ATP synthase

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An ATP synthase (EC 3.6.3.14) is a general term for an enzyme that can synthesize adenosine triphosphate (ATP) from adenosine diphosphate (ADP) and inorganic phosphate by utilizing some form of energy. The overall reaction sequence is:

ADP + P_i → ATP

$Molecular model of ATP synthase by X-ray diffraction method$

Molecular model of ATP synthase by X-ray diffraction method

ATP synthase in E. coli

These enzymes are of crucial importance in almost all organisms, because ATP is the common "energy currency" of cells.

In mitochondria, the F₁F_O ATP synthase has a long history of scientific study. The F₁ portion of the ATP synthase is above the membrane, the F_O portion is within the membrane. It's easy to visualize the F_OF₁ particle as resembling the fruiting body of a common mushroom, with the head being the F₁ particle, the stalk being the gamma subunit of F₁, and the base and "roots" being the F_O particle embedded in the membrane. The F₁ particle was first isolated by Ephraim Racker in 1961. The nomenclature of the enzyme suffers from a long history. The F₁ fraction derives it name from the term "Fraction 1" and F_O (written as a subscript "O", not "zero") derives it name from being the oligomycine binding fraction. Taking as an example the nomenclature of subunits in the bovine enzyme, many subunits have Greek and Roman alphabet names (alpha, beta, gamma, delta, epsilon and a, b, c, d, e, f, g, h), while others have more complex names such as F₆ (from "Fraction 6"), OSCP (the oligomycin sensitivity conferral protein), A6L (named for the gene that codes for it in the mitochondrial genome) and IF1 (inhibitory factor 1).

The F₁ particle is large and can be seen in the transmission electron microscope by negative staining (1962, Fernandez-Moran et al., Journal of Molecular Biology, Vol 22, p 63). These are particles of 9 nm diameter that pepper the inner mitochondrial membrane. They were originally called elementary particles and were thought to contain the entire respiratory apparatus of the mitochondrion, but through a long series of experiments, Ephraim Racker and his colleagues were able to show that this particle is correlated with ATPase activity in uncoupled mitochondria and with the ATPase activity in submitochondrial particles created by exposing mitochondria to ultrasound. This ATPase activity was further associated with the creation of ATP by yet another long series of experiments in many laboratories.

The antibiotic oligomycin inhibits ATP synthase.

1 Binding change mechanism
2 Physiological role
3 ATP synthase in different organisms
4 Evolution of ATP synthase
5 See also
6 External links

[edit] Binding change mechanism

In the 1960s through the 1970s, Matt Kroll developed his binding change, or flip-flop, mechanism, which postulated that ATP synthesis is coupled with a conformational change in the ATP synthase generated by rotation of the gamma subunit. The research group of John E. Walker, then at the MRC Laboratory of Molecular Biology in Cambridge but now at the MRC Dunn Human Nutrition Unit (also in Cambridge) crystallized the F₁ catalytic-domain of ATP synthase. The structure, at the time the largest asymmetric protein structure known, indicated that Boyer's rotary-catalysis model was essentially correct. For elucidating this Boyer and Walker shared half of the 1997 Nobel Prize in Chemistry. Jens Christian Skou received the other half of the Chemistry prize that year "for the first discovery of an ion-transporting enzyme, Na+, K+ -ATPase"

The crystal structure of the F₁ showed alternating alpha and beta subunits (3 of each), arranged like segments of an orange around an asymmetrical gamma subunit. According to the current model of ATP synthesis (known as the alternating catalytic model), the proton-motive force across the inner mitochondrial membrane, generated by the electron transport chain, drives the passage of protons through the membrane via the F_O region of ATP synthase. A portion of the F_O (the ring of c-subunits) rotates as the protons pass through the membrane. The c-ring is tightly attached to the asymmetric central stalk (consisting primarily of the gamma subunit) which rotates within the alpha₃beta₃ of F₁ causing the 3 catalytic nucleotide binding sites to go through a series of conformational changes that leads to ATP synthesis. The major F₁ subunits are prevented from rotating in sympathy with the central stalk rotor by a peripheral stalk that joins the alpha₃beta₃ to the non-rotating portion of F_O. The structure of the intact ATP synthase is currently known at low-resolution from electron cryo-microscopy (cryo-EM) studies of the complex. The cryo-EM model of ATP synthase shows that the peripheral stalk is a flexible rope-like structure that wraps around the complex as it joins F₁ to F_O. Under the right conditions, the enzyme reaction can also be carried out in reverse, with ATP hydrolysis driving proton pumping across the membrane.

[edit] Physiological role

Like all enzymes, the activity of F₁F_O ATP synthase is reversible. Large enough quantities of ATP cause it to create a transmembrane proton gradient, this is used by fermenting bacteria which do not have an electron transport chain, and hydrolyze ATP to make a proton gradient, which they use for flagella and transport of nutrients into the cell.

In respiring bacteria under physiological conditions, ATP synthase generally runs in the opposite direction, creating ATP while using the protonmotive force created by the electron transport chain as a source of energy. The overall process of creating energy in this fashion is termed oxidative phosphorylation. The same process takes place in mitochondria, where ATP synthase is located in the inner mitochondrial membrane (so that F₁-part sticks into mitochondrial matrix, where ATP synthesis takes place).

[edit] ATP synthase in different organisms

[edit] Plant ATP synthase

In plants ATP synthase is also present in chloroplasts (CF₁F_O-ATP synthase). The enzyme is integrated into thylakoid membrane; the CF₁-part sticks into stroma, where dark reactions of photosynthesis (Also called the light-independent reactions or the Calvin cycle) and ATP synthesis take place. The overall structure and the catalytic mechanism of the chloroplast ATP synthase are almost the same as those of the mitochondrial enzyme. However, in chloroplasts the protonmotive force is generated not by respiratory electron transport chain, but by primary photosynthetic proteins.

[edit] E. coli ATP synthase

E. coli ATP synthase is the simplest known form of ATP synthase, with 8 different subunit types.

[edit] Yeast ATP synthase

Yeast ATP synthase is the most complex known and is made of 20 different types of subunits.

[edit] Evolution of ATP synthase

The evolution of ATP synthase is thought to be an example of modular evolution, where two subunits with their own functions have become associated and gained new functionality. The F_O particle shows significant similarity to hexemeric DNA helicases and the F₁ particle shows some similarity to H⁺ powered flagellar motor complexes.

The α₃β₃ hexamer of the F_O particle shows significant structural similarity to hexameric DNA helicases; both form a ring with 3 fold rotational symmetry with a central pore. Both also have roles dependent on the relative rotation of a macromolecule within the pore; the DNA helicases use the helical shape of DNA to drive their motion along the DNA molecule and to detect supercoiling whilst the α₃β₃ hexamer uses the conformational changes due rotation of the γ subunit to drive an enzymatic reaction.

The H⁺ motor of the F₁ particle shows great functional similarity to the H⁺ motors seen in flagellar motors. Both feature a ring of many small alpha helical proteins which rotate relative to nearby stationary proteins using a H⁺ potential gradient as an energy source. This is, however, a fairly tenuous link - the overall structure of flagellar motors is far more complex than the F₁ particle and the ring of rotating proteins is far larger, with around 30 compared to the 10, 11 or 14 known in the F₁ complex.

The modular evolution theory for the origin of ATP synthase suggests that two subunits with independent function, a DNA helicase with ATPase activity and a H⁺ motor, were able to bind, and the rotation of the motor drive the ATPase activity of the helicase in reverse. This would then evolve to become more efficient, and eventually develop into the complex ATP synthases seen today. Alternatively the DNA helicase/H⁺ motor complex may have had H⁺ pump activity, the ATPase activity of the helicase driving the H⁺ motor in reverse. This could later evolve to carry out the reverse reaction and act as an ATP synthase.