Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBPNIC0)

• DOT Name: Growth hormone-inducible transmembrane protein (GHITM)
• Synonyms: Dermal papilla-derived protein 2; Mitochondrial morphology and cristae structure 1; MICS1; Transmembrane BAX inhibitor motif-containing protein 5
• Gene Name: GHITM
• UniProt ID: GHITM_HUMAN
• Pfam ID: PF01027
• Sequence:
  MLAARLVCLRTLPSRVFHPAFTKASPVVKNSITKNQWLLTPSREYATKTRIGIRRGRTGQ
  ELKEAALEPSMEKIFKIDQMGRWFVAGGAAVGLGALCYYGLGLSNEIGAIEKAVIWPQYV
  KDRIHSTYMYLAGSIGLTALSAIAISRTPVLMNFMMRGSWVTIGVTFAAMVGAGMLVRSI
  PYDQSPGPKHLAWLLHSGVMGAVVAPLTILGGPLLIRAAWYTAGIVGGLSTVAMCAPSEK
  FLNMGAPLGVGLGLVFVSSLGSMFLPPTTVAGATLYSVAMYGGLVLFSMFLLYDTQKVIK
  RAEVSPMYGVQKYDPINSMLSIYMDTLNIFMRVATMLATGGNRKK
• Function: Plays an important role in maintenance of mitochondrial morphology and in mediating either calcium or potassium/proton antiport. Mediates proton-dependent calcium efflux from mitochondrion. Functions also as an electroneutral mitochondrial proton/potassium exchanger. Required for the mitochondrial tubular network and cristae organization. Involved in apoptotic release of cytochrome c. Inhibits the proteolytic activity of AFG3L2, stimulating respiration and stabilizing respiratory enzymes in actively respiring mitochondria. However, when mitochondria become hyperpolarized, GHITM loses its inhibitory activity toward AFG3L2 and the now the active AFG3L2 turns first on GHITM and, if hyperpolarization persists, on other proteins of the mitochondria, leading to a broad remodeling of the mitochondrial proteome.

Molecular Interaction Atlas (MIA) of This DOT

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 Growth hormone-inducible transmembrane protein (GHITM).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Growth hormone-inducible transmembrane protein (GHITM).	[9]

11 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 Growth hormone-inducible transmembrane protein (GHITM).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Growth hormone-inducible transmembrane protein (GHITM).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Growth hormone-inducible transmembrane protein (GHITM).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Growth hormone-inducible transmembrane protein (GHITM).	[5]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Growth hormone-inducible transmembrane protein (GHITM).	[6]
Aspirin	DM672AH	Approved	Aspirin increases the expression of Growth hormone-inducible transmembrane protein (GHITM).	[7]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Growth hormone-inducible transmembrane protein (GHITM).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Growth hormone-inducible transmembrane protein (GHITM).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Growth hormone-inducible transmembrane protein (GHITM).	[11]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Growth hormone-inducible transmembrane protein (GHITM).	[12]
chloropicrin	DMSGBQA	Investigative	chloropicrin affects the expression of Growth hormone-inducible transmembrane protein (GHITM).	[13]

References

• [1] 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.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] 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.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] 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.
• [6] 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.
• [7] Expression profile analysis of human peripheral blood mononuclear cells in response to aspirin. Arch Immunol Ther Exp (Warsz). 2005 Mar-Apr;53(2):151-8.
• [8] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [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.
• [10] 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.
• [11] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [12] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [13] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.