A Therapeutic Role for the F1FO-ATP Synthase

Abstract

Recently, the F1FO-ATP synthase, due to its dual role of life enzyme as main adenosine triphosphate (ATP) maker and of death enzyme, as ATP dissipator and putative structural component of the mitochondrial permeability transition pore (mPTP), which triggers cell death, has been increasingly considered as a drug target. Accordingly, the enzyme offers new strategies to counteract the increased antibiotic resistance. The challenge is to find or synthesize compounds able to discriminate between prokaryotic and mitochondrial F1FO-ATP synthase, exploiting subtle structural differences to kill pathogens without affecting the host. From this perspective, the eukaryotic enzyme could also be made refractory to macrolide antibiotics by chemically produced posttranslational modifications. Moreover, because the mitochondrial F1FO-ATPase activity stimulated by Ca2+ instead of by the natural modulator Mg2+ is most likely involved in mPTP formation, effectors preferentially targeting the Ca2+-activated enzyme may modulate the mPTP. If the enzyme involvement in the mPTP is confirmed, Ca2+-ATPase inhibitors may counteract conditions featured by an increased mPTP activity, such as neurodegenerative and cardiovascular diseases and physiological aging. Conversely, mPTP opening could be pharmacologically stimulated to selectively kill unwanted cells. On the basis of recent literature and promising lab findings, the action mechanism of F1 and FO inhibitors is considered. These molecules may act as enzyme modifiers and constitute new drugs to kill pathogens, improve compromised enzyme functions, and limit the deathly enzyme role in pathologies. The enzyme offers a wide spectrum of therapeutic strategies to fight at the molecular level diseases whose treatment is still insufficient or merely symptomatic.

Activation of P2×7 Receptor Promotes the Invasion and Migration of Colon Cancer Cells via the STAT3 Signaling

“…Therefore, it is of great significance to explore the relevant molecular basis and pathological mechanism affecting the pathogenesis of colon cancer, to inhibit the migration and metastasis of colon cancer, and to target the treatment of colon cancer. ATP is not only an important energy information substance, but also participates in the transmission of signals in the body, which plays an important role in regulating the life activities of cells including tumor cells (Ghosh et al, 2019;Nesci et al, 2019). Tumor cells can release large amounts of ATP into the microenvironment and play a role in regulating tumor progression by acting on other signaling molecule (such as P2Y and P2X receptors) (Lee et al, 2019).…”

Engineering protein fragments via evolutionary and protein–protein interaction algorithms: de novo design of peptide inhibitors for FOF1‐ATP synthase

“…After these findings, the inhibition of ATP synthase for clinical purposes has drawn special interest. A wide variety of molecules has been found to inhibit it, including exogenous natural compounds and peptides, and endogenous ATP synthase subunits [29,50]. This chemical spectrum of molecules inhibiting ATP synthase underscores the versatility of the enzyme as a molecular target and validates ongoing efforts by different groups to find and optimize new inhibitors targeting this enzyme to both develop new antibiotics or compounds to treat human disorders [29,52–54].…”

“…Additional to its most common locations (the inner membranes of mitochondria, bacteria, and chloroplast thylakoids), ATP synthase is found on the plasma membrane of several mammalian cell types (hepatocytes, adipocytes, and endothelial cells), playing crucial roles in regulating many cellular processes in humans [27]. These roles, as well as its involvement in various genetic diseases [28], have made human ATP synthase an attractive target for therapeutic molecules [29]. In addition, ATP synthase has been proven as a promising target for the development of new antibiotics [30].…”

“…This breakthrough has led to an accelerated search for compounds that could be used as new ATP synthase‐targeting antibiotics [22]. The ongoing search has also included many natural peptides that show appealing pharmaceutical activities [29]. Despite the variety of exogenous peptide inhibitors that evidence the high ‘druggability’ of this enzyme, which makes it an attractive target to develop new antimicrobial peptides (AMPs), to the best of our knowledge no inhibitory peptide derived from ATP synthase fragments and targeting the same enzyme have been previously designed [22].…”

Oxidative Phosphorylation—an Update on a New, Essential Target Space for Drug Discovery in Mycobacterium tuberculosis

“…The mechanism of action of BDQ has been extensively studied in mycobacteria [20,83,[162][163][164]. Briefly, BDQ binds to the c-subunit and the ε-subunit of the ATP synthase by mimicking key residues in the proton transfer chain and blocking the rotary movement of the c-subunit during the catalysis of ATP [165,166], disrupting a fundamental process for bacterial survival in both actively growing and non-growing states [20,162]. The inhibition of the ATP synthase leads to ATP depletion and also dissipation of the membrane potential, as BDQ was shown to have uncoupling properties mediated by the H+/K+ antiporter [167].…”