Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFBFPV4)

• DOT Name: Alkyldihydroxyacetonephosphate synthase, peroxisomal (AGPS)
• Synonyms: Alkyl-DHAP synthase; EC 2.5.1.26; Aging-associated gene 5 protein; Alkylglycerone-phosphate synthase
• Gene Name: AGPS
• Related Disease:
  Alkylglycerone-phosphate synthase deficiency
  Rhizomelic chondrodysplasia punctata
  Rhizomelic chondrodysplasia punctata type 3
  Advanced cancer
  Alzheimer disease
  Amyloidosis
  Chondrodysplasia punctata
  Glioma
  High blood pressure
  Neoplasm
  Zellweger spectrum disorders
  Dementia
  Hepatocellular carcinoma
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid tumor
• UniProt ID: ADAS_HUMAN
• EC Number: 2.5.1.26
• Pfam ID: PF02913 ; PF01565
• Sequence:
  MAEAAAAAGGTGLGAGASYGSAADRDRDPDPDRAGRRLRVLSGHLLGRPREALSTNECKA
  RRAASAATAAPTATPAAQESGTIPKKRQEVMKWNGWGYNDSKFIFNKKGQIELTGKRYPL
  SGMGLPTFKEWIQNTLGVNVEHKTTSKASLNPSDTPPSVVNEDFLHDLKETNISYSQEAD
  DRVFRAHGHCLHEIFLLREGMFERIPDIVLWPTCHDDVVKIVNLACKYNLCIIPIGGGTS
  VSYGLMCPADETRTIISLDTSQMNRILWVDENNLTAHVEAGITGQELERQLKESGYCTGH
  EPDSLEFSTVGGWVSTRASGMKKNIYGNIEDLVVHIKMVTPRGIIEKSCQGPRMSTGPDI
  HHFIMGSEGTLGVITEATIKIRPVPEYQKYGSVAFPNFEQGVACLREIAKQRCAPASIRL
  MDNKQFQFGHALKPQVSSIFTSFLDGLKKFYITKFKGFDPNQLSVATLLFEGDREKVLQH
  EKQVYDIAAKFGGLAAGEDNGQRGYLLTYVIAYIRDLALEYYVLGESFETSAPWDRVVDL
  CRNVKERITRECKEKGVQFAPFSTCRVTQTYDAGACIYFYFAFNYRGISDPLTVFEQTEA
  AAREEILANGGSLSHHHGVGKLRKQWLKESISDVGFGMLKSVKEYVDPNNIFGNRNLL
• Function: Catalyzes the exchange of the acyl chain in acyl-dihydroxyacetonephosphate (acyl-DHAP) for a long chain fatty alcohol, yielding the first ether linked intermediate, i.e. alkyl-dihydroxyacetonephosphate (alkyl-DHAP), in the pathway of ether lipid biosynthesis.
• KEGG Pathway:
  Ether lipid metabolism (hsa00565)
  Metabolic pathways (hsa01100)
  Peroxisome (hsa04146)
• Reactome Pathway:
  Peroxisomal protein import (R-HSA-9033241)
  TYSND1 cleaves peroxisomal proteins (R-HSA-9033500)
  Plasmalogen biosynthesis (R-HSA-75896)
• BioCyc Pathway: MetaCyc:HS00389-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alkylglycerone-phosphate synthase deficiency	DISAJBBU	Definitive	Autosomal recessive	[1]
Rhizomelic chondrodysplasia punctata	DISF3YE7	Definitive	Biomarker	[2]
Rhizomelic chondrodysplasia punctata type 3	DISF8Z23	Definitive	Autosomal recessive	[3]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[4]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[5]
Amyloidosis	DISHTAI2	Strong	Biomarker	[6]
Chondrodysplasia punctata	DISERVGO	Strong	Biomarker	[7]
Glioma	DIS5RPEH	Strong	Biomarker	[8]
High blood pressure	DISY2OHH	Strong	Genetic Variation	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[9]
Zellweger spectrum disorders	DISW52CE	Strong	Biomarker	[10]
Dementia	DISXL1WY	Limited	Biomarker	[11]
Hepatocellular carcinoma	DIS0J828	Limited	Altered Expression	[8]
Thyroid cancer	DIS3VLDH	Limited	Biomarker	[4]
Thyroid gland carcinoma	DISMNGZ0	Limited	Biomarker	[4]
Thyroid tumor	DISLVKMD	Limited	Biomarker	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Alkyldihydroxyacetonephosphate synthase, peroxisomal (AGPS).	[12]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Alkyldihydroxyacetonephosphate synthase, peroxisomal (AGPS).	[13]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Alkyldihydroxyacetonephosphate synthase, peroxisomal (AGPS).	[14]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Alkyldihydroxyacetonephosphate synthase, peroxisomal (AGPS).	[15]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Alkyldihydroxyacetonephosphate synthase, peroxisomal (AGPS).	[16]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Alkyldihydroxyacetonephosphate synthase, peroxisomal (AGPS).	[17]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Alkyldihydroxyacetonephosphate synthase, peroxisomal (AGPS).	[18]
Dasatinib	DMJV2EK	Approved	Dasatinib increases the expression of Alkyldihydroxyacetonephosphate synthase, peroxisomal (AGPS).	[19]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone decreases the expression of Alkyldihydroxyacetonephosphate synthase, peroxisomal (AGPS).	[20]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of Alkyldihydroxyacetonephosphate synthase, peroxisomal (AGPS).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Alkyldihydroxyacetonephosphate synthase, peroxisomal (AGPS).	[23]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Alkyldihydroxyacetonephosphate synthase, peroxisomal (AGPS).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Alkyldihydroxyacetonephosphate synthase, peroxisomal (AGPS).	[21]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Alkyldihydroxyacetonephosphate synthase, peroxisomal (AGPS).	[22]

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] Mild reduction of plasmalogens causes rhizomelic chondrodysplasia punctata: functional characterization of a novel mutation.J Hum Genet. 2014 Jul;59(7):387-92. doi: 10.1038/jhg.2014.39. Epub 2014 May 22.
• [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] Effect of alkylglycerone phosphate synthase on the expression profile of circRNAs in the human thyroid cancer cell line FRO.Oncol Lett. 2018 May;15(5):7889-7899. doi: 10.3892/ol.2018.8356. Epub 2018 Mar 26.
• [5] Associations of White Matter Hyperintensities with Cognitive Decline: A Longitudinal Study.J Alzheimers Dis. 2020;73(2):759-768. doi: 10.3233/JAD-191005.
• [6] The combination of apolipoprotein E4, age and Alzheimer's Disease Assessment Scale - Cognitive Subscale improves the prediction of amyloid positron emission tomography status in clinically diagnosed mild cognitive impairment.Eur J Neurol. 2019 May;26(5):733-e53. doi: 10.1111/ene.13881. Epub 2019 Jan 20.
• [7] Blind sterile 2 (bs2), a hypomorphic mutation in Agps, results in cataracts and male sterility in mice.Mol Genet Metab. 2011 May;103(1):51-9. doi: 10.1016/j.ymgme.2011.02.002. Epub 2011 Feb 25.
• [8] Tudor-staphylococcal nuclease regulates the expression and biological function of alkylglycerone phosphate synthase via nuclear factor-B and microRNA-127 in human glioma U87MG cells.Oncol Lett. 2018 Jun;15(6):9553-9558. doi: 10.3892/ol.2018.8484. Epub 2018 Apr 13.
• [9] The effect of benzyl isothiocyanate and its computer-aided design derivants targeting alkylglycerone phosphate synthase on the inhibition of human glioma U87MG cell line.Tumour Biol. 2015 May;36(5):3499-509. doi: 10.1007/s13277-014-2986-6. Epub 2014 Dec 28.
• [10] Neonatal punctate calcifications associated with maternal mixed connective tissue disorder (MCTD).BMJ Case Rep. 2018 Oct 12;2018:bcr2017223373. doi: 10.1136/bcr-2017-223373.
• [11] Analyses of natural courses of Japanese patients with Alzheimer's disease using placebo data from placebo-controlled, randomized clinical trials: Japanese Study on the Estimation of Clinical course of Alzheimer's disease.Alzheimers Dement (N Y). 2019 Aug 29;5:398-408. doi: 10.1016/j.trci.2019.07.004. eCollection 2019.
• [12] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [13] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [14] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [15] 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.
• [16] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [17] 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.
• [18] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [19] Combination of arsenic trioxide and Dasatinib: a new strategy to treat Philadelphia chromosome-positive acute lymphoblastic leukaemia. J Cell Mol Med. 2018 Mar;22(3):1614-1626.
• [20] Differentially expressed genes in the prostate cancer cell line LNCaP after exposure to androgen and anti-androgen. Cancer Genet Cytogenet. 2006 Apr 15;166(2):130-8. doi: 10.1016/j.cancergencyto.2005.09.012.
• [21] 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.
• [22] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [23] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [24] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.