Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTH3W1RR)

• DOT Name: Histatin-1 (HTN1)
• Synonyms: Hst1; Histidine-rich protein 1; Post-PB protein; PPB
• Gene Name: HTN1
• Related Disease:
  Drug dependence
  Amelogenesis imperfecta
  Autism
  Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 1
  Leukemia
  Myeloid leukaemia
  Non-insulin dependent diabetes
  Pleuropulmonary blastoma
  Prostate carcinoma
  Embryonal neoplasm
  High blood pressure
  Keratoconjunctivitis sicca
• UniProt ID: HIS1_HUMAN
• Sequence: MKFFVFALVLALMISMISADSHEKRHHGYRRKFHEKHHSHREFPFYGDYGSNYLYDN
• Function: Histatins (Hsts) are cationic and histidine-rich secreted peptides mainly synthesized by saliva glands of humans and higher primates. Hsts are considered to be major precursors of the protective proteinaceous structure on tooth surfaces (enamel pellicle). Hsts can be divided into two major groups according to their biological functions: antimicrobial Hsts (e.g. Hst 5/HTN3) and cell-activating Hsts (e.g. Hst 1/HTN1 and Hst 2/HTN1). Hst 1/HTN1 and Hst 2/HTN1 act in different cell types (epithelium, fibroblasts and endothelium) in oral and non-oral mucosa ; [Histatin-1]: Hst 1 functions primarily as a wound healing factor by activating cell-surface and cell-cell adhesions, cell spreading and migration and it can also stimulate cellular metabolic activity. Hst 1 is internalized in host cells in a stereospecific and energy-dependent process, which is partially mediated by the G protein-coupled receptors (GPCR)-activated endocytosis. Internalized Hst 1 is targeted and released via early endosomes trafficking to the mitochondria, where it significantly enhances mitochondrial energy metabolism. At the mitochondria, Hst 1 increases mitochondria-ER contacts through binding with ER receptor TMEM97, which also stimulates metabolic activity and cell migration and may as well regulate calcium homeostasis of the cell. Also activates the ERK1/2 signaling pathway to promote cell migration, possibly upon interaction with GPRCs at the plasma membrane. Also triggers the RIN2/Rab5/Rac1 signaling cascade which activates endothelial cell adhesion, spreading and migration required for angiogenesis in the oral wound healing process, however the receptor that transduces Hst 1 signal has not yet been identified. Also displays antimicrobial functions against pathogenic yeast Candida albicans, although with less effectiveness than Hst 5 ; [His1-(31-57)-peptide]: Hst 2 consists of the fragment sequence 12-28 of Hst 1. Similar to Hst 1, actively and stereospecifically internalized in host cells and targeted to the mitochondria and the ER and promotes cell metabolic activity. Also activates the ERK1/2 signaling pathway to promote cell migration and wound closure. In contrast with Hst 1, not able to promote cell-substrate and cell-cell adhesion.
• Tissue Specificity: .Submandibular and parotid glands.
• KEGG Pathway: Salivary secretion (hsa04970)
• Reactome Pathway: Antimicrobial peptides (R-HSA-6803157)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Drug dependence	DIS9IXRC	Definitive	Genetic Variation	[1]
Amelogenesis imperfecta	DISGYR9E	Strong	Genetic Variation	[2]
Autism	DISV4V1Z	Strong	Biomarker	[3]
Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 1	DISBHBD6	Strong	Altered Expression	[4]
Leukemia	DISNAKFL	Strong	Biomarker	[5]
Myeloid leukaemia	DISMN944	Strong	Biomarker	[6]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[7]
Pleuropulmonary blastoma	DIS3UCS9	Strong	Altered Expression	[8]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[9]
Embryonal neoplasm	DIS5MQSB	moderate	Biomarker	[10]
High blood pressure	DISY2OHH	moderate	Altered Expression	[11]
Keratoconjunctivitis sicca	DISNOENH	Limited	Biomarker	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Histatin-1 (HTN1).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Histatin-1 (HTN1).	[14]

References

• [1] Strong association of the alcohol dehydrogenase 1B gene (ADH1B) with alcohol dependence and alcohol-induced medical diseases.Biol Psychiatry. 2011 Sep 15;70(6):504-12. doi: 10.1016/j.biopsych.2011.02.024. Epub 2011 Apr 17.
• [2] Enamelin maps to human chromosome 4q21 within the autosomal dominant amelogenesis imperfecta locus.Eur J Oral Sci. 2000 Oct;108(5):353-8. doi: 10.1034/j.1600-0722.2000.108005353.x.
• [3] Hypo-phosphorylation of salivary peptidome as a clue to the molecular pathogenesis of autism spectrum disorders.J Proteome Res. 2008 Dec;7(12):5327-32. doi: 10.1021/pr8004088.
• [4] Evaluation of Accessory Lacrimal Gland in Muller's Muscle Conjunctival Resection Specimens for Precursor Cell Markers and Biological Markers of Dry Eye Disease.Curr Eye Res. 2017 Apr;42(4):491-497. doi: 10.1080/02713683.2016.1214966. Epub 2016 Sep 9.
• [5] Expression of the putative proto-oncogene His-1 in normal and neoplastic tissues.Am J Pathol. 1997 Apr;150(4):1297-305.
• [6] His-1 and His-2: identification and chromosomal mapping of two commonly rearranged sites of viral integration in a myeloid leukemia.Oncogene. 1991 Nov;6(11):2041-7.
• [7] Design, synthesis, biological evaluation and molecular dynamics studies of 4-thiazolinone derivatives as protein tyrosine phosphatase 1B (PTP1B) inhibitors.J Biomol Struct Dyn. 2020 Aug;38(13):3814-3824. doi: 10.1080/07391102.2019.1664333. Epub 2019 Sep 19.
• [8] Lichen planopilaris and pseudopelade of Brocq involve distinct disease associated gene expression patterns by microarray.J Dermatol Sci. 2010 Jan;57(1):27-36. doi: 10.1016/j.jdermsci.2009.10.011. Epub 2009 Nov 22.
• [9] Long-term oncologic outcomes of radiotherapy combined with maximal androgen blockade for localized, high-risk prostate cancer.World J Surg Oncol. 2018 Jun 11;16(1):107. doi: 10.1186/s12957-018-1395-5.
• [10] Hidden chromosomal abnormalities in pleuropulmonary blastomas identified by multiplex FISH.BMC Cancer. 2006 Jan 5;6:4. doi: 10.1186/1471-2407-6-4.
• [11] Hypertension Severity Is Associated With Impaired Cognitive Performance.J Am Heart Assoc. 2017 Jan 11;6(1):e004579. doi: 10.1161/JAHA.116.004579.
• [12] Presence of Histatin-1 in Human Tears and Association with Aqueous Deficient Dry Eye Diagnosis: A Preliminary Study.Sci Rep. 2019 Jul 16;9(1):10304. doi: 10.1038/s41598-019-46623-9.
• [13] 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.
• [14] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.