20-Residue and 11-residue peptaibols from the fungus Trichoderma longibrachiatum are synergistic in forming Na+/K+- permeable channels and adverse action towards mammalian cells

Raimo Mikkola, Maria A. Andersson, L. Kredics, Pavel A. Grigoriev, Nina Sundell, Mirja S. Salkinoja-Salonen

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Certain species of the filamentous fungal genus Trichoderma (e.g. Trichoderma longibrachiatum and Trichoderma citrinoviride) are among the emerging clinical pathogens and also the most common species in the indoor space of mould-damaged buildings. The molecules involved in its pathology are not known. In the present study, we report that 0.5-2.6 wt% of the T. longibrachiatum mycelial biomass consisted of thermostable secondary metabolites mitochondriotoxic to mammalian cells. These were identified by LC/MS as one 11-residue and eight 20-residue peptaibols, AcAib-Asn-Leu/Ile-Leu/Ile-Aib-Pro- Leu/Ile-Leu/Ile-Aib-Pro-Leuol/Ileol (1175 Da) and AcAib-Ala-Aib-Ala-Aib-Ala/Aib- Gln-Aib-Val/Iva-Aib-Gly-Leu/Ile-Aib-Pro-Val/Iva-Aib-Val/Iva/Aib-Gln/ Glu-Gln-Pheol(1936-1965 Da) (Aib, α-aminoisobutyric acid; Ac, acetyl; Ileol, isoleucinol; Iva, isovaline; Leuol, leucinol; Pheol, phenylalaninol). The toxic effects on boar sperm cells depended on these peptaibols, named trilongins. The trilongins formed voltage dependent, Na+/K + permeable channels in biomembranes. The permeability ratios for Na+ ions, relative to K+, of the 11-residue trilongin channel (0.95: 1) and the 20-residue trilongin channel (0.8: 1) were higher than those of alamethicin. The combined 11-residue and 20-residue trilongins generated channels that remained in an open state for a longer time than those formed by either one of the peptaibols alone. Corresponding synergy was observed in toxicokinetics. With 11-residue and 20-residue trilongins combined 1: 2 w/w, an effective median concentration (EC50) of 0.6 μg·mL -1 was reached within 30 min, and the EC50 shifted down to 0.2 μg·mL-1 upon extended exposure. By contrast, with 11-residue or 20-residue trilonging separately in 30 min of exposure, the EC50 values were 15 and 3 μg·mL-1, respectively, and shifted down to 1.5 and 0.4 μg·mL-1 upon extended exposure. This is the first report on ion-channel forming peptaibols with synergistic toxicity from T. longibrachiatum strains isolated from clinical samples. Database Nucleotide sequence data have been deposited in the GenBank database under accession numbers HQ593512 and HQ593513. The T. longibrachiatum strains produced 11- and 20-residue peptaibols (green and blue) forming Na +/K+ permeable ion-channels in lipid bilayer with synergistic properties. The combined 11- and 20-residue peptaibols generated channels that remained in an open state for a longer time than those formed by either peptaibol alone. As a result the two peptaibols were synergistically toxic toward mammalian cells.

Original languageEnglish
Pages (from-to)4172-4190
Number of pages19
JournalFEBS Journal
Volume279
Issue number22
DOIs
Publication statusPublished - Nov 2012

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Peptaibols
Trichoderma
Fungi
Cells
Poisons
Ion Channels
prolylvaline
prolylleucine
glycylleucine
Alamethicin
Databases
Aminoisobutyric Acids
Lipid bilayers
Nucleic Acid Databases
Lipid Bilayers
Pathology
Pathogens
Metabolites
Biomass
Toxicity

Keywords

  • indoor mold
  • ion channel
  • mitochondriotoxin
  • synergistically toxic
  • Trichoderma

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

20-Residue and 11-residue peptaibols from the fungus Trichoderma longibrachiatum are synergistic in forming Na+/K+- permeable channels and adverse action towards mammalian cells. / Mikkola, Raimo; Andersson, Maria A.; Kredics, L.; Grigoriev, Pavel A.; Sundell, Nina; Salkinoja-Salonen, Mirja S.

In: FEBS Journal, Vol. 279, No. 22, 11.2012, p. 4172-4190.

Research output: Contribution to journalArticle

Mikkola, Raimo ; Andersson, Maria A. ; Kredics, L. ; Grigoriev, Pavel A. ; Sundell, Nina ; Salkinoja-Salonen, Mirja S. / 20-Residue and 11-residue peptaibols from the fungus Trichoderma longibrachiatum are synergistic in forming Na+/K+- permeable channels and adverse action towards mammalian cells. In: FEBS Journal. 2012 ; Vol. 279, No. 22. pp. 4172-4190.
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abstract = "Certain species of the filamentous fungal genus Trichoderma (e.g. Trichoderma longibrachiatum and Trichoderma citrinoviride) are among the emerging clinical pathogens and also the most common species in the indoor space of mould-damaged buildings. The molecules involved in its pathology are not known. In the present study, we report that 0.5-2.6 wt{\%} of the T. longibrachiatum mycelial biomass consisted of thermostable secondary metabolites mitochondriotoxic to mammalian cells. These were identified by LC/MS as one 11-residue and eight 20-residue peptaibols, AcAib-Asn-Leu/Ile-Leu/Ile-Aib-Pro- Leu/Ile-Leu/Ile-Aib-Pro-Leuol/Ileol (1175 Da) and AcAib-Ala-Aib-Ala-Aib-Ala/Aib- Gln-Aib-Val/Iva-Aib-Gly-Leu/Ile-Aib-Pro-Val/Iva-Aib-Val/Iva/Aib-Gln/ Glu-Gln-Pheol(1936-1965 Da) (Aib, α-aminoisobutyric acid; Ac, acetyl; Ileol, isoleucinol; Iva, isovaline; Leuol, leucinol; Pheol, phenylalaninol). The toxic effects on boar sperm cells depended on these peptaibols, named trilongins. The trilongins formed voltage dependent, Na+/K + permeable channels in biomembranes. The permeability ratios for Na+ ions, relative to K+, of the 11-residue trilongin channel (0.95: 1) and the 20-residue trilongin channel (0.8: 1) were higher than those of alamethicin. The combined 11-residue and 20-residue trilongins generated channels that remained in an open state for a longer time than those formed by either one of the peptaibols alone. Corresponding synergy was observed in toxicokinetics. With 11-residue and 20-residue trilongins combined 1: 2 w/w, an effective median concentration (EC50) of 0.6 μg·mL -1 was reached within 30 min, and the EC50 shifted down to 0.2 μg·mL-1 upon extended exposure. By contrast, with 11-residue or 20-residue trilonging separately in 30 min of exposure, the EC50 values were 15 and 3 μg·mL-1, respectively, and shifted down to 1.5 and 0.4 μg·mL-1 upon extended exposure. This is the first report on ion-channel forming peptaibols with synergistic toxicity from T. longibrachiatum strains isolated from clinical samples. Database Nucleotide sequence data have been deposited in the GenBank database under accession numbers HQ593512 and HQ593513. The T. longibrachiatum strains produced 11- and 20-residue peptaibols (green and blue) forming Na +/K+ permeable ion-channels in lipid bilayer with synergistic properties. The combined 11- and 20-residue peptaibols generated channels that remained in an open state for a longer time than those formed by either peptaibol alone. As a result the two peptaibols were synergistically toxic toward mammalian cells.",
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T1 - 20-Residue and 11-residue peptaibols from the fungus Trichoderma longibrachiatum are synergistic in forming Na+/K+- permeable channels and adverse action towards mammalian cells

AU - Mikkola, Raimo

AU - Andersson, Maria A.

AU - Kredics, L.

AU - Grigoriev, Pavel A.

AU - Sundell, Nina

AU - Salkinoja-Salonen, Mirja S.

PY - 2012/11

Y1 - 2012/11

N2 - Certain species of the filamentous fungal genus Trichoderma (e.g. Trichoderma longibrachiatum and Trichoderma citrinoviride) are among the emerging clinical pathogens and also the most common species in the indoor space of mould-damaged buildings. The molecules involved in its pathology are not known. In the present study, we report that 0.5-2.6 wt% of the T. longibrachiatum mycelial biomass consisted of thermostable secondary metabolites mitochondriotoxic to mammalian cells. These were identified by LC/MS as one 11-residue and eight 20-residue peptaibols, AcAib-Asn-Leu/Ile-Leu/Ile-Aib-Pro- Leu/Ile-Leu/Ile-Aib-Pro-Leuol/Ileol (1175 Da) and AcAib-Ala-Aib-Ala-Aib-Ala/Aib- Gln-Aib-Val/Iva-Aib-Gly-Leu/Ile-Aib-Pro-Val/Iva-Aib-Val/Iva/Aib-Gln/ Glu-Gln-Pheol(1936-1965 Da) (Aib, α-aminoisobutyric acid; Ac, acetyl; Ileol, isoleucinol; Iva, isovaline; Leuol, leucinol; Pheol, phenylalaninol). The toxic effects on boar sperm cells depended on these peptaibols, named trilongins. The trilongins formed voltage dependent, Na+/K + permeable channels in biomembranes. The permeability ratios for Na+ ions, relative to K+, of the 11-residue trilongin channel (0.95: 1) and the 20-residue trilongin channel (0.8: 1) were higher than those of alamethicin. The combined 11-residue and 20-residue trilongins generated channels that remained in an open state for a longer time than those formed by either one of the peptaibols alone. Corresponding synergy was observed in toxicokinetics. With 11-residue and 20-residue trilongins combined 1: 2 w/w, an effective median concentration (EC50) of 0.6 μg·mL -1 was reached within 30 min, and the EC50 shifted down to 0.2 μg·mL-1 upon extended exposure. By contrast, with 11-residue or 20-residue trilonging separately in 30 min of exposure, the EC50 values were 15 and 3 μg·mL-1, respectively, and shifted down to 1.5 and 0.4 μg·mL-1 upon extended exposure. This is the first report on ion-channel forming peptaibols with synergistic toxicity from T. longibrachiatum strains isolated from clinical samples. Database Nucleotide sequence data have been deposited in the GenBank database under accession numbers HQ593512 and HQ593513. The T. longibrachiatum strains produced 11- and 20-residue peptaibols (green and blue) forming Na +/K+ permeable ion-channels in lipid bilayer with synergistic properties. The combined 11- and 20-residue peptaibols generated channels that remained in an open state for a longer time than those formed by either peptaibol alone. As a result the two peptaibols were synergistically toxic toward mammalian cells.

AB - Certain species of the filamentous fungal genus Trichoderma (e.g. Trichoderma longibrachiatum and Trichoderma citrinoviride) are among the emerging clinical pathogens and also the most common species in the indoor space of mould-damaged buildings. The molecules involved in its pathology are not known. In the present study, we report that 0.5-2.6 wt% of the T. longibrachiatum mycelial biomass consisted of thermostable secondary metabolites mitochondriotoxic to mammalian cells. These were identified by LC/MS as one 11-residue and eight 20-residue peptaibols, AcAib-Asn-Leu/Ile-Leu/Ile-Aib-Pro- Leu/Ile-Leu/Ile-Aib-Pro-Leuol/Ileol (1175 Da) and AcAib-Ala-Aib-Ala-Aib-Ala/Aib- Gln-Aib-Val/Iva-Aib-Gly-Leu/Ile-Aib-Pro-Val/Iva-Aib-Val/Iva/Aib-Gln/ Glu-Gln-Pheol(1936-1965 Da) (Aib, α-aminoisobutyric acid; Ac, acetyl; Ileol, isoleucinol; Iva, isovaline; Leuol, leucinol; Pheol, phenylalaninol). The toxic effects on boar sperm cells depended on these peptaibols, named trilongins. The trilongins formed voltage dependent, Na+/K + permeable channels in biomembranes. The permeability ratios for Na+ ions, relative to K+, of the 11-residue trilongin channel (0.95: 1) and the 20-residue trilongin channel (0.8: 1) were higher than those of alamethicin. The combined 11-residue and 20-residue trilongins generated channels that remained in an open state for a longer time than those formed by either one of the peptaibols alone. Corresponding synergy was observed in toxicokinetics. With 11-residue and 20-residue trilongins combined 1: 2 w/w, an effective median concentration (EC50) of 0.6 μg·mL -1 was reached within 30 min, and the EC50 shifted down to 0.2 μg·mL-1 upon extended exposure. By contrast, with 11-residue or 20-residue trilonging separately in 30 min of exposure, the EC50 values were 15 and 3 μg·mL-1, respectively, and shifted down to 1.5 and 0.4 μg·mL-1 upon extended exposure. This is the first report on ion-channel forming peptaibols with synergistic toxicity from T. longibrachiatum strains isolated from clinical samples. Database Nucleotide sequence data have been deposited in the GenBank database under accession numbers HQ593512 and HQ593513. The T. longibrachiatum strains produced 11- and 20-residue peptaibols (green and blue) forming Na +/K+ permeable ion-channels in lipid bilayer with synergistic properties. The combined 11- and 20-residue peptaibols generated channels that remained in an open state for a longer time than those formed by either peptaibol alone. As a result the two peptaibols were synergistically toxic toward mammalian cells.

KW - indoor mold

KW - ion channel

KW - mitochondriotoxin

KW - synergistically toxic

KW - Trichoderma

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