Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT40AJ5J)

• DOT Name: Pyridoxal kinase (PDXK)
• Synonyms: EC 2.7.1.35; Pyridoxine kinase
• Gene Name: PDXK
• Related Disease: Neuropathy, hereditary motor and sensory, type VIc, with optic atrophy
• UniProt ID: PDXK_HUMAN
• PDB ID: 2AJP; 2F7K; 2YXT; 2YXU; 3FHX; 3FHY; 3KEU; 4EN4; 4EOH
• EC Number: 2.7.1.35
• Pfam ID: PF08543
• Sequence:
  MEEECRVLSIQSHVIRGYVGNRAATFPLQVLGFEIDAVNSVQFSNHTGYAHWKGQVLNSD
  ELQELYEGLRLNNMNKYDYVLTGYTRDKSFLAMVVDIVQELKQQNPRLVYVCDPVLGDKW
  DGEGSMYVPEDLLPVYKEKVVPLADIITPNQFEAELLSGRKIHSQEEALRVMDMLHSMGP
  DTVVITSSDLPSPQGSNYLIVLGSQRRRNPAGSVVMERIRMDIRKVDAVFVGTGDLFAAM
  LLAWTHKHPNNLKVACEKTVSTLHHVLQRTIQCAKAQAGEGVRPSPMQLELRMVQSKRDI
  EDPEIVVQATVL
• Function: Catalyzes the phosphorylation of the dietary vitamin B6 vitamers pyridoxal (PL), pyridoxine (PN) and pyridoxamine (PM) to form pyridoxal 5'-phosphate (PLP), pyridoxine 5'-phosphate (PNP) and pyridoxamine 5'-phosphate (PMP), respectively (Probable). PLP is the active form of vitamin B6, and acts as a cofactor for over 140 different enzymatic reactions.
• Tissue Specificity: Ubiquitous . Highly expressed in testis .; [Isoform 3]: In adult testis and spermatozoa.
• KEGG Pathway:
  Vitamin B6 metabolism (hsa00750)
  Metabolic pathways (hsa01100)
  Biosynthesis of cofactors (hsa01240)
• Reactome Pathway:
  Vitamin B6 activation to pyridoxal phosphate (R-HSA-964975)
  Neutrophil degranulation (R-HSA-6798695)
• BioCyc Pathway: MetaCyc:HS08466-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neuropathy, hereditary motor and sensory, type VIc, with optic atrophy	DISUVC3Y	Strong	Autosomal recessive	[1]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Pyridoxal kinase (PDXK) affects the response to substance of Cisplatin.	[20]
Arsenic trioxide	DM61TA4	Approved	Pyridoxal kinase (PDXK) decreases the response to substance of Arsenic trioxide.	[21]
Mitomycin	DMH0ZJE	Approved	Pyridoxal kinase (PDXK) affects the response to substance of Mitomycin.	[20]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Pyridoxal Phosphate	DMO2K0J	Approved	Pyridoxal kinase (PDXK) increases the abundance of Pyridoxal Phosphate.	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Pyridoxal kinase (PDXK).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Pyridoxal kinase (PDXK).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Pyridoxal kinase (PDXK).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Pyridoxal kinase (PDXK).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Pyridoxal kinase (PDXK).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Pyridoxal kinase (PDXK).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Pyridoxal kinase (PDXK).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Pyridoxal kinase (PDXK).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Pyridoxal kinase (PDXK).	[8]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Pyridoxal kinase (PDXK).	[9]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Pyridoxal kinase (PDXK).	[10]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Pyridoxal kinase (PDXK).	[11]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Pyridoxal kinase (PDXK).	[12]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Pyridoxal kinase (PDXK).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Pyridoxal kinase (PDXK).	[16]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Pyridoxal kinase (PDXK).	[17]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone decreases the expression of Pyridoxal kinase (PDXK).	[18]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride increases the expression of Pyridoxal kinase (PDXK).	[19]

References

• [1] PDXK mutations cause polyneuropathy responsive to pyridoxal 5'-phosphate supplementation. Ann Neurol. 2019 Aug;86(2):225-240. doi: 10.1002/ana.25524. Epub 2019 Jul 1.
• [2] 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.
• [3] 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.
• [4] 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.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] 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.
• [8] 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.
• [9] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [10] Pharmacogenomic identification of novel determinants of response to chemotherapy in colon cancer. Cancer Res. 2006 Mar 1;66(5):2765-77.
• [11] 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.
• [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] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [14] 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.
• [15] 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.
• [16] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [17] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [18] Evaluation of an in vitro model of androgen ablation and identification of the androgen responsive proteome in LNCaP cells. Proteomics. 2007 Jan;7(1):47-63.
• [19] Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.
• [20] 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.
• [21] The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel. BMC Med Genomics. 2010 Aug 13;3:37. doi: 10.1186/1755-8794-3-37.
• [22] Anticonvulsant characteristics of pyridoxyl-gamma-aminobutyrate, PL-GABA. Neuropharmacology. 2008 May;54(6):954-64. doi: 10.1016/j.neuropharm.2008.02.001. Epub 2008 Feb 10.