Structure of ATP synthase, the F_O proton channel and rotating stalk are shown in blue, the F₁ synthase domain in red and the membrane in grey.

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 using some form of energy. This article is about the Enzyme Commission codes For the European Commission system for coding chemicals see EC-No. Enzymes are Biomolecules that catalyze ( ie increase the rates of Chemical reactions Almost all enzymes are Proteins Adenosine-5'-triphosphate ( ATP) is a multifunctional Nucleotide that is most important as a " molecular currency" of intracellular Energy Adenosine diphosphate, abbreviated ADP, is a Nucleotide. It is an Ester of Pyrophosphoric acid with the Nucleoside Adenosine A phosphate, an Inorganic chemical, is a salt of Phosphoric acid. This energy is often in the form of protons moving down a electrochemical gradient, such as from the lumen into the stroma of chloroplasts or from the inter-membrane space into the matrix in mitochondria. The proton ( Greek πρῶτον / proton "first" is a Subatomic particle with an Electric charge of one positive In Cellular biology, an electrochemical gradient is a spatial variation of both Electrical potential and chemical Concentration across a membrane Chloroplasts are Organelles found in Plant cells and eukaryotic Algae that conduct Photosynthesis. In Cell biology, a mitochondrion (plural mitochondria) is a membrane-enclosed Organelle found in most eukaryotic cells. The overall reaction sequence is:

ADP + P_i → ATP

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

The antibiotic oligomycin inhibits the F_O unit of ATP synthase. Oligomycins are Macrolides created by Streptomyces that can be Poisonous to other organisms

Structure and nomenclature

In mitochondria, the F₁F_O ATP synthase has a long history of scientific study. In Cell biology, a mitochondrion (plural mitochondria) is a membrane-enclosed Organelle found in most eukaryotic cells.

• the F_O portion is within the membrane.
• The F₁ portion of the ATP synthase is above 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 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 its name from being the oligomycin binding fraction.

Taking as an example the nomenclature of subunits in the bovine enzyme, many subunits have alphabet names:

• Greek letters: alpha, beta, gamma, delta, epsilon
• Roman letters: a, b, c, d, e, f, g, h

Others have more complex names:

• F₆ (from "Fraction 6")
• OSCP (the oligomycin sensitivity conferral protein), ATP5O
• A6L (named for the gene that codes for it in the mitochondrial genome)
• IF1 (inhibitory factor 1), ATPIF1

The F₁ particle is large and can be seen in the transmission electron microscope by negative staining. ^[1] 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 (who first isolated the F₁ particle in 1961) 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. A submitochondrial particle is a compartmentalized membranous product of exposing Mitochondria to ultrasound This ATPase activity was further associated with the creation of ATP by a long series of experiments in many laboratories.

Binding change mechanism

In the 1960s through the 1970s, Paul Boyer 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. Paul Boyer is the name of Paul D Boyer (born 1918 American chemist and Nobel Prize winner Paul S 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. John Ernest Walker (born January 7, 1941) is an English chemist who won the Nobel Prize in Chemistry in 1997 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. Year 1997 ( MCMXCVII) was a Common year starting on Wednesday (link will display full 1997 Gregorian calendar The Nobel Prize in Chemistry (Nobelpriset i kemi is awarded annually by the Royal Swedish Academy of Sciences to scientists in the various fields of 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"

Mechanism of ATP synthase. Jens Christian Skou kʰʁæsd̥jæn ˈsg̊ʌʊ̯ˀ (born October 8, 1918) is a Danish chemist and Nobel laureate ATP is shown in red, ADP and phosphate in pink and the rotating γ subunit in black.

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. In Structural biology, a protein subunit or subunit protein is a single Protein Molecule that assembles (or " coassembles " 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. The proton ( Greek πρῶτον / proton "first" is a Subatomic particle with an Electric charge of one positive A portion of the F_O (the ring of c-subunits) rotates as the protons pass through the membrane. ATPase subunit C of F0/V0 complex is the main transmembrane subunit of V-type, A-type and F-type ATP synthases ATPases (or ATP synthases are membrane-bound enzyme 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. ATPase subunit C of F0/V0 complex is the main transmembrane subunit of V-type, A-type and F-type ATP synthases ATPases (or ATP synthases are membrane-bound enzyme 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. Electron cryomicroscopy ( cryo-EM or sometimes cryo-electron microscopy) is a form of Electron microscopy (EM where the sample is studied at Cryogenic 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.

The binding change mechanism involves the active site of a β subunit cycling between three states. ^[2] In the "open" state, ADP and phosphate enter the active site, in the diagram to the right this is shown in brown. The protein then closes up around the molecules and binds them loosely - the "loose" state (shown in red). The enzyme then undergoes another change in shape and forces these molecules together, with the active site in the resulting "tight" state (shown in pink) binding the newly-produced ATP molecule with very high affinity. Finally, the active site cycles back to the open state, releasing ATP and binding more ADP and phosphate, ready for the next cycle of ATP production.

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 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. The proton ( Greek πρῶτον / proton "first" is a Subatomic particle with an Electric charge of one positive In Vector calculus, the gradient of a Scalar field is a Vector field which points in the direction of the greatest rate of increase of the scalar A flagellum ( plural flagella) is a tail-like structure that projects from the Cell body of certain Prokaryotic and Eukaryotic cells and it

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 Bacteria ( singular: bacterium) are a large group of unicellular Microorganisms Typically a few Micrometres in length bacteria have In Electrochemistry, the electrochemical potential, \bar{\mu} sometimes confusingly abbreviated to ECP is a Thermodynamic measure that combines the An electron transport chain couples a chemical reaction between an electron donor (such as NADH) and an electron acceptor (such as O2) to the transfer The overall process of creating energy in this fashion is termed oxidative phosphorylation. Oxidative phosphorylation is a Metabolic pathway that uses energy released by the oxidation of Nutrients to produce Adenosine triphosphate (ATP 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). In Cell biology, a mitochondrion (plural mitochondria) is a membrane-enclosed Organelle found in most eukaryotic cells.

ATP synthase in different organisms

Plant ATP synthase

In plants ATP synthase is also present in chloroplasts (CF₁F_O-ATP synthase). Chloroplasts are Organelles found in Plant cells and eukaryotic Algae that conduct Photosynthesis. 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. A Thylakoid is a membrane-bound compartment inside Chloroplasts and cyanobacteria. The Calvin cycle (or Calvin-Benson-Bassham cycle or carbon fixation is a series of biochemical reactions that takes place in the Stroma of Chloroplasts 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. Chloroplasts are Organelles found in Plant cells and eukaryotic Algae that conduct Photosynthesis. In Electrochemistry, the electrochemical potential, \bar{\mu} sometimes confusingly abbreviated to ECP is a Thermodynamic measure that combines the

E. coli ATP synthase

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

Yeast ATP synthase

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

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. eVolution is the third Album by eLDee, it was due to be released in 2008 The F₁ particle shows significant similarity to hexameric DNA helicases and the F_O particle shows some similarity to H⁺ powered flagellar motor complexes. Helicases are a class of Enzymes vital to all living Organisms They are motor proteins that move directionally along a Nucleic acid phosphodiester backbone A flagellum ( plural flagella) is a tail-like structure that projects from the Cell body of certain Prokaryotic and Eukaryotic cells and it

The α₃β₃ hexamer of the F₁ 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 F_O 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 F_O particle and the ring of rotating proteins is far larger, with around 30 compared to the 10, 11 or 14 known 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 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.

See also

• Oxidative phosphorylation
• Mitochondrion
• Chloroplast
• Electron transfer chain
• Proton pump
• Transmembrane ATPase
• Flavoprotein
• P-ATPase

Subunits of ATP synthase

1. ATP synthase alpha/beta subunits
2. ATP synthase delta subunit
3. ATP synthase gamma subunit
4. ATP synthase subunit C

References

1. ^ Fernandez-Moran et al. Oxidative phosphorylation is a Metabolic pathway that uses energy released by the oxidation of Nutrients to produce Adenosine triphosphate (ATP In Cell biology, a mitochondrion (plural mitochondria) is a membrane-enclosed Organelle found in most eukaryotic cells. Chloroplasts are Organelles found in Plant cells and eukaryotic Algae that conduct Photosynthesis. An electron transport chain couples a chemical reaction between an electron donor (such as NADH) and an electron acceptor (such as O2) to the transfer This article is about proton pumps in general For the proton P-type ATPase see Proton ATPase. ATPases are a class of Enzymes that catalyze the Decomposition of Adenosine triphosphate (ATP into Adenosine diphosphate (ADP and Flavoproteins are Proteins that contain a Nucleic acid derivative of Riboflavin: the Flavin adenine dinucleotide (FAD or Flavin mononucleotide P-type (or E1-E2-type ATPases constitute a superfamily of cation transport enzymes present both in prokaryota and eukaryota whose members mediate membrane flux of all common biologically ATPases (or ATP synthases are membrane-bound enzyme complexes/ Ion transporters that combine ATP synthesis and/or hydrolysis with the ATP synthase delta subunit is a subunit of bacterial and chloroplast ATPase or OSCP (oligomycin sensitivity conferral protein in mitochondrial ATPase (note that in mitochondria Gamma subunit of ATP synthase F1 complex forms the central shaft that connects the F0 rotary motor to the F1 catalytic core ATPase subunit C of F0/V0 complex is the main transmembrane subunit of V-type, A-type and F-type ATP synthases ATPases (or ATP synthases are membrane-bound enzyme , Journal of Molecular Biology, Vol 22, p 63, 1962
2. ^ Gresser MJ, Myers JA, Boyer PD (1982). "Catalytic site cooperativity of beef heart mitochondrial F1 adenosine triphosphatase. Correlations of initial velocity, bound intermediate, and oxygen exchange measurements with an alternating three-site model". J. Biol. Chem. 257 (20): 12030-8. PMID 6214554.  

External links

• "ATP synthase - a splendid molecular machine"
• Well illustrated ATP synthase lecture by Antony Crofts of the University of Illinois at Urbana-Champaign. This article is about the flagship campus For other uses and locations of University of Illinois, see University of Illinois (disambiguation The University of
• 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