A role for anions in ATP synthesis and its molecular mechanistic interpretation

Bhawana Agarwal

ATP, the 'universal biological energy currency', is synthesized by utilizing energy either from oxidation of fuels or from light, via the process of oxidative and photo-phosphorylation respectively. The process is mediated by the enzyme F(1)F(0)-ATP synthase, using the free energy of ion gradients in the final energy catalyzing step, i.e., the synthesis of ATP from ADP and inorganic phosphate (P(i)). The details of the molecular mechanism of ATP synthesis are among the most important fundamental issues in biology and hence need to be properly understood. In this work, a role for anions in making ATP has been found. New experimental data has been reported on the inhibition of ATP synthesis at nanomolar concentrations by the potent, specific anion channel blockers 4,4'-diisothiocyanostilbene-2, 2'-disulphonic acid (DIDS) and tributyltin chloride (TBTCl). Based on these inhibition studies, attention has been drawn to anion translocation (in addition to proton translocation) as a requirement for ATP synthesis. The type of inhibition has been quantified and an overall kinetic scheme for mixed inhibition that explains the data has been evolved. The experimental data and the type of inhibition found have been interpreted in the light of the torsional mechanism of energy transduction and ATP synthesis (Nath J Bioenerg Biomembr 42:293-300, 2010a; J Bioenerg Biomembr 42:301-309, 2010b). This detailed and unified mechanism resolves long-standing problems and inconsistencies in the first theories (Slater Nature 172:975-978, 1953; Williams J Theor Biol 1:1-17, 1961; Mitchell Nature 191:144-148, 1961; Mitchell Biol Rev 41:445-502, 1966), makes several novel predictions that are experimentally verifiable (Nath Biophys J 90:8-21, 2006a; Process Biochem 41:2218-2235, 2006b), and provides us with a new and fruitful paradigm in bioenergetics. The interpretation presented here provides intelligent answers to the unexplained existing results in the literature. It is shown that mechanistic interpretation of the experimental data requires substantial addition to available conceptual foundations such that present concepts, theories, and mechanisms must be revised.