Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2KCI00)

• DOT Name: Lipoyl amidotransferase LIPT1, mitochondrial (LIPT1)
• Synonyms: EC 2.3.1.200; Lipoate biosynthesis protein; Lipoate-protein ligase; Lipoyl ligase; Lipoyltransferase 1; EC 2.3.1.-
• Gene Name: LIPT1
• Related Disease:
  Glycine encephalopathy
  Inborn error of metabolism
  Infantile epileptic-dyskinetic encephalopathy
  Lactic acidosis
  Lipoyl transferase 1 deficiency
  Pyruvate dehydrogenase complex deficiency
  Leigh syndrome
  Obsolete Leigh syndrome with leukodystrophy
• UniProt ID: LIPT_HUMAN
• EC Number: 2.3.1.-; 2.3.1.200
• Sequence:
  MLIPFSMKNCFQLLCNCQVPAAGFKKTVKNGLILQSISNDVYQNLAVEDWIHDHMNLEGK
  PILFFWQNSPSVVIGRHQNPWQECNLNLMREEGIKLARRRSGGGTVYHDMGNINLTFFTT
  KKKYDRMENLKLIVRALNAVQPQLDVQATKRFDLLLDGQFKISGTASKIGRTTAYHHCTL
  LCSTDGTFLSSLLKSPYQGIRSNATASIPSLVKNLLEKDPTLTCEVLMNAVATEYAAYHQ
  IDNHIHLINPTDETLFPGINSKAKELQTWEWIYGKTPKFSINTSFHVLYEQSHLEIKVFI
  DIKNGRIEICNIEAPDHWLPLEIRDKLNSSLIGSKFCPTETTMLTNILLRTCPQDHKLNS
  KWNILCEKIKGIM
• Function: Lipoyl amidotransferase that catalyzes the transfer of lipoyl moieties from lipoyl-protein H of the glycine cleavage system (lipoyl-GCSH) to E2 subunits of the pyruvate dehydrogenase complex (PDCE2). Unable to catalyze the transfer of octanoyl from octanoyl-GCSH to PDCE2. In vitro, it is also able to catalyze the transfer of the lipoyl group from lipoyl-AMP to the specific lysine residue of lipoyl domains of lipoate-dependent enzymes but this reaction may not be physiologically relevant (Probable).
• Tissue Specificity: Highly expressed in skeletal muscle and heart, moderately in kidney and pancreas, and detected at lower levels in liver, brain, placenta and lung.
• 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:HS07153-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glycine encephalopathy	DISI2XE5	Strong	Biomarker	[1]
Inborn error of metabolism	DISO5FAY	Strong	Biomarker	[2]
Infantile epileptic-dyskinetic encephalopathy	DISD2ZNC	Strong	Biomarker	[1]
Lactic acidosis	DISZI1ZK	Strong	Genetic Variation	[1]
Lipoyl transferase 1 deficiency	DIS3UTZA	Strong	Autosomal recessive	[3]
Pyruvate dehydrogenase complex deficiency	DIS8RZP9	Strong	Biomarker	[1]
Leigh syndrome	DISWQU45	Moderate	Autosomal recessive	[4]
Obsolete Leigh syndrome with leukodystrophy	DISABU9D	Supportive	Autosomal recessive	[5]

3 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 Lipoyl amidotransferase LIPT1, mitochondrial (LIPT1).	[6]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Lipoyl amidotransferase LIPT1, mitochondrial (LIPT1).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Lipoyl amidotransferase LIPT1, mitochondrial (LIPT1).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Lipoyl amidotransferase LIPT1, mitochondrial (LIPT1).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Lipoyl amidotransferase LIPT1, mitochondrial (LIPT1).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Lipoyl amidotransferase LIPT1, mitochondrial (LIPT1).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Lipoyl amidotransferase LIPT1, mitochondrial (LIPT1).	[10]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Lipoyl amidotransferase LIPT1, mitochondrial (LIPT1).	[12]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Lipoyl amidotransferase LIPT1, mitochondrial (LIPT1).	[13]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Lipoyl amidotransferase LIPT1, mitochondrial (LIPT1).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Lipoyl amidotransferase LIPT1, mitochondrial (LIPT1).	[15]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of Lipoyl amidotransferase LIPT1, mitochondrial (LIPT1).	[16]

References

• [1] LIPT1 deficiency presenting as early infantile epileptic encephalopathy, Leigh disease, and secondary pyruvate dehydrogenase complex deficiency.Am J Med Genet A. 2018 May;176(5):1184-1189. doi: 10.1002/ajmg.a.38654.
• [2] Functional Assessment of Lipoyltransferase-1 Deficiency in Cells, Mice, and Humans.Cell Rep. 2019 Apr 30;27(5):1376-1386.e6. doi: 10.1016/j.celrep.2019.04.005.
• [3] 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.
• [4] 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.
• [5] Mutations in human lipoyltransferase gene LIPT1 cause a Leigh disease with secondary deficiency for pyruvate and alpha-ketoglutarate dehydrogenase. Orphanet J Rare Dis. 2013 Dec 17;8:192. doi: 10.1186/1750-1172-8-192.
• [6] 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.
• [7] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [11] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [12] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [13] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [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] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [16] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.