The small molecular mass antifungal protein of <i>Penicillium chrysogenum</i> – a mechanism of action oriented review

Hegedűs, Nikoletta; Leiter, Éva; Kovács, Barbara; Tomori, Valéria; Kwon, Nak‐Jung; Emri, Tamás; Marx, Florentine; Batta, Gyula; Csernoch, László; Haas, Hubertus; Yu, Jae Hyuk; Pócsi, István

doi:10.1002/jobm.201100041

Cited by 36 publications

(42 citation statements)

References 123 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Details of the mode of action of PAF remain elusive but it seems to be distinct46, 64 from its closest homologue AFP. PAF induces plasma membrane hyperpolarization in sensitive fungi.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

“Invisible” Conformers of an Antifungal Disulfide Protein Revealed by Constrained Cold and Heat Unfolding, CEST‐NMR Experiments, and Molecular Dynamics Calculations

Fizil

Gáspári

Barna

et al. 2015

Chemistry A European J

Self Cite

View full text Add to dashboard Cite

Transition between conformational states in proteins is being recognized as a possible key factor of function. In support of this, hidden dynamic NMR structures were detected in several cases up to populations of a few percent. Here, we show by two- and three-state analysis of thermal unfolding, that the population of hidden states may weight 20–40 % at 298 K in a disulfide-rich protein. In addition, sensitive 15N-CEST NMR experiments identified a low populated (0.15 %) state that was in slow exchange with the folded PAF protein. Remarkably, other techniques failed to identify the rest of the NMR “dark matter”. Comparison of the temperature dependence of chemical shifts from experiments and molecular dynamics calculations suggests that hidden conformers of PAF differ in the loop and terminal regions and are most similar in the evolutionary conserved core. Our observations point to the existence of a complex conformational landscape with multiple conformational states in dynamic equilibrium, with diverse exchange rates presumably responsible for the completely hidden nature of a considerable fraction.

show abstract

“…Details of the mode of action of PAF remain elusive but it seems to be distinct46, 64 from its closest homologue AFP. PAF induces plasma membrane hyperpolarization in sensitive fungi.…”

Section: Resultsmentioning

confidence: 99%

“…These 50–60 residue proteins exhibit a beta‐sheet dominated fold and are stabilized by three or four disulfide bonds. Although they are all abundant in basic residues, they differ in their specificity and mode of action 46. 47 However, the latter is not yet well understood at a molecular level.…”

Section: Introductionmentioning

confidence: 99%

“Invisible” Conformers of an Antifungal Disulfide Protein Revealed by Constrained Cold and Heat Unfolding, CEST‐NMR Experiments, and Molecular Dynamics Calculations

Fizil

Gáspári

Barna

et al. 2015

Chemistry A European J

Self Cite

View full text Add to dashboard Cite

show abstract

“…It has been proposed that G protein is responsible for the transduction of PAF-initiated apoptotic cell death signals (Leiter et al 2005). This is achieved through modulation of the intracellular glutathione (GSH) and ROS levels in Aspergillus nidulans (Hegedus et al 2011). Here we used PgAFP, one of these small, basic, and cysteine-rich proteins that inhibits growth of some toxigenic molds (Rodríguez-Martín et al 2010), to study the effect on the growth of A. flavus.…”

Section: Introductionmentioning

confidence: 99%

Impact of the antifungal protein PgAFP from Penicillium chrysogenum on the protein profile in Aspergillus flavus

Delgado

Owens

Doyle

et al. 2015

Appl Microbiol Biotechnol

View full text Add to dashboard Cite

Antifungal proteins produced by molds are generally small, highly basic, and cysteine-rich. The best known effects of these proteins include morphological changes, metabolic inactivation, and membrane perturbation on sensitive fungi. Reactive oxygen species (ROS) generation leads to apoptosis, with G -protein playing a key role in transduction of cell death signals. The antifungal protein PgAFP from Penicillium chrysogenum inhibits growth of some toxigenic molds. Here we analyzed the effect of the antifungal protein PgAFP on the growth of Aspergillus flavus. For this, comparative proteomic analysis was used to identify the whole protein profile and protein change in abundance after PgAFP treatment. PgAFP provoked metabolic changes related to reduced energy metabolism, cell wall integrity alteration, and increased stress response due to higher levels of ROS. The observed changes in protein abundance, favoring a higher glutathione concentration as well as the increased abundance in heat shock proteins, do not seem to be enough to avoid necrosis. The decreased chitin deposition observed in PgAFP-treated A. flavus is attributed to a lower relative quantity of Rho1. The reduced relative abundance of a β subunit of G -protein seems to be the underlying reason for modulation of apoptosis in PgAFP-treated A. flavus hyphae. We propose Rho1 and G -protein subunit β CpcB to be the main factors in the mode of action of PgAFP in A. flavus. Additionally, enzymes essential for the biosynthesis of aflatoxin were no longer detectable in A. flavus hyphae at 24 h, following treatment with PgAFP. This presents a promising effect of PgAFP, which may prevent A. flavus from producing mycotoxins. However, the impact of PgAFP on actual aflatoxin production requires further study.

show abstract

“…16, 17 The protein enters sensitive fungi through internalization via an endocytotic mechanism 18 and elicits the increased production of harmful reactive oxygen species enhancing the oxidation of intracellular molecules, decreases the metabolism of fungal cells, and triggers disintegration of mitochondrial membranes. 16, 19, 20 …”

Section: Introductionmentioning

confidence: 99%

Application of a low molecular weight antifungal protein from Penicillium chrysogenum (PAF) to treat pulmonary aspergillosis in mice

Palicz

Gáll

Leiter

et al. 2016

Emerging Microbes & Infections

Self Cite

View full text Add to dashboard Cite

PAF, a small antifungal protein from Penicillium chrysogenum, inhibits the growth of several pathogenic filamentous fungi, including members of the Aspergillus genus. PAF has been proven to have no toxic effects in vivo in mice by intranasal application. To test its efficacy against invasive pulmonary aspergillosis (IPA), experiments were carried out in mice suffering from IPA. Adult mice were immunosuppressed and then infected with Aspergillus fumigatus. After stable infection, the animals were inoculated with PAF intranasally at a concentration of 2.7 mg/kg twice per day. At this concentration—which is highly toxic in vitro to A. fumigatus—the mortality of the animals was slightly delayed but finally all animals died. Histological examinations revealed massive fungal infections in the lungs of both PAF-treated and untreated animal groups. Because intranasally administered PAF was unable to overcome IPA, modified and combined therapies were introduced. The intraperitoneal application of PAF in animals with IPA prolonged the survival of the animals only 1 day. Similar results were obtained with amphotericin B (AMB), with PAF and AMB being equally effective. Combined therapy with AMB and PAF—which are synergistic in vitro—was found to be more effective than either AMB or PAF treatment alone. As no toxic effects of PAF in mammals have been described thus far, and, moreover, there are so far no A. fumigatus strains with reported inherent or acquired PAF resistance, it is worth carrying out further studies to introduce PAF as a potential antifungal drug in human therapy.

show abstract

The small molecular mass antifungal protein of Penicillium chrysogenum – a mechanism of action oriented review

Cited by 36 publications

References 123 publications

“Invisible” Conformers of an Antifungal Disulfide Protein Revealed by Constrained Cold and Heat Unfolding, CEST‐NMR Experiments, and Molecular Dynamics Calculations

“Invisible” Conformers of an Antifungal Disulfide Protein Revealed by Constrained Cold and Heat Unfolding, CEST‐NMR Experiments, and Molecular Dynamics Calculations

Impact of the antifungal protein PgAFP from Penicillium chrysogenum on the protein profile in Aspergillus flavus

Application of a low molecular weight antifungal protein from Penicillium chrysogenum (PAF) to treat pulmonary aspergillosis in mice

Contact Info

Product

Resources

About