Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0BGJQS)

• DOT Name: Protein fem-1 homolog A (FEM1A)
• Synonyms: FEM1a; FEM1-alpha; Prostaglandin E receptor 4-associated protein
• Gene Name: FEM1A
• Related Disease:
  Myocardial infarction
  Polycystic ovarian syndrome
  Rhabdomyosarcoma
• UniProt ID: FEM1A_HUMAN
• Pfam ID: PF00023 ; PF12796
• Sequence:
  MDLRTAVYNAARDGKLQLLQKLLSGRSREELDELTGEVAGGGTPLLIAARYGHLDVVEYL
  VDRCGASVEAGGSVHFDGETIEGAPPLWAASAAGHLDVVRSLLRRGASVNRTTRTNSTPL
  RAACFDGHLEVVRYLVGEHQADLEVANRHGHTCLMISCYKGHREIARYLLEQGAQVNRRS
  AKGNTALHDCAESGSLEILQLLLGCKARMERDGYGMTPLLAASVTGHTNIVEYLIQEQPG
  QEQVAGGEAQPGLPQEDPSTSQGCAQPQGAPCCSSSPEEPLNGESYESCCPTSREAAVEA
  LELLGATYVDKKRDLLGALKHWRRAMELRHQGGEYLPKPEPPQLVLAYDYSREVNTTEEL
  EALITDPDEMRMQALLIRERILGPSHPDTSYYIRYRGAVYADSGNFERCIRLWKYALDMQ
  QSNLEPLSPMTASSFLSFAELFSYVLQDRAAKGSLGTQIGFADLMGVLTKGVREVERALQ
  LPREPGDSAQFTKALAIILHLLYLLEKVECTPSQEHLKHQTVYRLLKCAPRGKNGFTPLH
  MAVDKDTTNVGRYPVGRFPSLHVVKVLLDCGADPDSRDFDNNTPLHIAAQNNCPAIMNAL
  IEAGAHMDATNAFKKTAYELLDEKLLARGTMQPFNYVTLQCLAARALDKNKIPYKGFIPE
  DLEAFIELH
• Function: Substrate-recognition component of a Cul2-RING (CRL2) E3 ubiquitin-protein ligase complex of the DesCEND (destruction via C-end degrons) pathway, which recognizes a C-degron located at the extreme C terminus of target proteins, leading to their ubiquitination and degradation. The C-degron recognized by the DesCEND pathway is usually a motif of less than ten residues and can be present in full-length proteins, truncated proteins or proteolytically cleaved forms. The CRL2(FEM1A) complex specifically recognizes proteins with an arginine at the C-terminus: recognizes and binds proteins ending with -Lys/Arg-Xaa-Arg and -Lys/Arg-Xaa-Xaa-Arg C-degrons, such as SIL1 or OR51B2, leading to their ubiquitination and degradation. Promotes ubiquitination and degradation of SLBP. Involved in PGE2-EP4-mediated inhibition of inflammation of macrophages via interaction with NFKB1 and PTGER4. Promotes inflammation in brain microglia through MAP2K4/MKK4-mediated signaling.
• Tissue Specificity: Present in macrophages derived from peripheral blood monocytes. Also present in atheromata (at protein level).
• Reactome Pathway: Neddylation (R-HSA-8951664)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Myocardial infarction	DIS655KI	Strong	Altered Expression	[1]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Genetic Variation	[2]
Rhabdomyosarcoma	DISNR7MS	moderate	Altered Expression	[3]

2 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 Protein fem-1 homolog A (FEM1A).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Protein fem-1 homolog A (FEM1A).	[6]

3 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 fem-1 homolog A (FEM1A).	[5]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Protein fem-1 homolog A (FEM1A).	[7]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Protein fem-1 homolog A (FEM1A).	[8]

References

• [1] Fem1a is a mitochondrial protein up-regulated upon ischemia-reperfusion injury.FEBS Lett. 2009 May 19;583(10):1625-30. doi: 10.1016/j.febslet.2009.04.035. Epub 2009 May 4.
• [2] FEM1A and FEM1B: novel candidate genes for polycystic ovary syndrome.Hum Reprod. 2008 Dec;23(12):2842-9. doi: 10.1093/humrep/den324. Epub 2008 Aug 29.
• [3] The Fem1a gene is downregulated in Rhabdomyosarcoma.Tumour Biol. 2005 Nov-Dec;26(6):294-9. doi: 10.1159/000089261. Epub 2005 Oct 25.
• [4] 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.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [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] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.