19.8: ATP Synthase: Mechanism

In animals, the mitochondrial F₁F₀ ATP synthase is the key protein that synthesizes ATP molecules through a complex catalytic mechanism. While the nuclear genome encodes the majority of ATP synthase subunits, the mitochondrial genome encodes some of the enzyme's most critical components. The formation of this multi-subunit enzyme is a complex multi-step process regulated at the level of transcription, translation, and assembly. Defects in one or more of these steps can result in decreased ATP synthase numbers and functionality, further leading to severe neuromuscular diseases.

Certain mutations in the genes encoding ATP synthase subunits have been recognized in both nuclear and mitochondrial genomes. For instance, a neurodegenerative disorder, Leigh syndrome, results from severe impairment of the ATP synthase mechanism due to a mutation in its α subunit. In the neuronal disease called Kufs, specific mutations lead to the accumulation of subunit c in the lysosome, reducing its abundance for normal ATP synthase assembly. In Alzheimer's, there is a cytosolic accumulation of α subunit and low expression of β subunit, causing a deficiency in ATP synthase subunits.

Furthermore, certain inhibitory compounds may bind to the ATP synthase subunits and impair their activity. For instance, rotation of the γ subunit is blocked by the binding of stilbenes, a phytochemical found in the grapevines. Aurovertin, an antibiotic, binds to the mitochondrial ATP synthase β subunit and inhibits ATP synthesis. Venturicidin binds to the c-subunit and blocks the complex's proton translocation and ATPase activity.

ATP synthase is a molecular machine where the movement of protons drives the rotation of the central stalk or the γ-subunit.

This rotating γ-subunit passes through a hexameric-globular head made of three α-β subunit pairs.

Each β subunit has a catalytic site that can attain three conformational states: open, loose, and tight, each varying in its affinity for the substrates and the product.

The catalytic cycle for ATP synthesis begins with the open-state of a β subunit. The substrates- ADP and inorganic phosphate can then enter the catalytic site.

When the γ-subunit rotates 120 degrees, it transforms the catalytic site into a loose-state. This allows substrates to weakly bind to the catalytic site.

As the γ-subunit rotates another 120 degrees, the catalytic site switches to the tight-state. This causes the substrates to tightly bind to the catalytic site and spontaneously condense into a tightly-bound ATP.

In the next γ-subunit rotation, the catalytic-site switches back to the open-state, where it loses the affinity for ATP, thereby releasing it.

Overall, the process continues with the proton-induced spinning of the rotor and the central stalk, followed by the conformation changes in the globular head that enable the entry of ADP and inorganic phosphate and subsequent generation of ATP.