A Therapeutic Connection between Dietary Phytochemicals and ATP Synthase

Abstract

For centuries, phytochemicals have been used to prevent and cure multiple health ailments. Phytochemicals have been reported to have antioxidant, antidiabetic, antitussive, antiparasitic, anticancer, and antimicrobial properties. Generally, the therapeutic use of phytochemicals is based on tradition or word of mouth with few evidence-based studies. Moreover, molecular level interactions or molecular targets for the majority of phytochemicals are unknown. In recent years, antibiotic resistance by microbes has become a major healthcare concern. As such, the use of phytochemicals with antimicrobial properties has become pertinent. Natural compounds from plants, vegetables, herbs, and spices with strong antimicrobial properties present an excellent opportunity for preventing and combating antibiotic resistant microbial infections. ATP synthase is the fundamental means of cellular energy. Inhibition of ATP synthase may deprive cells of required energy leading to cell death, and a variety of dietary phytochemicals are known to inhibit ATP synthase. Structural modifications of phytochemicals have been shown to increase the inhibitory potency and extent of inhibition. Sitedirected mutagenic analysis has elucidated the binding site(s) for some phytochemicals on ATP synthase. Amino acid variations in and around the phytochemical binding sites can result in selective binding and inhibition of microbial ATP synthase. In this review, the therapeutic connection between dietary phytochemicals and ATP synthase is summarized based on the inhibition of ATP synthase by dietary phytochemicals. Research suggests selective targeting of ATP synthase is a valuable alternative molecular level approach to combat antibiotic resistant microbial infections.

Keywords: Microbial and mammalian F1Fo ATP synthase; antimicrobial phytochemicals; enzyme inhibition; molecular drug target; polyphenols.

Fig. (1)

Backbone form of F₁F_o ATP synthase with phytochemical binding site. The F₁ sector of the enzyme shows the catalytic Pi (phosphate) binding subdomain, peptide, and phytochemical binding sites in space fill form. The resveratrol bound phytochemical binding site contributed by α-, β-, and γ-subunit residues is zoomed in wireframe form. Figure was taken from references [11, 28] and was generated by PDB files 1H8E [146] and 2JIZ [10] using Rasmol [147].

Fig. (2)

Phytochemical induced inhibition of F₁F_o ATP synthase. Thymoquinone, safranal, piceatannol, and baicalein induced inhibition of E. coli wild-type F₁F_o ATP synthase. Figure compiled from references [11, 12, 21, 22].

Fig. (3)

Inhibitory effect of resveratrol and structurally modified resveratrol containing nitro groups hydroxyl-nitrophenyl-imino methylphenol (MR1 & MR2). Structural modification caused 100% inhibition and reduced IC₅₀ from 94 µM to 2.5 µM and 7 µM. Figure taken from reference [89].