Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2R9ZXW)

• DOT Name: Protein adenylyltransferase FICD (FICD)
• Synonyms: EC 2.7.7.108; AMPylator FICD; De-AMPylase FICD; EC 3.1.4.-; FIC domain-containing protein; Huntingtin yeast partner E; Huntingtin-interacting protein 13; HIP-13; Huntingtin-interacting protein E
• Gene Name: FICD
• UniProt ID: FICD_HUMAN
• PDB ID: 4U04; 4U07; 4U0S; 4U0U; 4U0Z; 6I7G; 6I7H; 6I7I; 6I7J; 6I7K; 6I7L; 6ZMD; 7B7Z; 7B80
• EC Number: 2.7.7.108; 3.1.4.-
• Pfam ID: PF02661
• Sequence:
  MMLIPMASVMAVTEPKWVSVWSRFLWVTLLSMVLGSLLALLLPLGAVEEQCLAVLKGLYL
  LRSKPDRAQHAATKCTSPSTELSITSRGATLLVAKTKASPAGKLEARAALNQALEMKRQG
  KREKAQKLFMHALKMDPDFVDALTEFGIFSEEDKDIIQADYLYTRALTISPYHEKALVNR
  DRTLPLVEEIDQRYFSIIDSKVKKVMSIPKGNSALRRVMEETYYHHIYHTVAIEGNTLTL
  SEIRHILETRYAVPGKSLEEQNEVIGMHAAMKYINTTLVSRIGSVTISDVLEIHRRVLGY
  VDPVEAGRFRTTQVLVGHHIPPHPQDVEKQMQEFVQWLNSEEAMNLHPVEFAALAHYKLV
  YIHPFIDGNGRTSRLLMNLILMQAGYPPITIRKEQRSDYYHVLEAANEGDVRPFIRFIAK
  CTETTLDTLLFATTEYSVALPEAQPNHSGFKETLPVKP
• Function: Protein that can both mediate the addition of adenosine 5'-monophosphate (AMP) to specific residues of target proteins (AMPylation), and the removal of the same modification from target proteins (de-AMPylation), depending on the context. The side chain of Glu-231 determines which of the two opposing activities (AMPylase or de-AMPylase) will take place. Acts as a key regulator of the ERN1/IRE1-mediated unfolded protein response (UPR) by mediating AMPylation or de-AMPylation of HSPA5/BiP. In unstressed cells, acts as an adenylyltransferase by mediating AMPylation of HSPA5/BiP at 'Thr-518', thereby inactivating it. In response to endoplasmic reticulum stress, acts as a phosphodiesterase by mediating removal of ATP (de-AMPylation) from HSPA5/BiP at 'Thr-518', leading to restore HSPA5/BiP activity. Although it is able to AMPylate RhoA, Rac and Cdc42 Rho GTPases in vitro, Rho GTPases do not constitute physiological substrates.
• Tissue Specificity: Ubiquitous.

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Protein adenylyltransferase FICD (FICD).	[1]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Protein adenylyltransferase FICD (FICD).	[2]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Protein adenylyltransferase FICD (FICD).	[3]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Protein adenylyltransferase FICD (FICD).	[1]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Protein adenylyltransferase FICD (FICD).	[4]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Protein adenylyltransferase FICD (FICD).	[5]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Protein adenylyltransferase FICD (FICD).	[7]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Protein adenylyltransferase FICD (FICD).	[8]
Celastrol	DMWQIJX	Preclinical	Celastrol increases the expression of Protein adenylyltransferase FICD (FICD).	[9]

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 affects the methylation of Protein adenylyltransferase FICD (FICD).	[6]

References

• [1] 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.
• [2] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [3] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [4] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [5] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [6] 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.
• [7] 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.
• [8] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [9] Gene expression signature-based chemical genomic prediction identifies a novel class of HSP90 pathway modulators. Cancer Cell. 2006 Oct;10(4):321-30.