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Novel Drugs Targeting the c-Ring of the F1FO-ATP Synthase
Full text linkIncreasing evidence highlights the role of the ATP synthase/hydrolase, also known as F1FO-complex, as key molecular and enzymatic switch between cell life and death, thus increasing the enzyme attractiveness as drug target in pharmacology. Being inhibition of ATP production usually linked to antiproliferative properties, drugs targeting the enzyme complex have been mainly considered to fight pathogen parasites and cancer. In recent years, a number of natural macrolides, produced by bacterial fermentation and structurally related to the classical enzyme inhibitor oligomycin, have been shown to bind to the membrane-embedded FO sector and to inhibit the enzyme complex by an oligomycin-like mechanism, namely by interacting with the c-ring. Other than natural macrolide antibiotics, which display variegated inhibition power on different F1FO-complexes, synthetic compounds from the diarylquinoline and organotin families also target the c-ring and strongly inhibit the enzyme. Bioinformatic insights address drug design to target FO subunits. Additionally, the possible modulation of the drug inhibition power, by amino acid substitutions or post-translational modifications of c-subunits, adds further interest to the target. The present survey on compounds targeting the c-ring and bi-directionally blocking the transmembrane proton flux which drives ATP synthesis/hydrolysis, discloses new therapeutic options to fight cancer and infections sustained by therapeutically recalcitrant microorganisms. Additionally, c-ring targeting compounds may constitute new tools to eradicate undesired biofilms and to address at the molecular level the therapy of mammalian diseases linked to mitochondrial dysfunctions. In summary, studies on the only partially known molecular interactions within the c-ring of the F1FO-complex may renew hope to counteract mammalian diseases
Incoming news on the F-type ATPase structure and functions in mammalian mitochondria
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Crucial aminoacids in the F O sector of the F 1 F O -ATP synthase address H + across the inner mitochondrial membrane: molecular implications in mitochondrial dysfunctions
Full text linkThe eukaryotic F 1 F O -ATP synthase/hydrolase activity is coupled to H + translocation through the inner mitochondrial membrane. According to a recent model, two asymmetric H + half-channels in the a subunit translate a transmembrane vertical H + flux into the rotor rotation required for ATP synthesis/hydrolysis. Along the H + pathway, conserved aminoacid residues, mainly glutamate, address H + both in the downhill and uphill transmembrane movements to synthesize or hydrolyze ATP, respectively. Point mutations responsible for these aminoacid changes affect H + transfer through the membrane and, as a cascade, result in mitochondrial dysfunctions and related pathologies. The involvement of specific aminoacid residues in driving H + along their transmembrane pathway within a subunit, sustained by the literature and calculated data, leads to depict a model consistent with some mitochondrial disorders
The inhibition of gadolinium ion (Gd3+) on the mitochondrial F1FO-ATPase is linked to the modulation of the mitochondrial permeability transition pore
Full text linkThe mitochondrial permeability transition pore (PTP), which drives regulated cell death when Ca2+ concentration suddenly increases in mitochondria, was related to changes in the Ca2+-activated F1FO-ATPase. The effects of the gadolinium cation (Gd3+), widely used for diagnosis and therapy, and reported as PTP blocker, were evaluated on the F1FO-ATPase activated by Mg2+ or Ca2+ and on the PTP. Gd3+ more effectively inhibits the Ca2+-activated F1FO-ATPase than the Mg2+-activated F1FO-ATPase by a mixed-type inhibition on the former and by uncompetitive mechanism on the latter. Most likely Gd3+ binding to F1, is favoured by Ca2+ insertion. The maximal inactivation rates (Kinact) of pseudo-first order inactivation are similar either when the F1FO-ATPase is activated by Ca2+ or by Mg2+. The half-maximal inactivator concentrations (KI) are 2.35 ± 0.35 mM and 0.72 ± 0.11 mM, respectively. The potency of a mechanism-based inhibitor (Kinact/KI) also highlights a higher inhibition efficiency of Gd3+ on the Ca2+-activated F1FO-ATPase (0.59 ± 0.09 mM-1∙s-1) than on the Mg2+-activated F1FO-ATPase (0.13 ± 0.02 mM-1∙s-1). Consistently, the PTP is desensitized in presence of Gd3+. The Gd3+ inhibition on both the mitochondrial Ca2+-activated F1FO-ATPase and the PTP strengthens the link between the PTP and the F1FO-ATPase when activated by Ca2+ and provides insights on the biological effects of Gd3+
Mitochondrial F-type ATP synthase: multiple enzyme functions revealed by the membrane-embedded FO structure
Full text linkOf the two main sectors of the F-type ATP synthase, the membrane-intrinsic F(O)domain is the one which, during evolution, has undergone the highest structural variations and changes in subunit composition. The F(O)complexity in mitochondria is apparently related to additional enzyme functions that lack in bacterial and thylakoid complexes. Indeed, the F-type ATP synthase has the main bioenergetic role to synthesize ATP by exploiting the electrochemical gradient built by respiratory complexes. The F(O)membrane domain, essential in the enzyme machinery, also participates in the bioenergetic cost of synthesizing ATP and in the formation of thecristae, thus contributing to mitochondrial morphology. The recent enzyme involvement in a high-conductance channel, which forms in the inner mitochondrial membrane and promotes the mitochondrial permeability transition, highlights a new F-type ATP synthase role. Point mutations which cause amino acid substitutions in F(O)subunits produce mitochondrial dysfunctions and lead to severe pathologies. The F(O)variability in different species, pointed out by cryo-EM analysis, mirrors the multiple enzyme functions and opens a new scenario in mitochondrial biology
From the Ca2+-activated F1FO-ATPase to the mitochondrial permeability transition pore: an overview
Full text linkBased on recent advances on the Ca2+-activated F1FO-ATPase features, a novel multistep mechanism involving the mitochondrial F1FO complex in the formation and opening of the still enigmatic mitochondrial permeability transition pore (MPTP), is proposed. MPTP opening makes the inner mitochondrial membrane (IMM) permeable to ions and solutes and, through cascade events, addresses cell fate to death. Since MPTP forms when matrix Ca2+ concentration rises and ATP is hydrolyzed by the F1FO-ATPase, conformational changes, triggered by Ca2+ insertion in F1, may be transmitted to FO and locally modify the IMM curvature. These events would cause F1FO-ATPase dimer dissociation and MPTP opening
Putative role of the calcium-dependent F1FO-ATPase activity in mitochondrial permeability transition
No full textThe mitochondrial F1FO-ATPsynthase/ase is a bi-powered enzymatic engine, skilled for massive ATP production by oxidative phosphorylation, but also able to operate in reverse by hydrolyzing ATP and acting as a proton pump to re-energize the membrane [1]. Universally known as the enzyme of life, recently this complex has also been defined as enzymatic switch between life and death, due to its implication with the mitochondrial permeability transition pore (MPTP), in turn involved in cell death [2]. Since Ca2+ is essential for MPTP opening, when its concentration rises in the matrix Ca2+ may replace the natural Mg2+ cofactor in the F1FO-ATPase activation. The Mg2+ and Ca2+-dependent F1FO-ATPase activities, already shown to be both oligomycin-sensitive [3], have a similar pH dependence. However pH differently modulates the enzyme inhibition by DCCD depending on the activating cation and NAD+ only inhibits the Ca2+ dependent F1FO-ATPase. The enzyme desensitization to oligomycin by thiol oxidation, both when either Ca2+ or Mg2+ activate the enzyme, shoulders the enzyme involvement in MPTP, reported as oligomycin-insensitive when specific Cys are oxidized [2]. Taken together the findings suggest that Ca2+-activated F1FO-ATPase may be functionally involved in the MPTP
Mini-review. Nitrite as novel pore-shutter: hints from the preferential inhibition of the mitochondrial ATP-ase when activated by Ca2+
No full textSmall inorganic compounds able to prevent the mitochondrial permeability transition, the master player in apoptosis and necrosis, are increasingly considered as beneficial tools in cytoprotection. Nitrite, a known cellular nitric oxide reservoir, has a recognized role in cardioprotection, but the molecular mechanisms of its action are not thoroughly understood. Mitochondrial permeability changes are known to constitute the molecular bases of human cardiac diseases and pathologies related to mitochondrial dysfunctions. In turn oxidative stress and mitochondrial damage are related issues in degenerative and cardiovascular diseases. Assumed that the mitochondrial F1FO complex is structurally or functionally involved in the mitochondrial permeability transition pore (MPTP), which triggers the mitochondrial permeability transition, nitrite effects on the enzyme complex may be exploited to shut the MPTP. Many clues suggest that nitrite may prevent or limit cell death by modulating the F1FO complex. Accordingly, nitrite decreases the ATPase activity stimulated by Ca2+, it is ineffective on the Mg-ATPase up to 2 mM and the enzyme inhibition is apparently enhanced under oxidative stress conditions. Through the inhibition of the calcium-activated F1FO complex, nitrite would shut the MPTP, which is likely to be related to the calcium-dependent functioning mode of the F1FO complex, and limit mitochondrial impairment and cell death under physio-pathological conditions
Preferential nitrite inhibition of the mitochondrial F1FO-ATPase activities when activated by Ca(2+) in replacement of the natural cofactor Mg(2.)
Full text linkThe ATP synthase can be imagined as a reversible H+-translocating channel embedded in the membrane, FO portion, coupled to a protruding catalytic portion, F1. Under physiological conditions the F1FO complex synthesizes ATP by exploiting the transmembrane electrochemical gradient of protons and their downhill movement. Alternatively, under other patho-physiological conditions it exploits ATP hydrolysis to energize the membrane by uphill pumping protons. The reversibility of the mechanism is guaranteed by the structural coupling between the hydrophilic F1 and the hydrophobic FO. Which of the two opposite processes wins in the energy-transducing membrane complex depends on the thermodynamic balance between the protonmotive force (Δp) and the phosphorylation potential of ATP (ΔGP). Accordingly, while Δp prevalence drives ATP synthesis by translocating protons from the membrane P-side to the N-side and generating anticlockwise torque rotation (viewed from the matrix), ΔGP drives ATP hydrolysis by chemomechanical coupling of FO to F1 with clockwise torque. The direction of rotation is the same in all the ATP synthases, due to the conserved steric arrangement of the chiral a subunit of FO. The ability of this coupled bi-functional complex to produce opposite rotations in ATP synthesis and hydrolysis is explained on the basis of the a subunit asymmetry
The c-Ring of the F1FO-ATP Synthase: Facts and Perspectives
No full textThe F1FO-ATP synthase is the only enzyme in nature endowed with bi-functional catalytic mechanism of synthesis and hydrolysis of ATP. The enzyme functions, not only confined to energy transduction, are tied to three intrinsic features of the annular arrangement of c subunits which constitutes the so-called c-ring, the core of the membrane-embedded FO domain: (i) the c-ring constitution is linked to the number of ions (H+ or Na+) channeled across the membrane during the dissipation of the transmembrane electrochemical gradient, which in turn determines the species-specific bioenergetic cost of ATP, the “molecular currency unit” of energy transfer in all living beings; (ii) the c-ring is increasingly involved in the mitochondrial permeability transition, an event linked to cell death and to most mitochondrial dysfunctions; (iii) the c subunit species-specific amino acid sequence and susceptibility to post-translational modifications can address antibacterial drug design according to the model of enzyme inhibitors which target the c subunits. Therefore, the simple c-ring structure not only allows the F1FO-ATP synthase to perform the two opposite tasks of molecular machine of cell life and death, but it also amplifies the enzyme’s potential role as a drug target
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