Lipophilic Cations Rescue the Growth of Yeast under the Conditions of Glycolysis Overflow

Sokolov, Svyatoslav S.; Смирнова, Е. А.; Маркова, О. В.; Kireeva, Natalya A; Kirsanov, Roman S.; Khailova, Liudmila S; Knorre, Dmitry A.; Severin, Fedor F.

doi:10.3390/biom10091345

Cited by 5 publications

(1 citation statement)

References 45 publications

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“…Substances that violate the barrier function of membranes are considered promising antimicrobial agents. These antibiotics include, but are not limited to, amphipathic peptides [3][4][5], membrane-disrupting and penetrating lipocations [6,7], channel-forming peptides [8][9][10][11], polyene antibiotics [12,13]. Amphipathic and channel-forming peptides (like gramicidin A) are definitely known to locally decrease the thickness of lipid bilayers [14][15][16][17], that is observed by means of X-Ray diffraction, molecular dynamics, or inferred from comparison of known bilayer thickness and the length of the membrane-permeating structure formed by the above-mentioned compounds.…”

Section: Introductionmentioning

confidence: 99%

Alteration of Average Thickness of Lipid Bilayer by Membrane-Deforming Inclusions

Kondrashov,

Akimov

2023

Biomolecules

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Thickness of lipid bilayer membranes is a key physical parameter determining membrane permeability and stability with respect to formation of through pores. Most membrane inclusions or impurities like amphipathic peptides, transmembrane peptides, lipid inclusions of a different molecular shape, lipid domains, and protein-lipid domains, locally deform the membrane. The detailed structure of the locally deformed region of the membrane is a kind of “fingerprint” for the inclusion type. However, most experimental methods allow determining only averaged parameters of membranes with incorporated inclusions, thus preventing the direct obtaining of the characteristics of the inclusion. Here we developed a model that allows the obtaining of characteristic parameters of three types of membrane inclusions (amphipathic peptides, transmembrane peptides, monolayer lipid patches) from experimentally observable dependencies of the average thickness of lipid bilayer on the surface concentration of the inclusions. In the case of amphipathic peptides, the model provided the peptide parameters that were in qualitative agreement with the available experimental data.

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Section: Introductionmentioning

confidence: 99%

Alteration of Average Thickness of Lipid Bilayer by Membrane-Deforming Inclusions

Kondrashov,

Akimov

2023

Biomolecules

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Mitochondrial Membrane-Associated Protein Mba1 Confers Antifungal Resistance by Affecting the Production of Reactive Oxygen Species in Aspergillus fumigatus

Zhu

Shu

Zhang

et al. 2023

Antimicrob Agents Chemother

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Azole resistance in the human fungal pathogen Aspergillus fumigatus is becoming a major threat to global health. To date, mutations in the azole target-encoding cyp51A gene have been implicated in conferring azole resistance, but a steady increase in the number of A. fumigatus isolates with azole resistance resulting from non- cyp51A mutations has been recognized.

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Aberrant Intracellular pH Regulation Limiting Glyceraldehyde-3-Phosphate Dehydrogenase Activity in the Glucose-Sensitive Yeast tps1 Δ Mutant

Leemputte

Vanthienen

Wijnants

et al. 2020

mBio

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Whereas the yeast Saccharomyces cerevisiae shows great preference for glucose as a carbon source, a deletion mutant in trehalose-6-phosphate synthase, tps1Δ, is highly sensitive to even a few millimolar glucose, which triggers apoptosis and cell death. Glucose addition to tps1Δ cells causes deregulation of glycolysis with hyperaccumulation of metabolites upstream and depletion downstream of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). The apparent metabolic barrier at the level of GAPDH has been difficult to explain. We show that GAPDH isozyme deletion, especially Tdh3, further aggravates glucose sensitivity and metabolic deregulation of tps1Δ cells, but overexpression does not rescue glucose sensitivity. GAPDH has an unusually high pH optimum of 8.0 to 8.5, which is not altered by tps1Δ. Whereas glucose causes short, transient intracellular acidification in wild-type cells, in tps1Δ cells, it causes permanent intracellular acidification. The hxk2Δ and snf1Δ suppressors of tps1Δ restore the transient acidification. These results suggest that GAPDH activity in the tps1Δ mutant may be compromised by the persistently low intracellular pH. Addition of NH4Cl together with glucose at high extracellular pH to tps1Δ cells abolishes the pH drop and reduces glucose-6-phosphate (Glu6P) and fructose-1,6-bisphosphate (Fru1,6bisP) hyperaccumulation. It also reduces the glucose uptake rate, but a similar reduction in glucose uptake rate in a tps1Δ hxt2,4,5,6,7Δ strain does not prevent glucose sensitivity and Fru1,6bisP hyperaccumulation. Hence, our results suggest that the glucose-induced intracellular acidification in tps1Δ cells may explain, at least in part, the apparent glycolytic bottleneck at GAPDH but does not appear to fully explain the extreme glucose sensitivity of the tps1Δ mutant. IMPORTANCE Glucose catabolism is the backbone of metabolism in most organisms. In spite of numerous studies and extensive knowledge, major controls on glycolysis and its connections to the other metabolic pathways remain to be discovered. A striking example is provided by the extreme glucose sensitivity of the yeast tps1Δ mutant, which undergoes apoptosis in the presence of just a few millimolar glucose. Previous work has shown that the conspicuous glucose-induced hyperaccumulation of the glycolytic metabolite fructose-1,6-bisphosphate (Fru1,6bisP) in tps1Δ cells triggers apoptosis through activation of the Ras-cAMP-protein kinase A (PKA) signaling pathway. However, the molecular cause of this Fru1,6bisP hyperaccumulation has remained unclear. We now provide evidence that the persistent drop in intracellular pH upon glucose addition to tps1Δ cells likely compromises the activity of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a major glycolytic enzyme downstream of Fru1,6bisP, due to its unusually high pH optimum. Our work highlights the potential importance of intracellular pH fluctuations for control of major metabolic pathways.

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Lipophilic Cations Rescue the Growth of Yeast under the Conditions of Glycolysis Overflow

Cited by 5 publications

References 45 publications

Alteration of Average Thickness of Lipid Bilayer by Membrane-Deforming Inclusions

Alteration of Average Thickness of Lipid Bilayer by Membrane-Deforming Inclusions

Mitochondrial Membrane-Associated Protein Mba1 Confers Antifungal Resistance by Affecting the Production of Reactive Oxygen Species in Aspergillus fumigatus

Aberrant Intracellular pH Regulation Limiting Glyceraldehyde-3-Phosphate Dehydrogenase Activity in the Glucose-Sensitive Yeast tps1 Δ Mutant

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