Details of Drug Off-Target (DOT)

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

• DOT Name: Peroxisomal sarcosine oxidase (PIPOX)
• Synonyms: PSO; EC 1.5.3.1; EC 1.5.3.7; L-pipecolate oxidase; L-pipecolic acid oxidase
• Gene Name: PIPOX
• Related Disease:
  Peroxisomal disorder
  Advanced cancer
  Colorectal carcinoma
  Dilated cardiomyopathy 1A
  Major depressive disorder
  Prostate neoplasm
  Psoriasis
  Adrenoleukodystrophy
  High blood pressure
  Peroxisome biogenesis disorder
  Breast cancer
  Breast carcinoma
  Generalized pustular psoriasis
• UniProt ID: SOX_HUMAN
• EC Number: 1.5.3.1; 1.5.3.7
• Pfam ID: PF01266
• Sequence:
  MAAQKDLWDAIVIGAGIQGCFTAYHLAKHRKRILLLEQFFLPHSRGSSHGQSRIIRKAYL
  EDFYTRMMHECYQIWAQLEHEAGTQLHRQTGLLLLGMKENQELKTIQANLSRQRVEHQCL
  SSEELKQRFPNIRLPRGEVGLLDNSGGVIYAYKALRALQDAIRQLGGIVRDGEKVVEINP
  GLLVTVKTTSRSYQAKSLVITAGPWTNQLLRPLGIEMPLQTLRINVCYWREMVPGSYGVS
  QAFPCFLWLGLCPHHIYGLPTGEYPGLMKVSYHHGNHADPEERDCPTARTDIGDVQILSS
  FVRDHLPDLKPEPAVIESCMYTNTPDEQFILDRHPKYDNIVIGAGFSGHGFKLAPVVGKI
  LYELSMKLTPSYDLAPFRISRFPSLGKAHL
• Function: Metabolizes sarcosine and L-pipecolic acid.
• Tissue Specificity: Expressed in the liver and kidney.
• KEGG Pathway:
  Glycine, serine and threonine metabolism (hsa00260)
  Lysine degradation (hsa00310)
  Metabolic pathways (hsa01100)
  Peroxisome (hsa04146)
• Reactome Pathway:
  Peroxisomal protein import (R-HSA-9033241)
  Lysine catabolism (R-HSA-71064)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Peroxisomal disorder	DISV185U	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[3]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Altered Expression	[4]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[5]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[6]
Psoriasis	DIS59VMN	Strong	Biomarker	[7]
Adrenoleukodystrophy	DISTUD1F	moderate	Biomarker	[8]
High blood pressure	DISY2OHH	moderate	Genetic Variation	[9]
Peroxisome biogenesis disorder	DISBQ6QJ	Disputed	Altered Expression	[1]
Breast cancer	DIS7DPX1	Limited	Biomarker	[10]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[10]
Generalized pustular psoriasis	DISTSNLR	Limited	Biomarker	[11]

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 Peroxisomal sarcosine oxidase (PIPOX).	[12]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Peroxisomal sarcosine oxidase (PIPOX).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Peroxisomal sarcosine oxidase (PIPOX).	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Peroxisomal sarcosine oxidase (PIPOX).	[13]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Peroxisomal sarcosine oxidase (PIPOX).	[14]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Peroxisomal sarcosine oxidase (PIPOX).	[15]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Peroxisomal sarcosine oxidase (PIPOX).	[13]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Peroxisomal sarcosine oxidase (PIPOX).	[17]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Peroxisomal sarcosine oxidase (PIPOX).	[18]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Peroxisomal sarcosine oxidase (PIPOX).	[19]
Phenobarbital	DMXZOCG	Approved	Phenobarbital decreases the expression of Peroxisomal sarcosine oxidase (PIPOX).	[20]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Peroxisomal sarcosine oxidase (PIPOX).	[21]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Peroxisomal sarcosine oxidase (PIPOX).	[22]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol increases the expression of Peroxisomal sarcosine oxidase (PIPOX).	[23]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Peroxisomal sarcosine oxidase (PIPOX).	[24]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Peroxisomal sarcosine oxidase (PIPOX).	[21]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Peroxisomal sarcosine oxidase (PIPOX).	[25]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Peroxisomal sarcosine oxidase (PIPOX).	[21]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 decreases the expression of Peroxisomal sarcosine oxidase (PIPOX).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Peroxisomal sarcosine oxidase (PIPOX).	[25]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Peroxisomal sarcosine oxidase (PIPOX).	[28]

References

• [1] L-Pipecolic acid oxidase, a human enzyme essential for the degradation of L-pipecolic acid, is most similar to the monomeric sarcosine oxidases.Biochem J. 2000 Feb 1;345 Pt 3(Pt 3):487-94.
• [2] Cancer Diagnosis Epigenomics Scientific Workflow Scheduling in the Cloud Computing Environment Using an Improved PSO Algorithm.Asian Pac J Cancer Prev. 2018 Jan 27;19(1):243-246. doi: 10.22034/APJCP.2018.19.1.243.
• [3] Aging related methylation influences the gene expression of key control genes in colorectal cancer and adenoma.World J Gastroenterol. 2016 Dec 21;22(47):10325-10340. doi: 10.3748/wjg.v22.i47.10325.
• [4] Expression of sarcosine metabolism-related proteins in invasive lobular carcinoma: comparison to invasive ductal carcinoma.Yonsei Med J. 2015 May;56(3):598-607. doi: 10.3349/ymj.2015.56.3.598.
• [5] Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions.Nat Neurosci. 2019 Mar;22(3):343-352. doi: 10.1038/s41593-018-0326-7. Epub 2019 Feb 4.
• [6] The role of sarcosine metabolism in prostate cancer progression.Neoplasia. 2013 May;15(5):491-501. doi: 10.1593/neo.13314.
• [7] Crossed looks on the dermatologist's position and the patient's preoccupations as to psoriasis and pregnancy: preliminary results of the PREGNAN-PSO study.J Eur Acad Dermatol Venereol. 2019 May;33(5):880-885. doi: 10.1111/jdv.15423. Epub 2019 Feb 27.
• [8] Adrenoleukodystrophy and other peroxisomal disorders that affect the nervous system, including new observations on L-pipecolic acid oxidase in primates.Brain Dev. 1989;11(2):80-90. doi: 10.1016/s0387-7604(89)80074-9.
• [9] Particle swarm optimization algorithm for analyzing SNP-SNP interaction of renin-angiotensin system genes against hypertension.Mol Biol Rep. 2013 Jul;40(7):4227-33. doi: 10.1007/s11033-013-2504-8. Epub 2013 May 22.
• [10] Implications of differences in expression of sarcosine metabolism-related proteins according to the molecular subtype of breast cancer.J Transl Med. 2014 May 28;12:149. doi: 10.1186/1479-5876-12-149.
• [11] Generalized pustular psoriasis in Japan: two distinct groups formed by differences in symptoms and genetic background.Acta Derm Venereol. 1996 Jan;76(1):68-71. doi: 10.2340/00015555766871.
• [12] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [13] 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.
• [14] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [15] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [16] 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.
• [17] 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.
• [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] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [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] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [22] Gene expression signatures after ethanol exposure in differentiating embryoid bodies. Toxicol In Vitro. 2018 Feb;46:66-76.
• [23] The genomic response of a human uterine endometrial adenocarcinoma cell line to 17alpha-ethynyl estradiol. Toxicol Sci. 2009 Jan;107(1):40-55.
• [24] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [25] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [26] 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.
• [27] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [28] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.