ATP synthase

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ATP synthase is an enzyme that creates the energy storage molecule adenosine triphosphate (ATP). ATP is the most commonly used "energy currency" of cells for most organisms. It is formed from adenosine diphosphate (ADP) and inorganic phosphate (P_i). The overall reaction catalyzed by ATP synthase is:

• ADP + P_i + H⁺_out ? ATP + H₂O + H⁺_in

The formation of ATP from ADP and P_i is energetically unfavorable and would normally proceed in the reverse direction. In order to drive this reaction forward, ATP synthase couples ATP synthesis during cellular respiration to an electrochemical gradient created by the difference in proton (H⁺) concentration across the mitochondrial membrane in eukaryotes or the plasma membrane in bacteria. During photosynthesis in plants, ATP is synthesized by ATP synthase using a proton gradient created in the thylakoid lumen through the thylakoid membrane and into the chloroplast stroma.

ATP synthase consists of two main subunits, F_O and F₁, which has a rotational motor mechanism allowing for ATP production. Because of its rotating subunit ATP Synthase is a molecular machine.

Video ATP synthase

Nomenclature

The F₁ fraction derives its name from the term "Fraction 1" and F_O (written as a subscript letter "o", not "zero") derives its name from being the binding fraction for oligomycin, a type of naturally-derived antibiotic that is able to inhibit the F_O unit of ATP synthase. These functional regions consist of different protein subunits -- refer to tables.

Maps ATP synthase

Structure and function

Located within the thylakoid membrane and the inner mitochondrial membrane, ATP synthase consists of two regions F_O and F₁. F_O causes rotation of F₁ and is made of c-ring and subunits a, b, d, F6. F₁ is made of ${\displaystyle \alpha ,\beta ,\gamma ,\delta }$ subunits. F₁ has a water-soluble part that can hydrolyze ATP. F_O on the other hand has mainly hydrophobic regions. F_O F₁ creates a pathway for protons movement across the membrane.

F₁ region

The F₁ portion of ATP synthase is hydrophilic and responsible for hydrolyzing ATP. Subunits ${\displaystyle \alpha }$ and ${\displaystyle \beta }$ make a hexamer with 6 binding sites. Three of them are catalytically inactive and they bind ADP.

Other three subunits catalyze the ATP synthesis. The other F₁ subunits ${\displaystyle \gamma ,\delta ,\epsilon }$ are a part of a rotational motor mechanism. ${\displaystyle \gamma }$ subunit allows ${\displaystyle \beta }$ to go through conformational changes, i.e. closed, half open and open states allows for ATP to be bound and released once synthesized. The F₁ particle is large and can be seen in the transmission electron microscope by negative staining. These are particles of 9 nm diameter that pepper the inner mitochondrial membrane.

F_O region

Fo is a water insoluble protein with eight subunits and a transmembrane ring. The ring has a tetramer shape with a helix loop helix protein that goes though conformational changes when protonated and deprotonated, pushing neighboring subunits to rotate, causing the spinning of F_O which then also affects conformation of F₁, resulting in switching of states of alpha and beta subunits. The F_O region of ATP synthase is a proton pore that is embedded in the mitochondrial membrane. It consists of three main subunits a, b, and c, and (in humans) six additional subunits, d, e, f, g, F6, and 8 (or A6L). An atomic model for the dimeric yeast F_O region was determined by cryo-EM at an overall resolution of 3.6 Å

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Binding model

In the 1960s through the 1970s, Paul Boyer, a UCLA Professor, developed the binding change, or flip-flop, mechanism theory, which postulated that ATP synthesis is dependent on a conformational change in 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, 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, in essence, correct. For elucidating this, Boyer and Walker shared half of the 1997 Nobel Prize in Chemistry.

The crystal structure of the F₁ showed alternating alpha and beta subunits (3 of each), arranged like segments of an orange around a rotating asymmetrical gamma subunit. According to the current model of ATP synthesis (known as the alternating catalytic model), the transmembrane potential created by (H+) proton cations supplied by the electron transport chain, drives the (H+) proton cations from the intermembrane space 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), causing it to rotate within the alpha₃beta₃ of F₁ causing the 3 catalytic nucleotide binding sites to go through a series of conformational changes that lead 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 suggests that the peripheral stalk is a flexible 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.

The binding change mechanism involves the active site of a ? subunit's cycling between three states. In the "loose" state, ADP and phosphate enter the active site; in the adjacent diagram, this is shown in pink. The enzyme then undergoes a change in shape and forces these molecules together, with the active site in the resulting "tight" state (shown in red) binding the newly produced ATP molecule with very high affinity. Finally, the active site cycles back to the open state (orange), releasing ATP and binding more ADP and phosphate, ready for the next cycle of ATP production.

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Physiological role

Like other 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 that do not have an electron transport chain, but rather hydrolyze ATP to make a proton gradient, which they use to drive flagella and the transport of nutrients into the cell.

In respiring bacteria under physiological conditions, ATP synthase, in general, runs in the opposite direction, creating ATP while using the proton motive 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 the mitochondria, where ATP synthase is located in the inner mitochondrial membrane and the F₁-part projects into mitochondrial matrix. The consumption of ATP by ATP-synthase pumps proton cations into the matrix.

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Evolution

The evolution of ATP synthase is thought to have been modular whereby two functionally independent subunits became associated and gained new functionality. This association appears to have occurred early in evolutionary history, because essentially the same structure and activity of ATP synthase enzymes are present in all kingdoms of life. The F-ATP synthase displays high functional and mechanistic similarity to the V-ATPase. However, whereas the F-ATP synthase generates ATP by utilising a proton gradient, the V-ATPase generates a proton gradient at the expense of ATP, generating pH values of as low as 1.

The F₁ region also shows significant similarity to hexameric DNA helicases, and the F_O region shows some similarity to H⁺
-powered flagellar motor complexes. The ?₃?₃ hexamer of the F₁ region shows significant structural similarity to hexameric DNA helicases; both form a ring with 3-fold rotational symmetry with a central pore. Both 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, whereas the ?₃?₃ hexamer uses the conformational changes through the rotation of the ? subunit to drive an enzymatic reaction.

The H⁺
motor of the F_O particle shows great functional similarity to the H⁺
motors that drive flagella. Both feature a ring of many small alpha-helical proteins that rotate relative to nearby stationary proteins, using a H⁺
potential gradient as an energy source. This link is tenuous, however, as the overall structure of flagellar motors is far more complex than that of the F_O particle and the ring with about 30 rotating proteins is far larger than the 10, 11, or 14 helical proteins in the F_O 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 drove the ATPase activity of the helicase in reverse. This complex then evolved greater efficiency and eventually developed into today's intricate ATP synthases. Alternatively, the DNA helicase/H⁺
motor complex may have had H⁺
pump activity with the ATPase activity of the helicase driving the H⁺
motor in reverse. This may have evolved to carry out the reverse reaction and act as an ATP synthase.

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In different species

E. coli

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

Yeast

Yeast ATP synthase is one of the best-studied eukaryotic ATP synthases; and five F₁, eight F_O subunits, and seven associated proteins have been identified. Most of these proteins have homologues in other eukaryotes.

Plant

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 proton motive force is generated not by respiratory electron transport chain but by primary photosynthetic proteins.

Bovine

The ATP synthase isolated from bovine heart mitochondria (Bos taurus) is, in terms of biochemistry and structure, the best-characterized ATP synthase. Beef heart is used as a source for the enzyme because of the high concentration of mitochondria in cardiac muscle.

Human

The following is a list of humans genes that encode components of ATP synthases:

• ATP5A1, ATP5AL1
• ATP5B, ATP5BL1
• ATP5C2, ATP5D, ATP5E, ATP5F1, ATP5G1, ATP5G2, ATP5G3, ATP5H, ATP5HP1, ATP5I, ATP5J, ATP5J2, ATP5L, ATP5L2, ATP5O, ATP5S
• ATP6, ATP6AP1, ATP6AP2
• ATPSBL1, ATPSBL2
• MT-ATP6, MT-ATP8

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See also

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References

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Further reading

• Nick Lane: The Vital Question - Energy, Evolution, and the Origins of Complex Life, Ww Norton, 2015-07-20, ISBN 978-0393088816 (Link points to Figure 10 showing model of ATP synthase)

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External links

• Boris A. Feniouk: "ATP synthase -- a splendid molecular machine"
• Well illustrated ATP synthase lecture by Antony Crofts of the University of Illinois at Urbana-Champaign.
• Proton and Sodium translocating F-type, V-type and A-type ATPases in OPM database
• The Nobel Prize in Chemistry 1997 to Paul D. Boyer and John E. Walker for the enzymatic mechanism of synthesis of ATP; and to Jens C. Skou, for discovery of an ion-transporting enzyme, Na⁺
  , K⁺
  -ATPase.
• Harvard Multimedia Production Site -- Videos -- ATP synthesis animation
• David Goodsell: "ATP Synthase- Molecule of the Month"

Source of the article : Wikipedia