Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT36HLDO)

• DOT Name: Protein O-mannose kinase (POMK)
• Synonyms: POMK; EC 2.7.1.183; Protein kinase-like protein SgK196; Sugen kinase 196
• Gene Name: POMK
• Related Disease:
  Congenital hydrocephalus
  Familial congenital mirror movements
  Hydrocephalus
  Megalencephaly
  Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 12
  Limb-girdle muscular dystrophy due to POMK deficiency
  Muscular dystrophy-dystroglycanopathy, type A
  Obsolete congenital muscular dystrophy with cerebellar involvement
  Congenital muscular dystrophy
  Limb-girdle muscular dystrophy
• UniProt ID: SG196_HUMAN
• EC Number: 2.7.1.183
• Pfam ID: PF07714
• Sequence:
  MEKQPQNSRRGLAPREVPPAVGLLLIMALMNTLLYLCLDHFFIAPRQSTVDPTHCPYGHF
  RIGQMKNCSPWLSCEELRTEVRQLKRVGEGAVKRVFLSEWKEHKVALSQLTSLEMKDDFL
  HGLQMLKSLQGTHVVTLLGYCEDDNTMLTEYHPLGSLSNLEETLNLSKYQNVNTWQHRLE
  LAMDYVSIINYLHHSPVGTRVMCDSNDLPKTLSQYLLTSNFSILANDLDALPLVNHSSGM
  LVKCGHRELHGDFVAPEQLWPYGEDVPFHDDLMPSYDEKIDIWKIPDISSFLLGHIEGSD
  MVRFHLFDIHKACKSQTPSERPTAQDVLETYQKVLDTLRDAMMSQAREML
• Function: Protein O-mannose kinase that specifically mediates phosphorylation at the 6-position of an O-mannose of the trisaccharide (N-acetylgalactosamine (GalNAc)-beta-1,3-N-acetylglucosamine (GlcNAc)-beta-1,4-mannose) to generate phosphorylated O-mannosyl trisaccharide (N-acetylgalactosamine-beta-1,3-N-acetylglucosamine-beta-1,4-(phosphate-6-)mannose). Phosphorylated O-mannosyl trisaccharide is a carbohydrate structure present in alpha-dystroglycan (DAG1), which is required for binding laminin G-like domain-containing extracellular proteins with high affinity. Only shows kinase activity when the GalNAc-beta-3-GlcNAc-beta-terminus is linked to the 4-position of O-mannose, suggesting that this disaccharide serves as the substrate recognition motif.
• Tissue Specificity: Highest expression is observed in brain, skeletal muscle, kidney and heart in fetal and adult tissues.
• KEGG Pathway:
  Mannose type O-glycan biosynthesis (hsa00515)
  Metabolic pathways (hsa01100)
• Reactome Pathway: O-linked glycosylation (R-HSA-5173105)
• BioCyc Pathway: MetaCyc:G66-30734-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital hydrocephalus	DIS7O6UL	Strong	Biomarker	[1]
Familial congenital mirror movements	DISJLV92	Strong	Genetic Variation	[2]
Hydrocephalus	DISIZUF7	Strong	Genetic Variation	[1]
Megalencephaly	DISYW5SV	Strong	Genetic Variation	[1]
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 12	DIS70JW1	Strong	Autosomal recessive	[3]
Limb-girdle muscular dystrophy due to POMK deficiency	DISM63SY	Supportive	Autosomal recessive	[4]
Muscular dystrophy-dystroglycanopathy, type A	DISZTBC4	Supportive	Autosomal recessive	[5]
Obsolete congenital muscular dystrophy with cerebellar involvement	DIS8CGS1	Supportive	Autosomal recessive	[4]
Congenital muscular dystrophy	DISKY7OY	Limited	Biomarker	[1]
Limb-girdle muscular dystrophy	DISI9Y1Z	Limited	Genetic Variation	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Protein O-mannose kinase (POMK).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein O-mannose kinase (POMK).	[7]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Protein O-mannose kinase (POMK).	[8]

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 Protein O-mannose kinase (POMK).	[9]

References

• [1] Pathogenic homozygous variant in POMK gene is the cause of prenatally detected severe ventriculomegaly in two Lithuanian families.Am J Med Genet A. 2020 Mar;182(3):536-542. doi: 10.1002/ajmg.a.61453. Epub 2019 Dec 12.
• [2] Congenital mirror movements in a patient with alpha-dystroglycanopathy due to a novel POMK mutation.Neuromuscul Disord. 2017 Mar;27(3):239-242. doi: 10.1016/j.nmd.2016.12.008. Epub 2016 Dec 23.
• [3] 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.
• [4] POMK mutations disrupt muscle development leading to a spectrum of neuromuscular presentations. Hum Mol Genet. 2014 Nov 1;23(21):5781-92. doi: 10.1093/hmg/ddu296. Epub 2014 Jun 11.
• [5] Deciphering the glycosylome of dystroglycanopathies using haploid screens for lassa virus entry. Science. 2013 Apr 26;340(6131):479-83. doi: 10.1126/science.1233675. Epub 2013 Mar 21.
• [6] 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.
• [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] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [9] 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.