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1.C.79 The Channel-forming, Cell-penetrating Histatin Antimicrobial Peptide (Histatin) Family

Salivary histatins (Hst) are potent in vitro antifungal histidine-rich proteins that have promise as therapeutic agents. Three inhibitors of mitochondrial metabolism: carbonyl cyanide p-chlorophenylhydrazone, dinitrophenol, and azide inhibited Hst 5 killing of Candida albicans, while not inhibiting cellular ATP production (Koshlukova et al., 1999). In contrast, Hst 5 caused a drastic reduction of C. albicans intracellular ATP content, which was a result of efflux of ATP. Carbonyl cyanide p-chlorophenylhydrazone, dinitrophenol, and azide inhibited Hst 5-induced ATP efflux, thus establishing a correlation between ATP release and cell killing. Furthermore, C. albicans cells were respiring and had polarized membranes at least 80 min after ATP release, thus implying a non-lytic exit of cellular ATP in response to Hst 5. Transmembrane ATP efflux can occur in the absence of cytolysis through a channel-like pathway. Energy depletion may protect C. albicans against antimicrobial peptides by rigidifying its membrane (Veeman et al., 2007). These peptides are also cell-penetrating, facilitating the imiport of portein cargo when fused (Adhikari et al. 2018).

The transport reactions believed to be mediated by histatin 5 are:

ATP (in) → ATP (out)       and

Cargo protein (out) → Cargo protein (in)


References associated with 1.C.79 family:

Adhikari, S., T.I. Alahmadi, Z. Gong, and A.J. Karlsson. (2018). Expression of Cell-Penetrating Peptides Fused to Protein Cargo. J. Mol. Microbiol. Biotechnol. 28: 159-168. 30566948
Crosara, K.T.B., E.B. Moffa, Y. Xiao, and W.L. Siqueira. (2018). Merging in-silico and in vitro salivary protein complex partners using the STRING database: A tutorial. J Proteomics 171: 87-94. 28782718
Gusman, H., J. Travis, E.J. Helmerhorst, J. Potempa, R.F. Troxler, and F.G. Oppenheim. (2001). Salivary histatin 5 is an inhibitor of both host and bacterial enzymes implicated in periodontal disease. Infect. Immun. 69: 1402-1408. 11179305
Koshlukova, S.E., T.L. Lloyd, M.W. Araujo, and M. Edgerton. (1999). Salivary histatin 5 induces non-lytic release of ATP from Candida albicans leading to cell death. J. Biol. Chem. 274: 18872-18879. 10383383
Puri, S. and M. Edgerton. (2014). How does it kill?: understanding the candidacidal mechanism of salivary histatin 5. Eukaryot. Cell. 13: 958-964. 24951439
Torres, P., M. Castro, M. Reyes, and V.A. Torres. (2018). Histatins, wound healing, and cell migration. Oral Dis 24: 1150-1160. 29230909
Tsai, H., P.A. Raj, and L.A. Bobek. (1996). Candidacidal activity of recombinant human salivary histatin-5 and variants. Infect. Immun. 64: 5000-5007. 8945538
Veerman, E.C., M. Valentijn-Benz, K. Nazmi, A.L. Ruissen, E. Walgreen-Weterings, J. van Marle, A.B. Doust, W. van't Hof, J.G. Bolscher, and A.V. Amerongen. (2007). Energy depletion protects Candida albicans against antimicrobial peptides by ritcidifying its cell membrane. J. Biol. Chem. 282: 18831-18841. 17485465