Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNC1OKA)

• DOT Name: Glycine cleavage system H protein, mitochondrial (GCSH)
• Synonyms: Lipoic acid-containing protein
• Gene Name: GCSH
• Related Disease:
  Schizophrenia
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Glycine encephalopathy
  Multiple mitochondrial dysfunctions syndrome 7
  Silver-Russell syndrome
  Atypical glycine encephalopathy
  Infantile glycine encephalopathy
  Neonatal glycine encephalopathy
  Lymphoma
• UniProt ID: GCSH_HUMAN
• Pfam ID: PF01597
• Sequence:
  MALRVVRSVRALLCTLRAVPSPAAPCPPRPWQLGVGAVRTLRTGPALLSVRKFTEKHEWV
  TTENGIGTVGISNFAQEALGDVVYCSLPEVGTKLNKQDEFGALESVKAASELYSPLSGEV
  TEINEALAENPGLVNKSCYEDGWLIKMTLSNPSELDELMSEEAYEKYIKSIEE
• Function: The glycine cleavage system catalyzes the degradation of glycine. The H protein (GCSH) shuttles the methylamine group of glycine from the P protein (GLDC) to the T protein (GCST). Has a pivotal role in the lipoylation of enzymes involved in cellular energetics such as the mitochondrial dihydrolipoyllysine-residue acetyltransferase component of pyruvate dehydrogenase complex (DLAT), and the mitochondrial dihydrolipoyllysine-residue succinyltransferase component of 2-oxoglutarate dehydrogenase complex (DLST).
• KEGG Pathway:
  Glycine, serine and threonine metabolism (hsa00260)
  Glyoxylate and dicarboxylate metabolism (hsa00630)
  Lipoic acid metabolism (hsa00785)
  Metabolic pathways (hsa01100)
  Carbon metabolism (hsa01200)
• Reactome Pathway:
  Glycine degradation (R-HSA-6783984)
  Glyoxylate metabolism and glycine degradation (R-HSA-389661)
• BioCyc Pathway: MetaCyc:HS06771-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Schizophrenia	DISSRV2N	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Glycine encephalopathy	DISI2XE5	Strong	Autosomal recessive	[3]
Multiple mitochondrial dysfunctions syndrome 7	DISY3I1V	Strong	Autosomal recessive	[4]
Silver-Russell syndrome	DISSVJ1D	Strong	Genetic Variation	[5]
Atypical glycine encephalopathy	DIS9KV6Z	Supportive	Unknown	[6]
Infantile glycine encephalopathy	DISLOECI	Supportive	Autosomal recessive	[6]
Neonatal glycine encephalopathy	DIS7A6BM	Supportive	Autosomal recessive	[6]
Lymphoma	DISN6V4S	Limited	Biomarker	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Glycine cleavage system H protein, mitochondrial (GCSH) affects the response to substance of Methotrexate.	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Glycine cleavage system H protein, mitochondrial (GCSH).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Glycine cleavage system H protein, mitochondrial (GCSH).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Glycine cleavage system H protein, mitochondrial (GCSH).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Glycine cleavage system H protein, mitochondrial (GCSH).	[11]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Glycine cleavage system H protein, mitochondrial (GCSH).	[12]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Glycine cleavage system H protein, mitochondrial (GCSH).	[13]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Glycine cleavage system H protein, mitochondrial (GCSH).	[14]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Glycine cleavage system H protein, mitochondrial (GCSH).	[15]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Glycine cleavage system H protein, mitochondrial (GCSH).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Glycine cleavage system H protein, mitochondrial (GCSH).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Glycine cleavage system H protein, mitochondrial (GCSH).	[18]

References

• [1] Mutations of the glycine cleavage system genes possibly affect the negative symptoms of schizophrenia through metabolomic profile changes.Psychiatry Clin Neurosci. 2018 Mar;72(3):168-179. doi: 10.1111/pcn.12628. Epub 2018 Jan 31.
• [2] GCSH antisense regulation determines breast cancer cells' viability.Sci Rep. 2018 Oct 18;8(1):15399. doi: 10.1038/s41598-018-33677-4.
• [3] 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.
• [4] Heterozygous GLDC and GCSH gene mutations in transient neonatal hyperglycinemia. Ann Neurol. 2002 Nov;52(5):643-6. doi: 10.1002/ana.10367.
• [5] Methylation profiling in individuals with Russell-Silver syndrome.Am J Med Genet A. 2010 Feb;152A(2):347-55. doi: 10.1002/ajmg.a.33204.
• [6] Nonketotic Hyperglycinemia. 2002 Nov 14 [updated 2019 May 23]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [7] Clinicopathologic study of CD56 (NCAM)-positive angiocentric lymphoma occurring in sites other than the upper and lower respiratory tract.Am J Surg Pathol. 1995 Mar;19(3):284-96. doi: 10.1097/00000478-199503000-00006.
• [8] 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.
• [9] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [12] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [13] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [14] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [17] 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.
• [18] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [19] 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.