Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTE0FNAP)

• DOT Name: Vitamin K-dependent gamma-carboxylase (GGCX)
• Synonyms: EC 4.1.1.90; Gamma-glutamyl carboxylase; Peptidyl-glutamate 4-carboxylase; Vitamin K gamma glutamyl carboxylase
• Gene Name: GGCX
• Related Disease:
  Vitamin K-dependent clotting factors, combined deficiency of, type 1
  Body skin hyperlaxity due to vitamin K-dependent coagulation factor deficiency
  Pulmonary arterial hypertension
  Pseudoxanthoma elasticum-like skin manifestations with retinitis pigmentosa
• UniProt ID: VKGC_HUMAN
• EC Number: 4.1.1.90
• Pfam ID: PF05090
• Sequence:
  MAVSAGSARTSPSSDKVQKDKAELISGPRQDSRIGKLLGFEWTDLSSWRRLVTLLNRPTD
  PASLAVFRFLFGFLMVLDIPQERGLSSLDRKYLDGLDVCRFPLLDALRPLPLDWMYLVYT
  IMFLGALGMMLGLCYRISCVLFLLPYWYVFLLDKTSWNNHSYLYGLLAFQLTFMDANHYW
  SVDGLLNAHRRNAHVPLWNYAVLRGQIFIVYFIAGVKKLDADWVEGYSMEYLSRHWLFSP
  FKLLLSEELTSLLVVHWGGLLLDLSAGFLLFFDVSRSIGLFFVSYFHCMNSQLFSIGMFS
  YVMLASSPLFCSPEWPRKLVSYCPRRLQQLLPLKAAPQPSVSCVYKRSRGKSGQKPGLRH
  QLGAAFTLLYLLEQLFLPYSHFLTQGYNNWTNGLYGYSWDMMVHSRSHQHVKITYRDGRT
  GELGYLNPGVFTQSRRWKDHADMLKQYATCLSRLLPKYNVTEPQIYFDIWVSINDRFQQR
  IFDPRVDIVQAAWSPFQRTSWVQPLLMDLSPWRAKLQEIKSSLDNHTEVVFIADFPGLHL
  ENFVSEDLGNTSIQLLQGEVTVELVAEQKNQTLREGEKMQLPAGEYHKVYTTSPSPSCYM
  YVYVNTTELALEQDLAYLQELKEKVENGSETGPLPPELQPLLEGEVKGGPEPTPLVQTFL
  RRQQRLQEIERRRNTPFHERFFRFLLRKLYVFRRSFLMTCISLRNLILGRPSLEQLAQEV
  TYANLRPFEAVGELNPSNTDSSHSNPPESNPDPVHSEF
• Function: Mediates the vitamin K-dependent carboxylation of glutamate residues to calcium-binding gamma-carboxyglutamate (Gla) residues with the concomitant conversion of the reduced hydroquinone form of vitamin K to vitamin K epoxide. Catalyzes gamma-carboxylation of various proteins, such as blood coagulation factors (F2, F7, F9 and F10), osteocalcin (BGLAP) or matrix Gla protein (MGP).
• KEGG Pathway:
  Ubiquinone and other terpenoid-quinone biosynthesis (hsa00130)
  Metabolic pathways (hsa01100)
  Biosynthesis of cofactors (hsa01240)
• Reactome Pathway:
  Defective gamma-carboxylation of F9 (R-HSA-9673240)
  Gamma-carboxylation of protein precursors (R-HSA-159740)
• BioCyc Pathway: MetaCyc:HS03897-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Vitamin K-dependent clotting factors, combined deficiency of, type 1	DIS1X7PX	Definitive	Autosomal recessive	[1]
Body skin hyperlaxity due to vitamin K-dependent coagulation factor deficiency	DISXJ5O8	Strong	Autosomal recessive	[2]
Pulmonary arterial hypertension	DISP8ZX5	Moderate	Autosomal dominant	[1]
Pseudoxanthoma elasticum-like skin manifestations with retinitis pigmentosa	DIS2YFDG	Supportive	Autosomal recessive	[3]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Vinblastine	DM5TVS3	Approved	Vitamin K-dependent gamma-carboxylase (GGCX) affects the response to substance of Vinblastine.	[13]
Warfarin	DMJYCVW	Approved	Vitamin K-dependent gamma-carboxylase (GGCX) decreases the response to substance of Warfarin.	[14]

8 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 Vitamin K-dependent gamma-carboxylase (GGCX).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Vitamin K-dependent gamma-carboxylase (GGCX).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Vitamin K-dependent gamma-carboxylase (GGCX).	[6]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Vitamin K-dependent gamma-carboxylase (GGCX).	[7]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Vitamin K-dependent gamma-carboxylase (GGCX).	[8]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Vitamin K-dependent gamma-carboxylase (GGCX).	[9]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Vitamin K-dependent gamma-carboxylase (GGCX).	[10]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of Vitamin K-dependent gamma-carboxylase (GGCX).	[12]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Vitamin K-dependent gamma-carboxylase (GGCX).	[11]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Pseudoxanthoma elasticum-like phenotype with cutis laxa and multiple coagulation factor deficiency represents a separate genetic entity. J Invest Dermatol. 2007 Mar;127(3):581-7. doi: 10.1038/sj.jid.5700610. Epub 2006 Nov 16.
• [3] Retinitis pigmentosa, cutis laxa, and pseudoxanthoma elasticum-like skin manifestations associated with GGCX mutations. J Invest Dermatol. 2014 Sep;134(9):2331-2338. doi: 10.1038/jid.2014.191. Epub 2014 Apr 16.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] 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.
• [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] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [8] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [9] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [10] 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.
• [11] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [12] Classification of heavy-metal toxicity by human DNA microarray analysis. Environ Sci Technol. 2007 May 15;41(10):3769-74.
• [13] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.
• [14] The influence of sequence variations in factor VII, gamma-glutamyl carboxylase and vitamin K epoxide reductase complex genes on warfarin dose requirement. Thromb Haemost. 2006 May;95(5):782-7.