Histatins (HTNs) is a family of small, histidine-rich (18-28 mol%), cationic peptides that present in the saliva and secreted by parotid, submandibular and sub-lingual salivary glands (Oppenheim FG et al. 1988; Troxler RF et al. 1990; Hu S et al. 2005; Gornowicz A et al. 2014). Histatins 1, 3, and 5 are the most abundant peptides (Flora B et al. 2001; Gusman H et al. 2004; Hardt M et al. 2005). Histatin 1 and 3 are encoded by the HTN1 and HTN3 gene respectively (Sabatini LM et al 1993). Other histatin peptides are proteolytic derivatives of HTN1 and HTN3 (Troxler RF et al. 1990; Castagnola M et al. 2004; Messana I et al. 2008; Sun X et al. 2009). HTN3(20-43), a proteolytic product of histatin 3, is known as histatine 5.
The functional role of HTNs peptides in vivo involves prevention of the oral overgrowth of Candida albicans in oropharyngeal candidiasis (Jainkittivong A et al. 1998; Khan SA et al. 2013). HTNs display candidacidal and candidastatic activities in vitro against Candida albicans, Candida glabrata, Candida dubliniensis, Candida krusei, Saccharomyces cerevisiae, Cryptococcus neoformans and Neurospora crassa (Tsai H & Bobek LA 1997, 1998; Oppenheim FG et al. 1988; Xu T et al. 1991; Rayhan R et al. 1992; Helmerhorst EJ et al. 1999; van't Hof W et al. 2000; Fitzgerald DH et al. 2003). Histatin 5 shows the highest anticandicidal activity of the family in vitro at physiological concentrations found in saliva (15–50 microM) (Xu T et al. 1991). The candidacidal activity of histatin 5 results from a multistep molecular mechanism involving the recognition and binding of the peptide to the yeast cell wall proteins Ssa1/2p followed by the peptide internalization (Edgerton M et al. 1998; Li XS et al. 2003; Sun JN et al. 2008). Histatin 5 internalization is required for fungicidal activity in Candida species (Li XS et al. 2006; Jang WS et al. 2010). Ultimately, histatin 5 is transported into the cell through the fungal polyamine transporters Dur3 and Dur31 in an energy-dependent process (Kumar R et al. 2011; Tati S et al. 2013). Histatin 5- mediated killing involves interaction with the fungal mitochondrial membrane (Helmerhorst EJ et al. 1999; Gyurko C et al. 2000; 2001). Interference with mitochondrial respiratory machinery can lead to generation of reactive oxygen species (ROS) and ATP release (Helmerhorst EJ et al. 2001; Gyurko C et al. 2000; 2001). The killing of C. albicans is accompanied by the release of intracellular potassium ions and the Trk1 potassium channel is critical (Pollock JJ et al. 1984; Baev D et al 2004; Vylkova S et al. 2006). Histatine 5 has also been shown to bind various metals in saliva namely, Zn, Cu, Fe and Ni that can modulate the peptide candidacidal properties (Melino S et al. 1999; 2014; Puri S et al. 2015).