Phosphorus Chemistry at the Roots of Bioenergetics: Ligand Permutation as the Molecular Basis of the Mechanism of ATP Synthesis/Hydrolysis by FOF1-ATP Synthase
Abstract
:1. Introduction
2. Results and Discussion
2.1. Novel Insights from Oxygen Exchange Experiments on Submitochondrial Particles
- (i).
- The energy of the ion gradients is required primarily to induce a conformational change that enables product ATP release from an F1 catalytic site;
- (ii).
- ATP synthesis occurs at a second catalytic site in F1 without external energy input.
2.2. Biological Implications of the Results of Isotope Exchange Experiments on Submitochondrial Particles
2.2.1. Derivation of Limitations on the Rates of Oxygen Exchange
- (i).
- Release of Pi is limiting. In this case, bound ATP can rapidly exchange with 18O in H18OH, which will cause the label to appear in ATP or subsequently in Pi. However, each inorganic phosphate molecule released can contain at most four oxygens from 18O labeled water. Thus, in this case, the rate of ATP–HOH exchange can be high relative to the Pi–ATP exchange, but the rate of Pi–HOH exchange relative to the Pi–ATP exchange cannot be greater than four;
- (ii).
- Release of ATP is limiting. In such a case, tightly bound Pi can rapidly exchange with the oxygens of 18O water, but the γ-phosphate of ATP can contain at most three labeled oxygens. Thus, in this situation, the rate of Pi–HOH exchange can be high relative to the Pi–ATP exchange, but the ratio of the rate of ATP–HOH exchange to that of the Pi–ATP exchange cannot exceed three.
2.2.2. Measurement of the Relative Rates of Isotope Exchanges and Difficulties of Their Rationalization by the Existing Model
2.2.3. Possible Explanation of the Kinetic Data on Relative Rates of Oxygen Exchanges
2.2.4. Resolution of the Apparently Conflicting Experimental Data and Discussion of Other Key Mechanistic Aspects of ATP Synthesis/Hydrolysis
- (i).
- The meeting of the nucleotide requirement for the intermediate Pi–HOH exchange by ATP, but not by ADP, with the latter postulated as an obligatory requirement by the binding change mechanism [81], goes against the mechanism (Section 2.1);
- (ii).
- The concomitant enhancement (Section 2.2.2) above theoretical limits of both the intermediate Pi–HOH and ATP–HOH exchanges with respect to the Pi–ATP exchange (Section 2.2.1) is impossible to explain using Boyer’s simple model containing only a single route of water entry.
- (iii).
- The equations of the binding change mechanism have not been cast in a model-independent way [57,91]. There is no independent verification of the reversals postulated to occur as a result of the mechanism at low substrate concentrations during ATP synthesis/hydrolysis. At physiological ATP, for the F1-ATPase, leading in essence to an irreversible cleavage of ATP. As formulated, has to be an integer, and it is difficult to interpret a non-integer value of in molecular terms;
- (iv).
- For ATP hydrolysis by the FOF1-ATPase, the incorporation of water oxygens into ATP/Pi that arises from the postulated repeated cycles of reversal of the ATP formation reaction has to also be accompanied by a reversal in the direction of H+ translocation across the membrane. However, such a rapid fluctuation/change in direction of the electrochemical ion gradients, and such cycles of bidirectional ion movement, have never been demonstrated in any biochemical system. It was stated by Boyer in 1997 that this “remains an important question” [92], but it has not been addressed, let alone answered, even after the passage of 25 years;
- (v).
- Point (iv) is further exacerbated by the fact that mechanical aspects of the ATP synthase motor also need to be included in the analysis. We stated that, “it is imperative to relate the chemical kinetics (the arrows representing an elementary step in the kinetic scheme) to the mechanical aspects (structure and dynamics of the molecular machine). It is very difficult to conceive how a unidirectional, discrete motion can take place by a reversible mode of catalysis (E.ATP E.ADP.Pi), i.e., how can a subunit of a single enzyme molecule oscillate back and forth in the presence of a driving force in one direction? This irreversibility of operation in a single molecule mode contradicts the fundamental tenet of the binding change mechanism that ATP synthesis occurs reversibly (and spontaneously) in a catalytic site of the enzyme” [33];
- (vi).
- During the operation of a molecular motor at physiological conditions, a species is encouraged to bind to its site on the enzyme mainly to undergo the reaction to the product, and thereafter immediately unbind and release the product. There is no logical explanation as to why it should bind and be released before its conversion to product, or why a reaction should move back and forth numerous times before its product is finally released. Nor can this be considered an efficient mode of operation of the system;
- (vii).
- The binding change mechanism proposed a catalytic site at which during steady-state catalysis by the ATP synthase/F1-ATPase [59]. Later, in one of his last papers on the subject, Boyer acknowledged that “during hydrolysis the quasi-equilibrium may be shifted toward bound ADP so that essentially only ADP will be released” [61]. It further added that “how this could be achieved is not known” [61]. We are none the wiser twenty years on after that statement was made;
- (viii).
- The bisite binding change mechanism revealed fundamental flaws, in that low-affinity F1 catalytic sites were occupied by bound MgATP, while higher-affinity catalytic sites were left unfilled during the catalysis of ATP hydrolysis [33];
- (ix).
- While “unisite” catalysis and its acceleration by chase ATP binding at a second catalytic site has been amply demonstrated [78], there has been no report of “unisite” ATP synthesis. Nor has the acceleration of the rate of ATP synthesis been demonstrated to achieve the physiological catalysis of synthesis. In fact, classical biochemical experiments on the mitochondrial F1 using radioactive probes showed that rapid steady-state ATP synthesis is achieved by the enzyme only after the filling of three catalytic sites [93];
- (x).
- Pioneering biochemical studies by Senior and coworkers [94] using fluorescent probes have conclusively demonstrated that trisite catalysis is the true operating mode of steady-state Vmax hydrolysis by F1-ATPase. The technologically sophisticated single-molecule studies of Kinosita and coworkers on F1-ATPase offer further support to a trisite mode of ATP hydrolysis from nanomolar to millimolar ATP concentrations [95]. Finally, high-resolution X-ray structures of F1-ATPase that visualized the transition state have proven beyond doubt that Mg-nucleotide binds to all three β-catalytic sites of the F1-ATPase during catalysis [76]. It is very difficult, if not impossible, to explain these important findings based on bisite models of catalysis, such as the binding change mechanism;
- (xi).
- It was very important to distinguish between bisite activation and trisite catalysis during the process of ATP hydrolysis. The binding change mechanism did not do that, which, in retrospect, can be considered a major shortcoming. Trisite catalysis with bisite activation in ATP hydrolysis by F1-ATPase has been explained only very recently [77,91];
- (xii).
- The cleavage of bonds followed by their re-formation by irregular processes leads to intermediates of lower coordination number. Hence, such processes do not satisfy the general chemical concept of the preservation of coordination number. The latter is only possible if the molecular skeleton is flexible, i.e., the numbered positions on the skeleton (such as the trigonal bipyramid skeleton) can be interconverted with the maintenance of coordination numbers via the deformation of bond angles or rotation about bonds (dynamic skeletal symmetry). Hence there is no chemical necessity to propose mechanisms involving bond breaking and bond re-forming processes as done by the binding change mechanism in order to rationalize the oxygen exchange reactions. We shall further discuss this concept, which is of great importance to phosphorus chemistry, in Section 2.2.5 and Section 2.2.6.
2.2.5. New Concepts for Rationalization and Explanation of Oxygen Exchange in Oxidative Phosphorylation and Photophosphorylation
2.2.6. Stereochemical Consequences
3. Experimental
3.1. Preparation of Submitochondrial Particles
3.2. Determination of Incorporation of the 18O
3.3. Oxygen Exchange
3.4. Experiments on Particles in the Presence of Uncoupler
3.5. Separation of Pi
3.6. Mass Spectroscopic Experiments for Determination of 18O in Pi
4. Conclusions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Nath, S. Phosphorus Chemistry at the Roots of Bioenergetics: Ligand Permutation as the Molecular Basis of the Mechanism of ATP Synthesis/Hydrolysis by FOF1-ATP Synthase. Molecules 2023, 28, 7486. https://doi.org/10.3390/molecules28227486
Nath S. Phosphorus Chemistry at the Roots of Bioenergetics: Ligand Permutation as the Molecular Basis of the Mechanism of ATP Synthesis/Hydrolysis by FOF1-ATP Synthase. Molecules. 2023; 28(22):7486. https://doi.org/10.3390/molecules28227486
Chicago/Turabian StyleNath, Sunil. 2023. "Phosphorus Chemistry at the Roots of Bioenergetics: Ligand Permutation as the Molecular Basis of the Mechanism of ATP Synthesis/Hydrolysis by FOF1-ATP Synthase" Molecules 28, no. 22: 7486. https://doi.org/10.3390/molecules28227486