Details of Drug Off-Target (DOT)

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

• DOT Name: Acylglycerol kinase, mitochondrial (AGK)
• Synonyms: hAGK; EC 2.7.1.107; EC 2.7.1.138; EC 2.7.1.94; Multiple substrate lipid kinase; HsMuLK; MuLK; Multi-substrate lipid kinase
• Gene Name: AGK
• Related Disease:
  Mitochondrial disease
  Sengers syndrome
  Total early-onset cataract
  Cataract 38
• UniProt ID: AGK_HUMAN
• PDB ID: 7CGP
• EC Number: 2.7.1.107; 2.7.1.138; 2.7.1.94
• Pfam ID: PF19712 ; PF00781
• Sequence:
  MTVFFKTLRNHWKKTTAGLCLLTWGGHWLYGKHCDNLLRRAACQEAQVFGNQLIPPNAQV
  KKATVFLNPAACKGKARTLFEKNAAPILHLSGMDVTIVKTDYEGQAKKLLELMENTDVII
  VAGGDGTLQEVVTGVLRRTDEATFSKIPIGFIPLGETSSLSHTLFAESGNKVQHITDATL
  AIVKGETVPLDVLQIKGEKEQPVFAMTGLRWGSFRDAGVKVSKYWYLGPLKIKAAHFFST
  LKEWPQTHQASISYTGPTERPPNEPEETPVQRPSLYRRILRRLASYWAQPQDALSQEVSP
  EVWKDVQLSTIELSITTRNNQLDPTSKEDFLNICIEPDTISKGDFITIGSRKVRNPKLHV
  EGTECLQASQCTLLIPEGAGGSFSIDSEEYEAMPVEVKLLPRKLQFFCDPRKREQMLTSP
  TQ
• Function: Lipid kinase that can phosphorylate both monoacylglycerol and diacylglycerol to form lysophosphatidic acid (LPA) and phosphatidic acid (PA), respectively. Does not phosphorylate sphingosine. Phosphorylates ceramide. Phosphorylates 1,2-dioleoylglycerol more rapidly than 2,3-dioleoylglycerol. Independently of its lipid kinase activity, acts as a component of the TIM22 complex. The TIM22 complex mediates the import and insertion of multi-pass transmembrane proteins into the mitochondrial inner membrane by forming a twin-pore translocase that uses the membrane potential as the external driving force. In the TIM22 complex, required for the import of a subset of metabolite carriers into mitochondria, such as ANT1/SLC25A4 and SLC25A24, while it is not required for the import of TIMM23. Overexpression increases the formation and secretion of LPA, resulting in transactivation of EGFR and activation of the downstream MAPK signaling pathway, leading to increased cell growth.
• Tissue Specificity: Highly expressed in muscle, heart, kidney and brain.
• KEGG Pathway:
  Glycerolipid metabolism (hsa00561)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Signaling by BRAF and RAF1 fusions (R-HSA-6802952)
  Glycerophospholipid biosynthesis (R-HSA-1483206)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mitochondrial disease	DISKAHA3	Definitive	Autosomal recessive	[1]
Sengers syndrome	DISV24KG	Definitive	Autosomal recessive	[2]
Total early-onset cataract	DISACMEZ	Supportive	Autosomal dominant	[3]
Cataract 38	DISGR7I0	Limited	Autosomal recessive	[3]

4 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 Acylglycerol kinase, mitochondrial (AGK).	[4]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Acylglycerol kinase, mitochondrial (AGK).	[9]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Acylglycerol kinase, mitochondrial (AGK).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Acylglycerol kinase, mitochondrial (AGK).	[13]

6 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 Acylglycerol kinase, mitochondrial (AGK).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Acylglycerol kinase, mitochondrial (AGK).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Acylglycerol kinase, mitochondrial (AGK).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Acylglycerol kinase, mitochondrial (AGK).	[8]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Acylglycerol kinase, mitochondrial (AGK).	[10]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Acylglycerol kinase, mitochondrial (AGK).	[12]

References

• [1] 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.
• [2] [Infantile cataract, hypertrophic cardiomyopathy and lactic acidosis following minor muscular exertion--a little known metabolic disease]. Klin Monbl Augenheilkd. 1986 Dec;189(6):482-5.
• [3] Identification of a truncation mutation of acylglycerol kinase (AGK) gene in a novel autosomal recessive cataract locus. Hum Mutat. 2012 Jun;33(6):960-2. doi: 10.1002/humu.22071. Epub 2012 Apr 16.
• [4] 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.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] 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.
• [10] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [11] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [12] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [13] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.