Details of Drug Off-Target (DOT)

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

• DOT Name: NAD-dependent protein deacylase sirtuin-5, mitochondrial (SIRT5)
• Synonyms: EC 2.3.1.-; Regulatory protein SIR2 homolog 5; SIR2-like protein 5
• Gene Name: SIRT5
• UniProt ID: SIR5_HUMAN
• PDB ID: 2B4Y; 2NYR; 3RIG; 3RIY; 4F4U; 4F56; 4G1C; 4HDA; 5BWL; 5XHS; 6ACE; 6ACL; 6ACO; 6ACP; 6EQS; 6LJK; 6LJM; 6LJN; 7X3P
• EC Number: 2.3.1.-
• Pfam ID: PF02146
• Sequence:
  MRPLQIVPSRLISQLYCGLKPPASTRNQICLKMARPSSSMADFRKFFAKAKHIVIISGAG
  VSAESGVPTFRGAGGYWRKWQAQDLATPLAFAHNPSRVWEFYHYRREVMGSKEPNAGHRA
  IAECETRLGKQGRRVVVITQNIDELHRKAGTKNLLEIHGSLFKTRCTSCGVVAENYKSPI
  CPALSGKGAPEPGTQDASIPVEKLPRCEEAGCGGLLRPHVVWFGENLDPAILEEVDRELA
  HCDLCLVVGTSSVVYPAAMFAPQVAARGVPVAEFNTETTPATNRFRFHFQGPCGTTLPEA
  LACHENETVS
• Function: NAD-dependent lysine demalonylase, desuccinylase and deglutarylase that specifically removes malonyl, succinyl and glutaryl groups on target proteins. Activates CPS1 and contributes to the regulation of blood ammonia levels during prolonged fasting: acts by mediating desuccinylation and deglutarylation of CPS1, thereby increasing CPS1 activity in response to elevated NAD levels during fasting. Activates SOD1 by mediating its desuccinylation, leading to reduced reactive oxygen species. Activates SHMT2 by mediating its desuccinylation. Modulates ketogenesis through the desuccinylation and activation of HMGCS2. Has weak NAD-dependent protein deacetylase activity; however this activity may not be physiologically relevant in vivo. Can deacetylate cytochrome c (CYCS) and a number of other proteins in vitro such as UOX.
• Tissue Specificity: Widely expressed.
• KEGG Pathway:
  Nicoti.te and nicoti.mide metabolism (hsa00760)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Transcriptional activation of mitochondrial biogenesis (R-HSA-2151201)

Molecular Interaction Atlas (MIA) of This DOT

9 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 NAD-dependent protein deacylase sirtuin-5, mitochondrial (SIRT5).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of NAD-dependent protein deacylase sirtuin-5, mitochondrial (SIRT5).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of NAD-dependent protein deacylase sirtuin-5, mitochondrial (SIRT5).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of NAD-dependent protein deacylase sirtuin-5, mitochondrial (SIRT5).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of NAD-dependent protein deacylase sirtuin-5, mitochondrial (SIRT5).	[5]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of NAD-dependent protein deacylase sirtuin-5, mitochondrial (SIRT5).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of NAD-dependent protein deacylase sirtuin-5, mitochondrial (SIRT5).	[7]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of NAD-dependent protein deacylase sirtuin-5, mitochondrial (SIRT5).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of NAD-dependent protein deacylase sirtuin-5, mitochondrial (SIRT5).	[5]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] 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.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Genome-Wide Analysis of Low Dose Bisphenol-A (BPA) Exposure in Human Prostate Cells. Curr Genomics. 2019 May;20(4):260-274. doi: 10.2174/1389202920666190603123040.
• [6] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [7] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [8] 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.