Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTL0KLRP)

• DOT Name: Phosphorylase b kinase gamma catalytic chain, liver/testis isoform (PHKG2)
• Synonyms: PHK-gamma-LT; PHK-gamma-T; EC 2.7.11.19; PSK-C3; Phosphorylase kinase subunit gamma-2
• Gene Name: PHKG2
• Related Disease:
  Glycogen storage disease IXc
  Glycogen storage disease due to liver phosphorylase kinase deficiency
• UniProt ID: PHKG2_HUMAN
• PDB ID: 2Y7J
• EC Number: 2.7.11.19
• Pfam ID: PF00069
• Sequence:
  MTLDVGPEDELPDWAAAKEFYQKYDPKDVIGRGVSSVVRRCVHRATGHEFAVKIMEVTAE
  RLSPEQLEEVREATRRETHILRQVAGHPHIITLIDSYESSSFMFLVFDLMRKGELFDYLT
  EKVALSEKETRSIMRSLLEAVSFLHANNIVHRDLKPENILLDDNMQIRLSDFGFSCHLEP
  GEKLRELCGTPGYLAPEILKCSMDETHPGYGKEVDLWACGVILFTLLAGSPPFWHRRQIL
  MLRMIMEGQYQFSSPEWDDRSSTVKDLISRLLQVDPEARLTAEQALQHPFFERCEGSQPW
  NLTPRQRFRVAVWTVLAAGRVALSTHRVRPLTKNALLRDPYALRSVRHLIDNCAFRLYGH
  WVKKGEQQNRAALFQHRPPGPFPIMGPEEEGDSAAITEDEAVLVLG
• Function: Catalytic subunit of the phosphorylase b kinase (PHK), which mediates the neural and hormonal regulation of glycogen breakdown (glycogenolysis) by phosphorylating and thereby activating glycogen phosphorylase. May regulate glycogeneolysis in the testis. In vitro, phosphorylates PYGM.
• KEGG Pathway:
  Calcium sig.ling pathway (hsa04020)
  Insulin sig.ling pathway (hsa04910)
  Glucagon sig.ling pathway (hsa04922)
• Reactome Pathway: Glycogen breakdown (glycogenolysis) (R-HSA-70221)
• BioCyc Pathway: MetaCyc:HS08155-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
Glycogen storage disease IXc	DISJ8ZS3	Strong	Autosomal recessive	[1]
Glycogen storage disease due to liver phosphorylase kinase deficiency	DISTTAS6	Supportive	Autosomal recessive	[2]

1 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 Phosphorylase b kinase gamma catalytic chain, liver/testis isoform (PHKG2).	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Phosphorylase b kinase gamma catalytic chain, liver/testis isoform (PHKG2).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Phosphorylase b kinase gamma catalytic chain, liver/testis isoform (PHKG2).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Phosphorylase b kinase gamma catalytic chain, liver/testis isoform (PHKG2).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Phosphorylase b kinase gamma catalytic chain, liver/testis isoform (PHKG2).	[7]

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] Clinical Practice Guidelines for Rare Diseases: The Orphanet Database. PLoS One. 2017 Jan 18;12(1):e0170365. doi: 10.1371/journal.pone.0170365. eCollection 2017.
• [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] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [5] 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.
• [6] 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.
• [7] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.