Biology:Histatin
Histatins are a family of histidine-rich (cationic) antimicrobial proteins found in saliva.[1] Histatin's involvement in antimicrobial activities makes histatin part of the innate immune system.[2] Histatin was first discovered (isolated) in 1988, with functions that are responsible in keeping homeostasis inside the oral cavity, helping in the formation of pellicles, and assist in bonding of metal ions.[3] Histatin has multiple structures, dependent on the specific protein of interest.
Structure
The structure of histatin is unique depending on whether the protein of interest is histatin 1, 3 or 5. Nonetheless, histatins mainly possess a cationic (positive) charge due to the primary structure consisting mostly of basic amino acids. An amino acid that is crucial to histatin's function is histidine. Studies show that the removal of histidine (especially in histatin 5) resulted in reduction of antifungal activity.[4]
Histatins are encoded by two genes, HTN1 and HTN3.[5] The primary members include histatin 1 (38 amino acids), histatin 3 (32 amino acids), and histatin 5 (24 amino acids), with histatin 5 derived from proteolytic cleavage of histatin 3.[5] Histatin 1 (UniProt ID: P15515) is notable for its phosphorylation at serine residues, which enhances its binding to hydroxyapatite in the acquired enamel pellicle.[6]
Function
Histatins are antimicrobial and antifungal proteins, and have been found to play a role in wound-closure.[7][8] A significant source of histatins is found in the serous fluid secreted by Ebner's glands, salivary glands at the back of the tongue, and produced by acinus cells.[9] Here they offer some early defense against incoming microbes.[10]
The three major histatins are 1, 3, and 5, which contains 38, 32, and 24 amino acids, respectively. Histatin 2 is a degradation product of histatin 1, and all other histatins are degradation products of Histatin 3 through the process of post-translational proteolysis of the HTN3 gene product.[11] Therefore there are only two genes, HTN1 and HTN3.[citation needed]
The N-terminus of histatin 5 allows it to bind with metals, and this can result in the production of reactive oxygen species.[3]
Histatins disrupt the fungal plasma membrane, resulting in release of the intracellular content of the fungal cell.[9] They also inhibit the growth of yeast, by binding to the potassium transporter and facilitating in the loss of azole-resistant species.[12]
The antifungal properties of histatins have been seen with fungi such as Candida glabrata, Candida krusei, Saccharomyces cerevisiae, and Cryptococcus neoformans.[13]
Histatins also precipitate tannins from solution, thus preventing alimentary adsorption.[14] Histatins are a family of small, histidine-rich, cationic peptides found in human saliva. They are part of the innate immune system and play critical roles in oral health, including antifungal activity,[5] wound healing,[15] and cell migration.[16]
Histatin 5
Histatin 5 is the protein that is associated with the most antifungal function. The antimicrobial activity is concentrated in a region known as the functional domain. An example of its antimicrobial activity is its mechanism of action against C. albicans. The peptide is consumed by the cell and it causes ATP efflux and the production of reactive oxygen species.[17]
Antifungal activity
Histatin 5 exerts potent antifungal effects against Candida albicans by disrupting mitochondrial respiration and generating reactive oxygen species (ROS), leading to fungal cell death.[5] This mechanism is distinct from pore-forming peptides and requires active fungal metabolism.[citation needed]
As mentioned, histatins are able to boost oral health. This is due to the its ability to inhibit adsorption of high-molecular-weight glycoproteins, which serve as sources for cariogenic bacteria. Moreover, histatins help maintain high calcium and phosphate ionic levels which boosts enamel integrity.[18] Enamel integrity is based upon its ability to remineralize, which requires the precipitation of calcium phosphate.[19]
Wound healing
Histatins 1 and 2 are major contributors to oral wound closure. They promote epithelial cell migration via stereospecific activation of the ERK1/2 signaling pathway, enhancing re-epithelialization in vitro and in vivo.[15] Histatin 1 also stimulates endothelial cell migration and angiogenesis, critical for tissue repair.[16]
Cell migration
Histatins enhance migration in oral keratinocytes, fibroblasts, and endothelial cells. By increasing the number of fibroblast cells, histatin improves collagen deposition as well.[20] Histatin 1 activates Rac1 GTPase through the RIN2/Rab5 signaling axis, facilitating cell adhesion and vascular morphogenesis.[16]
References
- ↑ Histatins at the US National Library of Medicine Medical Subject Headings (MeSH)
- ↑ "Innate immune cell response upon Candida albicans infection". Virulence 7 (5): 512–26. July 2016. doi:10.1080/21505594.2016.1138201. PMID 27078171.
- ↑ 3.0 3.1 Khurshid, Zohaib; Najeeb, Shariq; Mali, Maria; Moin, Syed Faraz; Raza, Syed Qasim; Zohaib, Sana; Sefat, Farshid; Zafar, Muhammad Sohail (January 2017). "Histatin peptides: Pharmacological functions and their applications in dentistry". Saudi Pharmaceutical Journal 25 (1): 25–31. doi:10.1016/j.jsps.2016.04.027. PMID 28223859.
- ↑ Edgerton, Mira; Jang, Woong Sik (2012-01-01). "Salivary Histatins: Structure, Function, and Mechanisms of Antifungal Activity". Candida and Candidiasis, Second Edition. pp. 185–194. doi:10.1128/9781555817176.ch13. ISBN 978-1-55581-539-4.
- ↑ 5.0 5.1 5.2 5.3 Helmerhorst, Eva J.; Troxler, Robert F.; Oppenheim, Frank G. (2001-12-04). "The human salivary peptide histatin 5 exerts its antifungal activity through the formation of reactive oxygen species" (in en). Proceedings of the National Academy of Sciences 98 (25): 14637–14642. doi:10.1073/pnas.141366998. ISSN 0027-8424. PMID 11717389. Bibcode: 2001PNAS...9814637H.
- ↑ McDonald, E E; Goldberg, H A; Tabbara, N; Mendes, F M; Siqueira, W L (12 November 2010). "Histatin 1 resists proteolytic degradation when adsorbed to hydroxyapatite". Journal of Dental Research 90 (2): 268–272. doi:10.1177/0022034510388653. PMID 21076122.
- ↑ "Histatins: antimicrobial peptides with therapeutic potential". The Journal of Pharmacy and Pharmacology 56 (3): 285–9. March 2004. doi:10.1211/0022357022971. PMID 15025852. https://eprints.maynoothuniversity.ie/354/1/R03014.pdf.
- ↑ "Histatins are the major wound-closure stimulating factors in human saliva as identified in a cell culture assay". FASEB Journal 22 (11): 3805–12. November 2008. doi:10.1096/fj.08-112003. PMID 18650243.
- ↑ 9.0 9.1 "Histatins, a novel family of histidine-rich proteins in human parotid secretion. Isolation, characterization, primary structure, and fungistatic effects on Candida albicans". The Journal of Biological Chemistry 263 (16): 7472–7. June 1988. doi:10.1016/S0021-9258(18)68522-9. PMID 3286634.
- ↑ "Salivary histatins in human deep posterior lingual glands (of von Ebner)". Archives of Oral Biology 51 (11): 967–73. November 2006. doi:10.1016/j.archoralbio.2006.05.011. PMID 16859632.
- ↑ "Histatin peptides: Pharmacological functions and their applications in dentistry". Saudi Pharmaceutical Journal 25 (1): 25–31. January 2017. doi:10.1016/j.jsps.2016.04.027. PMID 28223859.
- ↑ Swidergall, Marc; Ernst, Joachim F. (August 2014). "Interplay between Candida albicans and the Antimicrobial Peptide Armory". Eukaryotic Cell 13 (8): 950–957. doi:10.1128/EC.00093-14. PMID 24951441.
- ↑ "Human salivary histatin-5 exerts potent fungicidal activity against Cryptococcus neoformans". Biochimica et Biophysica Acta (BBA) - General Subjects 1336 (3): 367–9. October 1997. doi:10.1016/S0304-4165(97)00076-7. PMID 9367163.
- ↑ "Salivary proteins as a defense against dietary tannins". Journal of Chemical Ecology 32 (6): 1149–63. June 2006. doi:10.1007/s10886-006-9077-0. PMID 16770710. Bibcode: 2006JCEco..32.1149S.
- ↑ 15.0 15.1 Oudhoff, Menno J.; Bolscher, Jan G. M.; Nazmi, Kamran; Kalay, Hakan; Hof, Wim; Amerongen, Arie V. Nieuw; Veerman, Enno C. I. (November 2008). "Histatins are the major wound-closure stimulating factors in human saliva as identified in a cell culture assay" (in en). The FASEB Journal 22 (11): 3805–3812. doi:10.1096/fj.08-112003. ISSN 0892-6638. PMID 18650243.
- ↑ 16.0 16.1 16.2 Torres, P; Castro, M; Reyes, M; Torres, Va (October 2018). "Histatins, wound healing, and cell migration" (in en). Oral Diseases 24 (7): 1150–1160. doi:10.1111/odi.12816. ISSN 1354-523X. PMID 29230909. https://onlinelibrary.wiley.com/doi/10.1111/odi.12816.
- ↑ Zolin, Gabriela Vieira Silva; Fonseca, Fauller Henrique da; Zambom, Carolina Reis; Garrido, Saulo Santesso (2021-08-13). "Histatin 5 Metallopeptides and Their Potential against Candida albicans Pathogenicity and Drug Resistance" (in en). Biomolecules 11 (8): 1209. doi:10.3390/biom11081209. ISSN 2218-273X. PMID 34439875.
- ↑ Khurshid, Zohaib; Najeeb, Shariq; Mali, Maria; Faraz Moin, Syed; Qasim Raza, Syed; Zohaib, Sana; Sefat, Farshid; Sohail Zafar, Muhammad (19 October 2015). "Histatin peptides: Pharmacological functions and their applications in dentistry". Saudi Pharmaceutical Journal 25 (1): 25–31. doi:10.1016/j.jsps.2016.04.027. PMID 28223859.
- ↑ Meyer, Frederic; Amaechi, Bennett T.; Fabritius, Helge-Otto; Enax, Joachim (2018-05-31). "Overview of Calcium Phosphates used in Biomimetic Oral Care" (in en). The Open Dentistry Journal 12 (1): 406–423. doi:10.2174/1874210601812010406. ISSN 1874-2106. PMID 29988215. PMC 5997847. https://opendentistryjournal.com/VOLUME/12/PAGE/406/.
- ↑ Cheng, Liuhanghang; Lei, Xiaoxuan; Yang, Zengjun; Kong, Yanan; Xu, Pengcheng; Peng, Shiya; Wang, Jue; Chen, Cheng et al. (August 2021). "Histatin 1 enhanced the speed and quality of wound healing through regulating the behaviour of fibroblast" (in en). Cell Proliferation 54 (8). doi:10.1111/cpr.13087. ISSN 0960-7722. PMID 34255393.
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