Medicinal chemistry of ATP synthase: a potential drug target of dietary polyphenols and amphibian antimicrobial peptides

Abstract

In this review we discuss the inhibitory effects of dietary polyphenols and amphibian antimicrobial/antitumor peptides on ATP synthase. In the beginning general structural features highlighting catalytic and motor functions of ATP synthase will be described. Some details on the presence of ATP synthase on the surface of several animal cell types, where it is associated with multiple cellular processes making it an interesting drug target with respect to dietary polyphenols and amphibian antimicrobial peptides will also be reviewed. ATP synthase is known to have distinct polyphenol and peptide binding sites at the interface of α/β subunits. Molecular interaction of polyphenols and peptides with ATP synthase at their respective binding sites will be discussed. Binding and inhibition of other proteins or enzymes will also be covered so as to understand the therapeutic roles of both types of molecules. Lastly, the effects of polyphenols and peptides on the inhibition of Escherichia coli cell growth through their action on ATP synthase will also be presented.

Fig 1. Structure of Escherichia coli ATP synthase

In its simplest form in E. coli this enzyme is composed of two sectors, water soluble F₁ and membrane bound F_o. Catalytic activity occurs at the interface of α/β subunits of F₁ sector which consists of five subunits (α₃β₃γδε ) and proton conduction occurs at the F_o sector consisting of three subunits (ab₂c). In mitochondria and chloroplasts additional subunits are present. Polyphenol and peptide binding sites are identified with circles at the interface of α/β subunits. This model of E. coli ATP synthase is reproduced from Weber [11] with permission; copyright Elsevier.

Fig 2. Structure of polyphenolic compounds

All polyphenolic compound indentified here are known to bind and inhibit ATP synthase.

Fig 3. X-ray crystallographic structure of polyphenol binding site of ATP synthase

(A) Empty and (B) piceatannol bound polyphenol binding pocket. Residues from α, β, and γ subunits involved in interaction with polyphenols are identified. In bovine two variants, Q274K and T277I, occur in the γ subunit and are identified in the figure. PDB file 2jj 1 [84] with RasMol [161] was used to generate this figure.

Fig 4. Inhibitory effects of polyphenols on ATP synthase

Inhibition profiles induced by resveratrol (ο), quercetin (□), and piceatannol (Δ) resulting in partial or complete inhibition of ATP synthase are shown. For experimental details see Dadi et al. [34].

Fig 5. X-ray crystallographic structure of proposed peptide binding βDELSEED-loop of ATP synthase with amphibian AMPs magainin II and dermaseptin

Important residue side chains involved in the electrostatic interaction between βDELSEED-loop and peptides are illustrated. PDB files used were 2MAG [162], 2DCX [163], and 1H8E [24]. RasMol [161] was used to generate this figure.

Fig. 6. Inhibitory effects of amphibian AMPs on ATP synthase

Inhibition profiles induced by MRP (ο), MRP-NH₂ (●), maginin II (Δ), maginin II-NH₂ (▲), caerin 1.8 (□), and caerin 1.9 (◊) resulting in partial or complete inhibition of ATP synthase are shown. For experimental details see Laughlin and Ahmad [35].