Details of Drug Off-Target (DOT)

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

• DOT Name: Glutaryl-CoA dehydrogenase, mitochondrial (GCDH)
• Synonyms: GCD; EC 1.3.8.6
• Gene Name: GCDH
• Related Disease:
  Glutaryl-CoA dehydrogenase deficiency
  Lattice corneal dystrophy type I
  Metabolic disorder
  Colorectal carcinoma
  D-2-hydroxyglutaric aciduria 1
  Fleck corneal dystrophy
  Glutaric aciduria
  Liver cirrhosis
  Movement disorder
  Corneal dystrophy
  Inborn error of metabolism
  Dystonia
  Granular corneal dystrophy type II
  Nervous system disease
• UniProt ID: GCDH_HUMAN
• PDB ID: 1SIQ; 1SIR; 2R0M; 2R0N
• EC Number: 1.3.8.6
• Pfam ID: PF00441 ; PF02770 ; PF02771
• Sequence:
  MALRGVSVRLLSRGPGLHVLRTWVSSAAQTEKGGRTQSQLAKSSRPEFDWQDPLVLEEQL
  TTDEILIRDTFRTYCQERLMPRILLANRNEVFHREIISEMGELGVLGPTIKGYGCAGVSS
  VAYGLLARELERVDSGYRSAMSVQSSLVMHPIYAYGSEEQRQKYLPQLAKGELLGCFGLT
  EPNSGSDPSSMETRAHYNSSNKSYTLNGTKTWITNSPMADLFVVWARCEDGCIRGFLLEK
  GMRGLSAPRIQGKFSLRASATGMIIMDGVEVPEENVLPGASSLGGPFGCLNNARYGIAWG
  VLGASEFCLHTARQYALDRMQFGVPLARNQLIQKKLADMLTEITLGLHACLQLGRLKDQD
  KAAPEMVSLLKRNNCGKALDIARQARDMLGGNGISDEYHVIRHAMNLEAVNTYEGTHDIH
  ALILGRAITGIQAFTASK
• Function: Catalyzes the oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA and CO(2) in the degradative pathway of L-lysine, L-hydroxylysine, and L-tryptophan metabolism. It uses electron transfer flavoprotein as its electron acceptor. Isoform Short is inactive.
• Tissue Specificity: Isoform Long and isoform Short are expressed in fibroblasts and liver.
• KEGG Pathway:
  Fatty acid degradation (hsa00071)
  Lysine degradation (hsa00310)
  Tryptophan metabolism (hsa00380)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Lysine catabolism (R-HSA-71064)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glutaryl-CoA dehydrogenase deficiency	DISRAMPH	Definitive	Autosomal recessive	[1]
Lattice corneal dystrophy type I	DISNKVHC	Definitive	Genetic Variation	[2]
Metabolic disorder	DIS71G5H	Definitive	Genetic Variation	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[4]
D-2-hydroxyglutaric aciduria 1	DISFYZD5	Strong	Genetic Variation	[5]
Fleck corneal dystrophy	DISERQJ1	Strong	Biomarker	[6]
Glutaric aciduria	DISGE8NR	Strong	Biomarker	[7]
Liver cirrhosis	DIS4G1GX	Strong	Biomarker	[8]
Movement disorder	DISOJJ2D	Strong	Genetic Variation	[9]
Corneal dystrophy	DISRDPA6	moderate	Genetic Variation	[10]
Inborn error of metabolism	DISO5FAY	moderate	Biomarker	[11]
Dystonia	DISJLFGW	Limited	Biomarker	[12]
Granular corneal dystrophy type II	DISAEE20	Limited	Genetic Variation	[13]
Nervous system disease	DISJ7GGT	Limited	Biomarker	[14]

9 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 Glutaryl-CoA dehydrogenase, mitochondrial (GCDH).	[15]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Glutaryl-CoA dehydrogenase, mitochondrial (GCDH).	[16]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Glutaryl-CoA dehydrogenase, mitochondrial (GCDH).	[17]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Glutaryl-CoA dehydrogenase, mitochondrial (GCDH).	[18]
Phenobarbital	DMXZOCG	Approved	Phenobarbital decreases the expression of Glutaryl-CoA dehydrogenase, mitochondrial (GCDH).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Glutaryl-CoA dehydrogenase, mitochondrial (GCDH).	[16]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Glutaryl-CoA dehydrogenase, mitochondrial (GCDH).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Glutaryl-CoA dehydrogenase, mitochondrial (GCDH).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Glutaryl-CoA dehydrogenase, mitochondrial (GCDH).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Glutaryl-CoA dehydrogenase, mitochondrial (GCDH).	[19]

References

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• [2] Corneal Dystrophy Mutations Drive Pathogenesis by Targeting TGFBIp Stability and Solubility in a Latent Amyloid-forming Domain.J Mol Biol. 2018 Apr 13;430(8):1116-1140. doi: 10.1016/j.jmb.2018.03.001. Epub 2018 Mar 7.
• [3] Clinical and molecular investigation of 19 Japanese cases of glutaric acidemia type 1.Mol Genet Metab. 2011 Mar;102(3):343-8. doi: 10.1016/j.ymgme.2010.11.159. Epub 2010 Nov 25.
• [4] Somatic mutations of amino acid metabolism-related genes in gastric and colorectal cancers and their regional heterogeneity--a short report.Cell Oncol (Dordr). 2014 Dec;37(6):455-61. doi: 10.1007/s13402-014-0209-1. Epub 2014 Dec 2.
• [5] D-2-hydroxyglutaric aciduria and glutaric aciduria type 1 in siblings: coincidence, or linked disorders?.Neuropediatrics. 2004 Jun;35(3):151-6. doi: 10.1055/s-2004-817905.
• [6] Reelin: a possible link between hippocampal sclerosis and cortical dyslamination in the setting of FCD type IIIa.Neurol Sci. 2012 Dec;33(6):1479-81. doi: 10.1007/s10072-011-0895-7. Epub 2011 Dec 28.
• [7] Studies on glutaryl-CoA dehydrogenase in leucocytes, fibroblasts and amniotic fluid cells. The normal enzyme and the mutant form in patients with glutaric aciduria.Clin Chim Acta. 1978 Sep 1;88(2):267-76. doi: 10.1016/0009-8981(78)90431-x.
• [8] Advance care planning (ACP) for specialists managing cirrhosis: A focus on patient-centered care.Hepatology. 2018 May;67(5):2025-2040. doi: 10.1002/hep.29731. Epub 2018 Apr 6.
• [9] Prenatal diagnosis of fetal glutaric aciduria type 1 with rare compound heterozygous mutations in GCDH gene.Taiwan J Obstet Gynecol. 2018 Feb;57(1):137-140. doi: 10.1016/j.tjog.2017.12.023.
• [10] Analysis of TGFBI gene mutations in Chinese patients with corneal dystrophies and review of the literature.Mol Vis. 2010 Jun 30;16:1186-93.
• [11] Molecular genetic study of glutaric aciduria, type I: Identification of a novel mutation.J Cell Biochem. 2019 Mar;120(3):3367-3372. doi: 10.1002/jcb.27607. Epub 2018 Sep 11.
• [12] Adult-onset glutaric aciduria type I presenting with white matter abnormalities and subependymal nodules.Neurogenetics. 2015 Oct;16(4):325-8. doi: 10.1007/s10048-015-0456-y. Epub 2015 Aug 29.
• [13] Decreased catalase expression and increased susceptibility to oxidative stress in primary cultured corneal fibroblasts from patients with granular corneal dystrophy type II.Am J Pathol. 2009 Jul;175(1):248-61. doi: 10.2353/ajpath.2009.081001. Epub 2009 Jun 4.
• [14] Nuclear magnetic resonance spectroscopy in glutaryl-CoA dehydrogenase deficiency.J Inherit Metab Dis. 2004;27(6):877-83. doi: 10.1023/B:BOLI.0000045772.09776.e0.
• [15] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [16] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [17] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [18] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [19] 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.
• [20] Proteomic analysis of hepatic effects of phenobarbital in mice with humanized liver. Arch Toxicol. 2022 Oct;96(10):2739-2754. doi: 10.1007/s00204-022-03338-7. Epub 2022 Jul 26.
• [21] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [22] Bisphenol-A and estradiol exert novel gene regulation in human MCF-7 derived breast cancer cells. Mol Cell Endocrinol. 2004 Jun 30;221(1-2):47-55. doi: 10.1016/j.mce.2004.04.010.
• [23] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.