Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOSW67J)

• DOT Name: Lipoyl synthase, mitochondrial (LIAS)
• Synonyms: EC 2.8.1.8; Lipoate synthase; LS; Lip-syn; Lipoic acid synthase
• Gene Name: LIAS
• Related Disease:
  Cardiac failure
  Cardiomyopathy
  Congestive heart failure
  Epilepsy
  Glycine encephalopathy
  Lipoic acid synthetase deficiency
  Metabolic disorder
  Neuromuscular disease
  Systemic sclerosis
  Type-1/2 diabetes
  Leigh syndrome
  Neoplasm
  Non-insulin dependent diabetes
  Peutz-Jeghers syndrome
• UniProt ID: LIAS_HUMAN
• EC Number: 2.8.1.8
• Pfam ID: PF16881 ; PF04055
• Sequence:
  MSLRCGDAARTLGPRVFGRYFCSPVRPLSSLPDKKKELLQNGPDLQDFVSGDLADRSTWD
  EYKGNLKRQKGERLRLPPWLKTEIPMGKNYNKLKNTLRNLNLHTVCEEARCPNIGECWGG
  GEYATATATIMLMGDTCTRGCRFCSVKTARNPPPLDASEPYNTAKAIAEWGLDYVVLTSV
  DRDDMPDGGAEHIAKTVSYLKERNPKILVECLTPDFRGDLKAIEKVALSGLDVYAHNVET
  VPELQSKVRDPRANFDQSLRVLKHAKKVQPDVISKTSIMLGLGENDEQVYATMKALREAD
  VDCLTLGQYMQPTRRHLKVEEYITPEKFKYWEKVGNELGFHYTASGPLVRSSYKAGEFFL
  KNLVAKRKTKDL
• Function: Catalyzes the radical-mediated insertion of two sulfur atoms into the C-6 and C-8 positions of the octanoyl moiety bound to the lipoyl domains of lipoate-dependent enzymes, thereby converting the octanoylated domains into lipoylated derivatives.
• KEGG Pathway:
  Lipoic acid metabolism (hsa00785)
  Metabolic pathways (hsa01100)
  Biosynthesis of cofactors (hsa01240)
• Reactome Pathway: Glyoxylate metabolism and glycine degradation (R-HSA-389661)
• BioCyc Pathway: MetaCyc:HS04528-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cardiac failure	DISDC067	Strong	Biomarker	[1]
Cardiomyopathy	DISUPZRG	Strong	Genetic Variation	[2]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[1]
Epilepsy	DISBB28L	Strong	Altered Expression	[3]
Glycine encephalopathy	DISI2XE5	Strong	Genetic Variation	[4]
Lipoic acid synthetase deficiency	DIS2EAEZ	Strong	Autosomal recessive	[5]
Metabolic disorder	DIS71G5H	Strong	Altered Expression	[3]
Neuromuscular disease	DISQTIJZ	Strong	Biomarker	[6]
Systemic sclerosis	DISF44L6	Strong	Biomarker	[7]
Type-1/2 diabetes	DISIUHAP	Strong	Altered Expression	[3]
Leigh syndrome	DISWQU45	Limited	Autosomal recessive	[8]
Neoplasm	DISZKGEW	Limited	Biomarker	[9]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Altered Expression	[10]
Peutz-Jeghers syndrome	DISF27ZJ	Limited	Biomarker	[11]

6 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 Lipoyl synthase, mitochondrial (LIAS).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Lipoyl synthase, mitochondrial (LIAS).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Lipoyl synthase, mitochondrial (LIAS).	[14]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Lipoyl synthase, mitochondrial (LIAS).	[15]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Lipoyl synthase, mitochondrial (LIAS).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Lipoyl synthase, mitochondrial (LIAS).	[17]

References

• [1] Left Atrial Dynamics During Exercise in Mitral Regurgitation of Primary and Secondary Origin: Pathophysiological Insights by Exercise Echocardiography Combined With Gas Exchange Analysis.JACC Cardiovasc Imaging. 2020 Jan;13(1 Pt 1):25-40. doi: 10.1016/j.jcmg.2018.12.031. Epub 2019 Mar 13.
• [2] Lipoic acid biosynthesis defects. J Inherit Metab Dis. 2014 Jul;37(4):553-63. doi: 10.1007/s10545-014-9705-8. Epub 2014 Apr 29.
• [3] Homology modeling of Homo sapiens lipoic acid synthase: Substrate docking and insights on its binding mode.J Theor Biol. 2017 May 7;420:259-266. doi: 10.1016/j.jtbi.2016.09.005. Epub 2016 Oct 5.
• [4] Biallelic Mutations in LIPT2 Cause a Mitochondrial Lipoylation Defect Associated with Severe Neonatal Encephalopathy.Am J Hum Genet. 2017 Aug 3;101(2):283-290. doi: 10.1016/j.ajhg.2017.07.001. Epub 2017 Jul 27.
• [5] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [6] LAS: Sizing of expanded trinucleotide repeats with femtomolar sensitivity in less than 5minutes.Sci Rep. 2019 Jan 10;9(1):23. doi: 10.1038/s41598-018-36632-5.
• [7] Lipoic acid plays a role in scleroderma: insights obtained from scleroderma dermal fibroblasts.Arthritis Res Ther. 2014;16(5):411. doi: 10.1186/s13075-014-0411-6.
• [8] 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.
• [9] EWSR1 genetic rearrangements in salivary gland tumors: a specific and very common feature of hyalinizing clear cell carcinoma.Am J Surg Pathol. 2013 Apr;37(4):571-8. doi: 10.1097/PAS.0b013e3182772a15.
• [10] Lipoic acid synthase (LASY): a novel role in inflammation, mitochondrial function, and insulin resistance.Diabetes. 2009 Mar;58(3):600-8. doi: 10.2337/db08-0473. Epub 2008 Dec 15.
• [11] Search for the second Peutz-Jeghers syndrome locus: exclusion of the STK13, PRKCG, KLK10, and PSCD2 genes on chromosome 19 and the STK11IP gene on chromosome 2.Cytogenet Genome Res. 2002;97(3-4):171-8. doi: 10.1159/000066620.
• [12] 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.
• [13] 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.
• [14] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [15] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [16] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [17] 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.