Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGEX4SR)

• DOT Name: Diphosphomevalonate decarboxylase (MVD)
• Synonyms: EC 4.1.1.33; Mevalonate (diphospho)decarboxylase; MDDase; Mevalonate pyrophosphate decarboxylase
• Gene Name: MVD
• Related Disease:
  Porokeratosis 7, multiple types
  Disseminated superficial actinic porokeratosis
• UniProt ID: MVD1_HUMAN
• PDB ID: 3D4J
• EC Number: 4.1.1.33
• Pfam ID: PF00288 ; PF18376
• Sequence:
  MASEKPLAAVTCTAPVNIAVIKYWGKRDEELVLPINSSLSVTLHQDQLKTTTTAVISKDF
  TEDRIWLNGREEDVGQPRLQACLREIRCLARKRRNSRDGDPLPSSLSCKVHVASVNNFPT
  AAGLASSAAGYACLAYTLARVYGVESDLSEVARRGSGSACRSLYGGFVEWQMGEQADGKD
  SIARQVAPESHWPELRVLILVVSAEKKLTGSTVGMRASVETSPLLRFRAESVVPARMAEM
  ARCIRERDFPSFAQLTMKDSNQFHATCLDTFPPISYLNAISWRIIHLVHRFNAHHGDTKV
  AYTFDAGPNAVIFTLDDTVAEFVAAVWHGFPPGSNGDTFLKGLQVRPAPLSAELQAALAM
  EPTPGGVKYIIVTQVGPGPQILDDPCAHLLGPDGLPKPAA
• Function: Catalyzes the ATP dependent decarboxylation of (R)-5-diphosphomevalonate to form isopentenyl diphosphate (IPP). Functions in the mevalonate (MVA) pathway leading to isopentenyl diphosphate (IPP), a key precursor for the biosynthesis of isoprenoids and sterol synthesis.
• Tissue Specificity: Expressed in heart, skeletal muscle, lung, liver, brain, pancreas, kidney and placenta.
• KEGG Pathway:
  Terpenoid backbone biosynthesis (hsa00900)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Activation of gene expression by SREBF (SREBP) (R-HSA-2426168)
  Synthesis of Dolichyl-phosphate (R-HSA-446199)
  Cholesterol biosynthesis (R-HSA-191273)
• BioCyc Pathway: MetaCyc:ENSG00000167508-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 7, multiple types	DIS8XEXM	Strong	Autosomal dominant	[1]
Disseminated superficial actinic porokeratosis	DISELZ77	Supportive	Autosomal dominant	[2]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Adenosine triphosphate	DM79F6G	Approved	Diphosphomevalonate decarboxylase (MVD) increases the hydrolysis of Adenosine triphosphate.	[25]

2 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 Diphosphomevalonate decarboxylase (MVD).	[3]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Diphosphomevalonate decarboxylase (MVD).	[21]

21 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 Diphosphomevalonate decarboxylase (MVD).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Diphosphomevalonate decarboxylase (MVD).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Diphosphomevalonate decarboxylase (MVD).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Diphosphomevalonate decarboxylase (MVD).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Diphosphomevalonate decarboxylase (MVD).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Diphosphomevalonate decarboxylase (MVD).	[9]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Diphosphomevalonate decarboxylase (MVD).	[10]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Diphosphomevalonate decarboxylase (MVD).	[11]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Diphosphomevalonate decarboxylase (MVD).	[12]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Diphosphomevalonate decarboxylase (MVD).	[13]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Diphosphomevalonate decarboxylase (MVD).	[14]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Diphosphomevalonate decarboxylase (MVD).	[15]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Diphosphomevalonate decarboxylase (MVD).	[16]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Diphosphomevalonate decarboxylase (MVD).	[17]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Diphosphomevalonate decarboxylase (MVD).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Diphosphomevalonate decarboxylase (MVD).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Diphosphomevalonate decarboxylase (MVD).	[19]
PMID26394986-Compound-22	DM43Z1G	Patented	PMID26394986-Compound-22 decreases the expression of Diphosphomevalonate decarboxylase (MVD).	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Diphosphomevalonate decarboxylase (MVD).	[22]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Diphosphomevalonate decarboxylase (MVD).	[23]
Okadaic acid	DM47CO1	Investigative	Okadaic acid decreases the expression of Diphosphomevalonate decarboxylase (MVD).	[24]

References

• [1] 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.
• [2] Genomic variations of the mevalonate pathway in porokeratosis. Elife. 2015 Jul 23;4:e06322. doi: 10.7554/eLife.06322.
• [3] 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.
• [4] 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.
• [5] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Characterisation of cisplatin-induced transcriptomics responses in primary mouse hepatocytes, HepG2 cells and mouse embryonic stem cells shows conservation of regulating transcription factor networks. Mutagenesis. 2014 Jan;29(1):17-26.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [13] 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.
• [14] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [15] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [16] Gene-expression profiling during curcumin-induced apoptosis reveals downregulation of CXCR4. Exp Hematol. 2007 Jan;35(1):84-95.
• [17] Changes in gene expressions elicited by physiological concentrations of genistein on human endometrial cancer cells. Mol Carcinog. 2006 Oct;45(10):752-63.
• [18] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [19] 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.
• [20] Effect of celecoxib on E-cadherin, VEGF, Microvessel density and apoptosis in gastric cancer. Cancer Biol Ther. 2007 Feb;6(2):269-75.
• [21] 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.
• [22] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [23] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [24] Whole genome mRNA transcriptomics analysis reveals different modes of action of the diarrheic shellfish poisons okadaic acid and dinophysis toxin-1 versus azaspiracid-1 in Caco-2 cells. Toxicol In Vitro. 2018 Feb;46:102-112.
• [25] 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.