the expression of NAD-dependent protein deacetylase sirtuin-3, mitochondrial (SIRT3).	[15]
D-glucose	DMMG2TO	Investigative	D-glucose increases the expression of NAD-dependent protein deacetylase sirtuin-3, mitochondrial (SIRT3).	[16]
Linalool	DMGZQ5P	Investigative	Linalool decreases the expression of NAD-dependent protein deacetylase sirtuin-3, mitochondrial (SIRT3).	[17]
MANGOSTIN	DMYQGDV	Investigative	MANGOSTIN increases the expression of NAD-dependent protein deacetylase sirtuin-3, mitochondrial (SIRT3).	[18]
Propanoic Acid	DM9TN2W	Investigative	Propanoic Acid increases the expression of NAD-dependent protein deacetylase sirtuin-3, mitochondrial (SIRT3).	[19]

2 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Hesperetin	DMKER83	Approved	Hesperetin affects the binding of NAD-dependent protein deacetylase sirtuin-3, mitochondrial (SIRT3).	[7]
Chloroquine	DMSI5CB	Phase 3 Trial	Chloroquine increases the stability of NAD-dependent protein deacetylase sirtuin-3, mitochondrial (SIRT3).	[5]

References

• [1] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [2] 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.
• [3] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [4] SIRT3 Mediates the Antioxidant Effect of Hydrogen Sulfide in Endothelial Cells. Antioxid Redox Signal. 2016 Feb 20;24(6):329-43. doi: 10.1089/ars.2015.6331. Epub 2015 Nov 10.
• [5] Effects of SIDT2 on the miR-25/NOX4/HuR axis and SIRT3 mRNA stability lead to ROS-mediated TNF- expression in hydroquinone-treated leukemia cells. Cell Biol Toxicol. 2023 Oct;39(5):2207-2225. doi: 10.1007/s10565-022-09705-5. Epub 2022 Mar 18.
• [6] Lon protease and eiF2 are involved in acute, but not prolonged, antiretroviral induced stress response in HepG2 cells. Chem Biol Interact. 2016 May 25;252:82-6. doi: 10.1016/j.cbi.2016.03.021. Epub 2016 Apr 1.
• [7] Various concentrations of hesperetin induce different types of programmed cell death in human breast cancerous and normal cell lines in a ROS-dependent manner. Chem Biol Interact. 2023 Sep 1;382:110642. doi: 10.1016/j.cbi.2023.110642. Epub 2023 Jul 23.
• [8] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [9] Concurrent acetylation of FoxO1/3a and p53 due to sirtuins inhibition elicit Bim/PUMA mediated mitochondrial dysfunction and apoptosis in berberine-treated HepG2 cells. Toxicol Appl Pharmacol. 2016 Jan 15;291:70-83. doi: 10.1016/j.taap.2015.12.006. Epub 2015 Dec 19.
• [10] Resveratrol inhibits growth of orthotopic pancreatic tumors through activation of FOXO transcription factors. PLoS One. 2011;6(9):e25166. doi: 10.1371/journal.pone.0025166. Epub 2011 Sep 27.
• [11] Sirtuins are Unaffected by PARP Inhibitors Containing Planar Nicotinamide Bioisosteres. Chem Biol Drug Des. 2016 Mar;87(3):478-82. doi: 10.1111/cbdd.12680. Epub 2015 Nov 26.
• [12] 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.
• [13] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [14] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [15] Downregulation of sirtuin 3 by palmitic acid increases the oxidative stress, impairment of mitochondrial function, and apoptosis in liver cells. J Biochem Mol Toxicol. 2019 Aug;33(8):e22337. doi: 10.1002/jbt.22337. Epub 2019 Apr 8.
• [16] SIRT3 overexpression antagonizes high glucose accelerated cellular senescence in human diploid fibroblasts via the SIRT3-FOXO1 signaling pathway. Age (Dordr). 2013 Dec;35(6):2237-53.
• [17] SIRT3-SOD2-ROS pathway is involved in linalool-induced glioma cell apoptotic death. Acta Biochim Pol. 2017;64(2):343-350. doi: 10.18388/abp.2016_1438. Epub 2017 Jun 2.
• [18] -Mangostin alleviates liver fibrosis through Sirtuin 3-superoxide-high mobility group box 1 signaling axis. Toxicol Appl Pharmacol. 2019 Jan 15;363:142-153. doi: 10.1016/j.taap.2018.11.011. Epub 2018 Nov 29.
• [19] Propionic acid induces mitochondrial dysfunction and affects gene expression for mitochondria biogenesis and neuronal differentiation in SH-SY5Y cell line. Neurotoxicology. 2019 Dec;75:116-122. doi: 10.1016/j.neuro.2019.09.009. Epub 2019 Sep 14.
• [20] Sirtuin-3 (SIRT3), a novel potential therapeutic target for oral cancer. Cancer. 2011 Apr 15;117(8):1670-8. doi: 10.1002/cncr.25676. Epub 2010 Nov 29.
• [21] Poly(ADP-ribose) polymerase 1 contributes to oxidative stress through downregulation of sirtuin 3 during cisplatin nephrotoxicity. Anat Cell Biol. 2016 Sep;49(3):165-176. doi: 10.5115/acb.2016.49.3.165. Epub 2016 Sep 29.