Histatins are cationic and histidine-rich peptides mainly found in the saliva of higher primates (PubMed:3286634). They 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, Hst 2/HTN1 and Hst 3/HTN3) (PubMed:32225006). {ECO:0000269|PubMed:32225006, ECO:0000269|PubMed:3286634}. [Histatin-3]: Histatin 3 (Hst 3) is mostly involved in cell migration and wound healing in the oral cavity (PubMed:18650243). Also stimulates cell proliferation after binding to heat shock protein HSC70, which enhances HSC70-CDKN1B complex formation and subsequent ubiquitination during G1/S transition (PubMed:26775844). Also displays antifungal activity against pathogenic yeast Candida albicans, however with less effectiveness than Hst 5 (PubMed:11083804, PubMed:3286634). {ECO:0000269|PubMed:11083804, ECO:0000269|PubMed:18650243, ECO:0000269|PubMed:26775844, ECO:0000269|PubMed:3286634}. [His3-(20-43)-peptide]: Histatin 5 (Hst 5), a fragment of Hst 3, is the major histatin exhibiting antifungal and antibacterial activities (PubMed:10066791, PubMed:11083804, PubMed:11179305, PubMed:11717389, PubMed:12939362, PubMed:15485849, PubMed:2372245, PubMed:8945538). It is effective against pathogenic yeast C.albicans, C.neoformans, C.glabrata and S.cerevisiae as well as ESKAPE bacterial pathogens (PubMed:18974864, PubMed:23613860, PubMed:2372245, PubMed:28261570, PubMed:8945538). Secreted Hst 5 mediates a multi-step intracellular mechanism of action against the pathogen. Depending on peptide concentration and pathogen, uptake across the membrane can occur through transporters, direct interaction with plasma membrane and/or receptor-mediated endocytosis (PubMed:18974864, PubMed:20487276, PubMed:28261570). Binds C.albicans cell wall proteins SSA1 and SSA2 and glycans in an energy-independent manner, then is taken up by the cells through fungal polyamine transporters DUR3 and DUR31 in an energy- dependent manner (PubMed:12761219, PubMed:20487276, PubMed:22033918, PubMed:23613860). Internalized Hst5 is then targeted to the energized mitochondrion to induce reactive oxygen species (ROS) formation and subsequent release of intracellular non-lytic ATP which ultimately leads to fungal cell death (PubMed:10066791, PubMed:11083804, PubMed:11717389). In addition, inhibits C.albicans TRK1 potassium- transporter which causes exudation of intracellular K(+), generating an osmotic imbalance leading to delayed membrane lysis and cell death (PubMed:15485849). Also acts as a potent inhibitor of bacterial proteases such as Lys-gingipain and Arg-gingipain (rgpB) from P.gingivalis as well as human metalloproteases MMP2 and MMP9 (PubMed:11179305). The binding of metals such as zinc, copper or nickel with Hst 5 results in the protection of the enamel and antimicrobial activities such as the inhibition of microbial growth by decreasing the metal concentration, the formation of ROS commonly associated with redox-active metals, the induction of membrane disruption mediated by zinc binding (PubMed:19846304, PubMed:28261570, PubMed:28763199, PubMed:32751915). Also involved in coating oral surfaces in the form of a salivary film which reduces colonization by C.albicans on epithelial cell surfaces (PubMed:26379655). Secreted Hst 5 can also internalize mammalian epithelial cells and target the mitochondria although it does not exert cytotoxic effects in these cells (PubMed:32225006). In contrast with Hst 3, not able to promote wound healing in mammalian host cells (PubMed:18650243). {ECO:0000269|PubMed:10066791, ECO:0000269|PubMed:11083804, ECO:0000269|PubMed:11179305, ECO:0000269|PubMed:11717389, ECO:0000269|PubMed:12761219, ECO:0000269|PubMed:12939362, ECO:0000269|PubMed:15485849, ECO:0000269|PubMed:18650243, ECO:0000269|PubMed:18974864, ECO:0000269|PubMed:19846304, ECO:0000269|PubMed:20487276, ECO:0000269|PubMed:22033918, ECO:0000269|PubMed:23613860, ECO:0000269|PubMed:2372245, ECO:0000269|PubMed:26379655, ECO:0000269|PubMed:28261570, ECO:0000269|PubMed:28763199, ECO:0000269|PubMed:32225006, ECO:0000269|PubMed:32751915, ECO:0000269|PubMed:8945538}. This is the function of HTN3 (histatin 3, Ensembl gene identifier ENSG00000205649).