ATP synthase

ATP synthase is an enzyme that catalyzes the formation of the energy storage molecule adenosine triphosphate (ATP) using adenosine diphosphate (ADP) and inorganic phosphate (P_i). ATP synthase is a molecular machine. The overall reaction catalyzed by ATP synthase is:

• ADP + P_i + 2H⁺_out ⇌ ATP + H₂O + 2H⁺_in

ATP synthase lies across a cellular membrane and forms an aperture that

Eukaryotic ATP synthases are F-ATPases, running "in reverse" for an ATPase. This article deals mainly with this type. An F-ATPase consists of two main subunits, F_O and F₁, which has a rotational motor mechanism allowing for ATP production.^[1][2]

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.^[3][4] These functional regions consist of different protein subunits — refer to tables. This enzyme is used in synthesis of ATP through aerobic respiration.

Structure and function

Located within the

Three other subunits catalyze the ATP synthesis. The other F₁ subunits γ, δ, and ε are a part of a rotational motor mechanism (rotor/axle). The γ subunit allows β to go through conformational changes (i.e., closed, half open, and open states) that allow 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.[8] These are particles of 9 nm diameter that pepper the inner mitochondrial membrane.

F_O region

F_O is a water

In the 1960s through the 1970s,

The binding change mechanism involves the active site of a β subunit's cycling between three states.[14] 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.^[15]

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

In respiring

The evolution of ATP synthase is thought to have been modular whereby two functionally independent subunits became associated and gained new functionality.^[16][17] 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.^[16] The F-ATP synthase displays high functional and mechanistic similarity to the V-ATPase.^[18] 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.^[19]

The F₁ region also shows significant similarity to hexameric

The H⁺
motor of the F_O particle shows great functional similarity to the H⁺
motors that drive flagella.[18] 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. More recent structural data do however show that the ring and the stalk are structurally similar to the F₁ particle.^[21]

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.^[16][22] 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.^[16] This may have evolved to carry out the reverse reaction and act as an ATP synthase.^[17][23][24]

Inhibitors

A variety of natural and synthetic inhibitors of ATP synthase have been discovered.^[25] These have been used to probe the structure and mechanism of ATP synthase. Some may be of therapeutic use. There are several classes of ATP synthase inhibitors, including peptide inhibitors, polyphenolic phytochemicals, polyketides, organotin compounds, polyenic α-pyrone derivatives, cationic inhibitors, substrate analogs, amino acid modifiers, and other miscellaneous chemicals.^[25] Some of the most commonly used ATP synthase inhibitors are oligomycin and DCCD.

In different organisms

Bacteria

E. coli ATP synthase is the simplest known form of ATP synthase, with 8 different subunit types.^[11]

Bacterial F-ATPases can occasionally operate in reverse, turning them into an ATPase.^[26] Some bacteria have no F-ATPase, using an A/V-type ATPase bidirectionally.^[9]

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.^[7] Most of these proteins have homologues in other eukaryotes.^{[27][28][29][30]}

Plant

In plants, ATP synthase is also present in

The ATP synthase isolated from bovine (Bos taurus) heart mitochondria 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. Their genes have close homology to human ATP synthases.[32]^[33][34]

Human genes that encode components of ATP synthases:

• ATP5A1
• ATP5B
• ATP5O
• MT-ATP6, MT-ATP8

Other eukaryotes

Eukaryotes belonging to some divergent lineages have very special organizations of the ATP synthase. A euglenozoa ATP synthase forms a dimer with a boomerang-shaped F₁ head like other mitochondrial ATP synthases, but the F_O subcomplex has many unique subunits. It uses cardiolipin. The inhibitory IF₁ also binds differently, in a way shared with trypanosomatida.^[35]

Archaea

Archaea do not generally have an F-ATPase. Instead, they synthesize ATP using the A-ATPase/synthase, a rotary machine structurally similar to the V-ATPase but mainly functioning as an ATP synthase.^[26] Like the bacteria F-ATPase, it is believed to also function as an ATPase.^[9]

LUCA and earlier

F-ATPase gene linkage and gene order are widely conserved across ancient prokaryote lineages, implying that this system already existed at a date before the last universal common ancestor, the LUCA.^[36]

See also

References