Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPBR06U)

• DOT Name: Phosphomevalonate kinase (PMVK)
• Synonyms: PMKase; hPMK; EC 2.7.4.2
• Gene Name: PMVK
• Related Disease:
  Porokeratosis 1, Mibelli type
  Porokeratosis of Mibelli
• UniProt ID: PMVK_HUMAN
• PDB ID: 3CH4
• EC Number: 2.7.4.2
• Pfam ID: PF04275
• Sequence:
  MAPLGGAPRLVLLFSGKRKSGKDFVTEALQSRLGADVCAVLRLSGPLKEQYAQEHGLNFQ
  RLLDTSTYKEAFRKDMIRWGEEKRQADPGFFCRKIVEGISQPIWLVSDTRRVSDIQWFRE
  AYGAVTQTVRVVALEQSRQQRGWVFTPGVDDAESECGLDNFGDFDWVIENHGVEQRLEEQ
  LENLIEFIRSRL
• Function: Catalyzes the reversible ATP-dependent phosphorylation of mevalonate 5-phosphate to produce mevalonate diphosphate and ADP, a key step in the mevalonic acid mediated biosynthesis of isopentenyl diphosphate and other polyisoprenoid metabolites.
• Tissue Specificity: Heart, liver, skeletal muscle, kidney, and pancreas. Lower level in brain, placenta and lung.
• KEGG Pathway:
  Terpenoid backbone biosynthesis (hsa00900)
  Metabolic pathways (hsa01100)
  Peroxisome (hsa04146)
• Reactome Pathway:
  Activation of gene expression by SREBF (SREBP) (R-HSA-2426168)
  Cholesterol biosynthesis (R-HSA-191273)
• BioCyc Pathway: MetaCyc:HS08830-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Porokeratosis 1, Mibelli type	DIS3ZU6G	Strong	Autosomal dominant	[1]
Porokeratosis of Mibelli	DISF48DQ	Supportive	Autosomal dominant	[1]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Adenosine triphosphate	DM79F6G	Approved	Phosphomevalonate kinase (PMVK) increases the hydrolysis of Adenosine triphosphate.	[14]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Afimoxifene	DMFORDT	Phase 2	Phosphomevalonate kinase (PMVK) decreases the response to substance of Afimoxifene.	[15]

11 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 Phosphomevalonate kinase (PMVK).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Phosphomevalonate kinase (PMVK).	[3]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Phosphomevalonate kinase (PMVK).	[4]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Phosphomevalonate kinase (PMVK).	[6]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Phosphomevalonate kinase (PMVK).	[7]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Phosphomevalonate kinase (PMVK).	[8]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Phosphomevalonate kinase (PMVK).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Phosphomevalonate kinase (PMVK).	[10]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Phosphomevalonate kinase (PMVK).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Phosphomevalonate kinase (PMVK).	[12]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Phosphomevalonate kinase (PMVK).	[13]

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 Phosphomevalonate kinase (PMVK).	[5]

References

• [1] Genomic variations of the mevalonate pathway in porokeratosis. Elife. 2015 Jul 23;4:e06322. doi: 10.7554/eLife.06322.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] 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.
• [5] 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.
• [6] 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.
• [7] Proteomic analysis of liver cancer cells treated with suberonylanilide hydroxamic acid. Cancer Chemother Pharmacol. 2008 Apr;61(5):791-802.
• [8] 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.
• [9] 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.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [12] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [13] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [14] Post-translational regulation of mevalonate kinase by intermediates of the cholesterol and nonsterol isoprene biosynthetic pathways. J Lipid Res. 1997 Nov;38(11):2216-23.
• [15] High-throughput ectopic expression screen for tamoxifen resistance identifies an atypical kinase that blocks autophagy. Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2058-63.