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Gene Review

HTN3  -  histatin 3

Homo sapiens

Synonyms: Basic histidine-rich protein, HIS2, HTN2, HTN5, Histatin-3, ...
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Disease relevance of HTN3


High impact information on HTN3

  • The deduced amino acid sequence shows that the encoded protein, EPF1, contains two repeats of a Cys2/His2 zinc finger motif [6].
  • Using simultaneous Hoechst 33342 (Hst) and Pyronin Y (PY) staining for determination of DNA and RNA content, respectively, human CD34(+) cells were isolated in subcompartments of the G0 /G1 phase of the cell cycle by flow cytometric cell sorting [7].
  • To test the hypothesis that primitive LTHC-ICs would reenter a state of relative quiescence after in vitro division, BM CD34(+) cells proliferating in ex vivo cultures were identified from their quiescent counterparts by a relative loss of membrane intercalating dye PKH2, and were further fractionated with Hst and PY [7].
  • They include, with the exception of histatin 4, all the known histatin 3 fragments, namely histatins 5-12 and the peptides corresponding to 15-24, 26-32, 29-32 residues, and 13 new fragments corresponding to 1-11, 1-12, 1-13, 5-13, 6-11, 6-13, 7-11, 7-12, 7-13, 14-24, 14-25, 15-25, and 28-32 residues of histatin 3 [8].
  • Carbonyl cyanide p-chlorophenylhydrazone, dinitrophenol, and azide inhibited Hst 5-induced ATP efflux, thus establishing a correlation between ATP release and cell killing [9].

Chemical compound and disease context of HTN3

  • These results suggest that histatin 3 may have potential as an effective antifungal agent, particularly in the treatment of oral candidiasis in HIV-infected patients and patients with AIDS in which resistance to the commonly used antifungal drug fluconazole has emerged [4].

Biological context of HTN3

  • Nucleotide sequence analysis of the human salivary protein genes HIS1 and HIS2, and evolution of the STATH/HIS gene family [1].
  • The amino acid sequences of histatins 7-12 formally correspond to residues 12-24, 13-24, 12-25, 13-25, 5-11, and 5-12, respectively, of histatin 3, but could also arise proteolytically from histatin 5 or 6 [10].
  • Indeed, a low extracellular salt concentration was essential for cell death to occur, even when histatin 3 was already bound to the cell [11].
  • A single histatin 3 binding site with a K(d) = 5.1 microM was detected [11].
  • This novel process of fungicidal activity by a human salivary protein has highlighted potential interactions of Hst 5 with volume regulatory mechanisms and the process of yeast cell cycle control [2].

Anatomical context of HTN3


Associations of HTN3 with chemical compounds

  • H3 becomes much more ordered in a mixture of 50:50 H2O-dimethyl sulfoxide as indicated by the numerous NOEs, including several side chain to side chain and side chain to backbone connectivities [14].
  • 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 [9].
  • Consistent with this hypothesis, purinergic agonists BzATP and adenosine 5'O-(thiotriphosphate) induced loss of C. albicans cell viability and purinergic antagonists prevented Hst 5 killing [9].
  • Subtle changes in overall conformation are seen with the addition of Cu(2+) to both H3 and H5 [15].
  • H3 and H5 formed high affinity complexes with Cu(2+) and Ni(2+) and, to a lesser extent, with Zn(2+) [15].

Regulatory relationships of HTN3

  • When the histatin 3 uptake into cells was inhibited by monodansylcadaverine or when histatin 3 binding to HSC70 was precluded by 15-deoxyspergualin, DNA synthesis by histatin 3 was approximately 2-fold less than that without monodansylcadaverine or 15-deoxyspergualin [16].

Other interactions of HTN3

  • The structural data suggest that histatins 1 and 3 are derived from different structural genes, whereas histatin 5 is a proteolytic product of histatin 3 [17].
  • The molecular cloning of sequences encoding human submandibular gland (SMG) statherin and a basic histidine-rich peptide is described [12].
  • Cells with intracellularly expressed Hst 5 had greatly reduced G(1) cyclin transcript levels, indicating that they arrested in the G(1) phase before the onset of Start [2].
  • Salivary protein polymorphism was studied in 200 schoolboys, mainly Kisii and Luo from Kenya, East Africa. The frequencies of PR, PA, DB, PB and AMY1 genes were as follows: PR*1: 0.66, PA*(+): 0.18, DB*(+): 0.55, PB*2: 0.12, AMY1*A2: 0.008, AMY1*E: 0.03 [18].
  • Hst 5 and HNP-1 are basic proteins of about 3 kDa; however, they have unique primary sequences and solution structures that cannot explain how these two molecules act so similarly on C. albicans to induce cell death [19].

Analytical, diagnostic and therapeutic context of HTN3


  1. Nucleotide sequence analysis of the human salivary protein genes HIS1 and HIS2, and evolution of the STATH/HIS gene family. Sabatini, L.M., Ota, T., Azen, E.A. Mol. Biol. Evol. (1993) [Pubmed]
  2. Human salivary histatin 5 causes disordered volume regulation and cell cycle arrest in Candida albicans. Baev, D., Li, X.S., Dong, J., Keng, P., Edgerton, M. Infect. Immun. (2002) [Pubmed]
  3. Transfer of a gene encoding the anticandidal protein histatin 3 to salivary glands. O'Connell, B.C., Xu, T., Walsh, T.J., Sein, T., Mastrangeli, A., Crystal, R.G., Oppenheim, F.G., Baum, B.J. Hum. Gene Ther. (1996) [Pubmed]
  4. Susceptibility of Candida dubliniensis to salivary histatin 3. Fitzgerald, D.H., Coleman, D.C., O'Connell, B.C. Antimicrob. Agents Chemother. (2003) [Pubmed]
  5. Identification of zinc finger mRNAs using domain-specific differential display. Johnson, S.W., Lissy, N.A., Miller, P.D., Testa, J.R., Ozols, R.F., Hamilton, T.C. Anal. Biochem. (1996) [Pubmed]
  6. Characterization of a zinc finger DNA-binding protein expressed specifically in Petunia petals and seedlings. Takatsuji, H., Mori, M., Benfey, P.N., Ren, L., Chua, N.H. EMBO J. (1992) [Pubmed]
  7. Functional heterogeneity of human CD34(+) cells isolated in subcompartments of the G0 /G1 phase of the cell cycle. Gothot, A., Pyatt, R., McMahel, J., Rice, S., Srour, E.F. Blood (1997) [Pubmed]
  8. A cascade of 24 histatins (histatin 3 fragments) in human saliva. Suggestions for a pre-secretory sequential cleavage pathway. Castagnola, M., Inzitari, R., Rossetti, D.V., Olmi, C., Cabras, T., Piras, V., Nicolussi, P., Sanna, M.T., Pellegrini, M., Giardina, B., Messana, I. J. Biol. Chem. (2004) [Pubmed]
  9. Salivary histatin 5 induces non-lytic release of ATP from Candida albicans leading to cell death. Koshlukova, S.E., Lloyd, T.L., Araujo, M.W., Edgerton, M. J. Biol. Chem. (1999) [Pubmed]
  10. Structural relationship between human salivary histatins. Troxler, R.F., Offner, G.D., Xu, T., Vanderspek, J.C., Oppenheim, F.G. J. Dent. Res. (1990) [Pubmed]
  11. Histatin 3-mediated killing of Candida albicans: effect of extracellular salt concentration on binding and internalization. Xu, Y., Ambudkar, I., Yamagishi, H., Swaim, W., Walsh, T.J., O'Connell, B.C. Antimicrob. Agents Chemother. (1999) [Pubmed]
  12. Human submandibular gland statherin and basic histidine-rich peptide are encoded by highly abundant mRNA's derived from a common ancestral sequence. Dickinson, D.P., Ridall, A.L., Levine, M.J. Biochem. Biophys. Res. Commun. (1987) [Pubmed]
  13. Candidacidal activity of salivary histatins. Identification of a histatin 5-binding protein on Candida albicans. Edgerton, M., Koshlukova, S.E., Lo, T.E., Chrzan, B.G., Straubinger, R.M., Raj, P.A. J. Biol. Chem. (1998) [Pubmed]
  14. NMR studies of the antimicrobial salivary peptides histatin 3 and histatin 5 in aqueous and nonaqueous solutions. Brewer, D., Hunter, H., Lajoie, G. Biochem. Cell Biol. (1998) [Pubmed]
  15. Evaluation of the metal binding properties of the histidine-rich antimicrobial peptides histatin 3 and 5 by electrospray ionization mass spectrometry. Brewer, D., Lajoie, G. Rapid Commun. Mass Spectrom. (2000) [Pubmed]
  16. Cooperation of salivary protein histatin 3 with heat shock cognate protein 70 relative to the G1/S transition in human gingival fibroblasts. Imamura, Y., Fujigaki, Y., Oomori, Y., Usui, S., Wang, P.L. J. Biol. Chem. (2009) [Pubmed]
  17. Histatins, a novel family of histidine-rich proteins in human parotid secretion. Isolation, characterization, primary structure, and fungistatic effects on Candida albicans. Oppenheim, F.G., Xu, T., McMillian, F.M., Levitz, S.M., Diamond, R.D., Offner, G.D., Troxler, R.F. J. Biol. Chem. (1988) [Pubmed]
  18. Salivary protein polymorphism in Kenya: evidence for a new AMY1 allele. Pronk, J.C., Jansen, W.J., Pronk, A., vd Pol, C.F., Frants, R.R., Eriksson, A.W. Hum. Hered. (1984) [Pubmed]
  19. Salivary histatin 5 and human neutrophil defensin 1 kill Candida albicans via shared pathways. Edgerton, M., Koshlukova, S.E., Araujo, M.W., Patel, R.C., Dong, J., Bruenn, J.A. Antimicrob. Agents Chemother. (2000) [Pubmed]
  20. Human salivary histatin 5 fungicidal action does not induce programmed cell death pathways in Candida albicans. Wunder, D., Dong, J., Baev, D., Edgerton, M. Antimicrob. Agents Chemother. (2004) [Pubmed]
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