Details of Drug Off-Target (DOT)

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

• DOT Name: Mevalonate kinase (MVK)
• Synonyms: MK; EC 2.7.1.36
• Gene Name: MVK
• Related Disease:
  Hyperimmunoglobulinemia D with periodic fever
  Mevalonic aciduria
  Porokeratosis 3, disseminated superficial actinic type
  Disseminated superficial actinic porokeratosis
  Porokeratosis of Mibelli
• UniProt ID: KIME_HUMAN
• PDB ID: 2R3V
• EC Number: 2.7.1.36
• Pfam ID: PF08544 ; PF00288
• Sequence:
  MLSEVLLVSAPGKVILHGEHAVVHGKVALAVSLNLRTFLRLQPHSNGKVDLSLPNIGIKR
  AWDVARLQSLDTSFLEQGDVTTPTSEQVEKLKEVAGLPDDCAVTERLAVLAFLYLYLSIC
  RKQRALPSLDIVVWSELPPGAGLGSSAAYSVCLAAALLTVCEEIPNPLKDGDCVNRWTKE
  DLELINKWAFQGERMIHGNPSGVDNAVSTWGGALRYHQGKISSLKRSPALQILLTNTKVP
  RNTRALVAGVRNRLLKFPEIVAPLLTSIDAISLECERVLGEMGEAPAPEQYLVLEELIDM
  NQHHLNALGVGHASLDQLCQVTRARGLHSKLTGAGGGGCGITLLKPGLEQPEVEATKQAL
  TSCGFDCLETSIGAPGVSIHSATSLDSRVQQALDGL
• Function: Catalyzes the phosphorylation of mevalonate to mevalonate 5-phosphate, a key step in isoprenoid and cholesterol biosynthesis.
• 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:ENSG00000110921-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hyperimmunoglobulinemia D with periodic fever	DISWB92Q	Definitive	Autosomal recessive	[1]
Mevalonic aciduria	DISHJKP5	Definitive	Mitochondrial	[1]
Porokeratosis 3, disseminated superficial actinic type	DISPRT4O	Strong	Autosomal dominant	[2]
Disseminated superficial actinic porokeratosis	DISELZ77	Supportive	Autosomal dominant	[3]
Porokeratosis of Mibelli	DISF48DQ	Supportive	Autosomal dominant	[4]

This DOT Affected the Biotransformations of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Adenosine triphosphate	DM79F6G	Approved	Mevalonate kinase (MVK) increases the hydrolysis of Adenosine triphosphate.	[23]
ANW-32821	DMMJOZD	Phase 2	Mevalonate kinase (MVK) decreases the chemical synthesis of ANW-32821.	[27]

27 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 Mevalonate kinase (MVK).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Mevalonate kinase (MVK).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Mevalonate kinase (MVK).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Mevalonate kinase (MVK).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Mevalonate kinase (MVK).	[9]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Mevalonate kinase (MVK).	[10]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Mevalonate kinase (MVK).	[11]
Selenium	DM25CGV	Approved	Selenium increases the expression of Mevalonate kinase (MVK).	[12]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Mevalonate kinase (MVK).	[13]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Mevalonate kinase (MVK).	[14]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Mevalonate kinase (MVK).	[15]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Mevalonate kinase (MVK).	[16]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Mevalonate kinase (MVK).	[17]
Methamphetamine	DMPM4SK	Approved	Methamphetamine increases the expression of Mevalonate kinase (MVK).	[18]
Fluoxetine	DM3PD2C	Approved	Fluoxetine increases the expression of Mevalonate kinase (MVK).	[19]
Clavulanate	DM2FGRT	Approved	Clavulanate decreases the expression of Mevalonate kinase (MVK).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Mevalonate kinase (MVK).	[22]
SQ-32709	DMSQRXW	Discontinued in Phase 2	SQ-32709 decreases the activity of Mevalonate kinase (MVK).	[23]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Mevalonate kinase (MVK).	[24]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Mevalonate kinase (MVK).	[25]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Mevalonate kinase (MVK).	[20]
Farnesol	DMV2X1B	Investigative	Farnesol decreases the activity of Mevalonate kinase (MVK).	[23]
Ganoderic acid A	DM42EVG	Investigative	Ganoderic acid A decreases the expression of Mevalonate kinase (MVK).	[26]
ISOPENTENYL PYROPHOSPHATE	DMTU05Y	Investigative	ISOPENTENYL PYROPHOSPHATE decreases the activity of Mevalonate kinase (MVK).	[23]
Dimethylallyl Diphosphate	DMP5I47	Investigative	Dimethylallyl Diphosphate decreases the activity of Mevalonate kinase (MVK).	[23]
Geranyl Diphosphate	DMB9LE1	Investigative	Geranyl Diphosphate decreases the activity of Mevalonate kinase (MVK).	[23]
GERANYLGERANYL DIPHOSPHATE	DMJZ0AM	Investigative	GERANYLGERANYL DIPHOSPHATE decreases the activity of Mevalonate kinase (MVK).	[23]

1 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 decreases the methylation of Mevalonate kinase (MVK).	[21]

References

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• [3] Exome sequencing identifies MVK mutations in disseminated superficial actinic porokeratosis. Nat Genet. 2012 Oct;44(10):1156-60. doi: 10.1038/ng.2409. Epub 2012 Sep 16.
• [4] Genomic variations of the mevalonate pathway in porokeratosis. Elife. 2015 Jul 23;4:e06322. doi: 10.7554/eLife.06322.
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• [23] 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.
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• [25] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [26] Ganoderic Acid A improves high fat diet-induced obesity, lipid accumulation and insulin sensitivity through regulating SREBP pathway. Chem Biol Interact. 2018 Jun 25;290:77-87.
• [27] Temperature and drug treatments in mevalonate kinase deficiency: an ex vivo study. Biomed Res Int. 2013;2013:715465. doi: 10.1155/2013/715465. Epub 2013 Sep 1.