Biological effects of deuteronation: ATP synthase as an example

In mitochondria, the release of a deuteron into the matrix side half-channel of F0 is likely to be slower than that of a proton. As another example, deuteronation may slow down electron transfer in the electron transport chain (ETC) by interfering with proton coupled electron transport reactions (PCET), and increase free radical production through the leakage of temporarily accumulated electrons at the downstream complexes.Deuteronation, as exemplified by ATP synthase and the ETC, may interfere with the conformations and functions of many macromolecules and contribute to some pathologies like heavy water toxicity and aging.In nature, the ratio of deuterium to hydrogen is ~1/6600 [1], therefore the ratio of deuterated + heavy water (HOD + D2O) to water (H2O) is ~1/3300. In the atomic nucleus of hydrogen there is only one proton, while in deuterium there is one proton and neutron. One dissociation product of water is a proton (H+)/H3O+; for D2O, the equivalent product is a deuteron (proton + neutron) (D+)/H2OD+ + D3O+. The ionization constant of D2O (1.95 × 10-15, pD = 7.35) is 5.17-fold lower than that of H2O (1.008 × 10-14, pH = 6.99) [2]; thus, the ratio of protons in water to deuterons in heavy water is 2.27. Although the ratio of hydrogen to deuterium is 1/6600, the ratio of deuterons to protons is 1/2.27 × 6600 = ~1/15000 (Table 1). Therefore, in any biological process in which protonation is involved, there is ~1/15000 chance of deuteronation.ATP synthase (F0F1 ATPase), an inner mitochondrial membrane enzyme complex, is a molecular motor that uses protonation to generate a wheel-like rotation to catalyse the synthesis of ATP, which is the most important energy currency in living systems. During mitochondrial electron transport, protons are pumped from the matrix to the intermembrane space by the electron transport chain (ETC) complexes I, III and IV by a mechanism coupling electron transport to proton passage. The proton gradient thus formed and the consequent