ATP motors


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ATP motors

  1. 1. Mechanochemistry
  2. 2. • Mechanochemistry is the coupling of the mechanical and the  chemical phenomena on a molecular scale. • Molecular motors are biological molecular machines that are  the essential agents of movement in living organisms. • A motor may be defined as a device that consumes energy in  one form and converts it into motion or mechanical work; for  example, many protein-based molecular motors harness the  chemical free  energy released  by  the hydrolysis of ATP in  order to perform mechanical work
  3. 3. Examples • Cytoskeletal motors • Myosin is responsible for muscle contraction • Dynein produces  beating of cilia and flagella • Polymerisation motors • Microtubule polymerization using GTP. • Rotary motors: • FoF1-ATP synthase family of proteins convert the chemical energy in ATP to the  electrochemical potential energy of a proton gradient across a membrane or  the other way around.  • The  bacterial flagellum responsible  for  the  swimming  and  tumbling  of   bacteria acts as a rigid propeller that is powered by a rotary motor.  • Nucleic acid motors: • RNA polymerase transcribes RNA from a DNA template 
  4. 4. The Motor of Life • An enzyme within our body's cells called an ATP Synthase. • Like any other motor it rotates, and surprisingly fast - in fact  at about 6,000 revs per minute! • Further,  it  is  the  last  word  in  ultra-miniaturisation,  being  200,000 times smaller than a pinhead! • We have some 100 trillion (1 followed by 14 zeros) cells, there  are  in  excess  of  10  quadrillion  (1  followed  by  16  zeros)  of  these amazing ultra-tiny little motors which drive our bodies  and upon which our very lives depend!  • The  ATP  Synthase  motor's  job  is  to  manufacture  a  little  molecule  called  ATP  -  short  for  Adenosine  triphosphate  -  which  is  of  enormous  importance  for  the  successful  functioning of our bodies.
  5. 5. The food we eat is ultimately converted into energy
  6. 6. Oxidative phosphorylation • Process  in  which  ATP  is  formed  as  a  result  of  transfer  of  electrons from NADH or FADH2 to O2 by a series of electron  carriers. • All oxidative steps in the degradation of carbohydrates, fats,  and  amino  acids  converge  at  this  final  stage  of  cellular  respiration,  in  which  the  energy  of  oxidation  drives  the  synthesis of ATP. • This process takes place in mitochondrion • Major source of energy in our body. • 36-38  molecules  of  ATP  are  produced  when  glucose  is  completely oxidized to CO2 and H2O.
  7. 7. Mitochondrion:  Site for ATP synthesis
  8. 8. The Respiratory chain • An electron transport chain (ETC) couples electron transfer between  an electron  donor (such  as NADH)  and  an  electron  acceptor (such  as O2)  with the transfer of H+  ions (protons) across a membrane. The  resulting electrochemical  proton  gradient is  used  to  generate chemical  energy in  the  form  of adenosine  triphosphate. • If  protons  flow  back  through  the  membrane,  they  enable  mechanical  work,  such  as  rotating  bacterial flagella. ATP  synthase,  an  enzyme  converts  this  mechanical  energy  into  chemical  energy  by  producing  ATP, which  powers  most  cellular reactions.
  9. 9. ETC • The electron transport chain comprises an enzymatic series of electron donors and acceptors. Each electron donor passes electrons to a more electronegative acceptor, which in turn donates these electrons to another acceptor, a process that continues down the series until electrons are passed to oxygen, the most electronegative and terminal electron acceptor in the chain. • Passage of electrons between donor and acceptor releases energy, which is used to generate a proton gradient across the mitochondrial membrane by actively “pumping” protons into the intermembrane space. • This electrochemical proton gradient allows ATP synthase to use the flow of H+ through the enzyme back into the matrix to generate ATP from ADP and inorganic phosphate.
  10. 10. • Oxidative phosphorylation begins with the entry of electrons into the respiratory chain via electron carriers- nicotinamide nucleotides (NAD or NADP) or flavin nucleotides (FMN or FAD). • NAD+ + 2H+ + 2e-  NADH + H+ • NADP+ + 2H+ + 2e-  NADPH + H+ • FMN or FAD can accept 1 e- + 1 H+ to become semiquinone form or 2 e- + 2 H+ to form FMNH2 or FADH2 .
  11. 11. Respiratory chain consists of four complexes • Complex I (NADH coenzyme Q reductase): accepts electrons from the Krebs cycle electron carrier nicotinamide adenine dinucleotide (NADH), and passes them to coenzyme UQ (ubiquinone) • Complex II (succinate dehydrogenase): also passes electrons to UQ. • Complex III (cytochrome bc1 complex): passes electrons to cyt c • Complex IV (cytochrome c oxidase) recieves electrons from cyt c and uses the electrons and hydrogen ions to reduce molecular oxygen to water.
  12. 12. ETC
  13. 13. Complex I • Two electrons are removed from NADH and transferred to ubiquinone (Q). The reduced product, ubiquinol (QH2) freely diffuses within the membrane, and Complex I translocates four protons (H+ ) across the membrane, thus producing a proton gradient.
  14. 14. Complex II • Additional electrons are delivered into the quinone pool (Q) originating from succinate and transferred (via FAD) to Q.
  15. 15. Complex III • Two electrons are removed from QH2 and sequentially transferred to two molecules of cytochrome c
  16. 16. Complex IV • four electrons are removed from four molecules of cytochrome c and transferred to molecular oxygen (O2), producing two molecules of water. At the same time, four protons are translocated across the membrane, contributing to the proton gradient.
  17. 17. Proton gradient powers synthesis of ATP • Flow of electrons from NADH to oxygen is an exergonic process which is coupled to ATP synthesis, an endergonic process.
  18. 18. Chemiosmotic Theory • Peter Mitchell proposed that electron transport and ATP synthesis are coupled by a proton gradient across the inner mitochondrial membrane. • The transfer of electrons through the respiratory chain leads to the pumping of protons from the matrix to the cytosolic side of the inner mitochondrial membrane. • The H+ concentration becomes lower in the matrix, and an electrical field with the matrix side negative is generated. • Mitchell's idea, called the chemiosmotic hypothesis, was that this proton-motive force drives the synthesis of ATP by ATP synthase
  19. 19. ATP motors • ATP synthase (mitochon-drial ATPase or F1-F0 ATPase or Complex V) is an important enzyme that provides energy for the cell to use through the synthesis of adenosine triphosphate (ATP). • ATP is the most commonly used "energy currency" of cells from most organisms. • It is formed from adenosine diphosphate (ADP) and inorganic phosphate (Pi), and needs energy. • ATP synthase + ADP + Pi → ATP Synthase + ATP
  20. 20. ATP synthase • Is located within the mitochondria • ATP synthase consists of 2 regions – the FO portion is within the membrane. – The F1 portion of the ATP synthase is above the membrane, inside the matrix of the mitochondria.
  21. 21. Fo-F1 complex • It is a large, complex membrane-embedded enzyme that looks like a ball on a stick. • The 85-Å diameter ball, called the F1 subunit, protrudes into the mitochondrial matrix and contains the catalytic activity of the synthase. • The F1 subunit consists of five types of polypeptide chains (α3β3γδε). • The α and β subunits, which make up the bulk of the F1, are arranged alternately in a hexameric ring. Both bind nucleotides but only the β subunits participate directly in catalysis. • The central stalk consists of two proteins: γ and ε. The γ subunit includes a long a-helical coiled coil that extends into the center of the α3β3hexamer. • Each of the β subunits interacts with a different face of γ.
  22. 22. • The F0 subunit is a hydrophobic segment that spans the inner mitochondrial membrane. • F0 contains the proton channel of the complex. • This channel consists of a ring comprising from 10 to 14 c subunits that are embedded in the membrane. • A single a subunit binds to the outside of this ring. • The proton channel depends on both the a subunit and the c ring. • The F0 and F1 subunits are connected in two ways, by the central γε stalk and by an exterior column. • The exterior column consists of one a subunit, two b subunits, and the δ subunit.
  23. 23. ATP Synthase as Motor Protein: The Binding Change Mechanism • ATP synthesis is coupled with a conformational change in the ATP synthase generated by rotation of the gamma subunit. • 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 FO region of ATP synthase. • The changes in the properties of the three β subunits allow sequential ADP and Pi binding, ATP synthesis, and ATP release.
  24. 24. • interactions with the gamma subunit make the three b subunits inequivalent. • The three β subunits can exist in three different conformations: – T, or tight, conformation: binds ATP with great avidity to convert bound ADP and Pi into ATP – L, or loose, conformation: binds ADP and Pi but is sufficiently constrained that it cannot release bound nucleotides. – O, or open, form: exist with a bound nucleotide but it can also convert to form a more open conformation and release a bound nucleotide.
  25. 25. • The interconversion of these three forms can be driven by rotation of the γ subunit. If the γ subunit is rotated 120 degrees in a counterclockwise direction there will be a change in the subunit in the T conformation into the O conformation, allowing the subunit to release the ATP that has been formed within it. The subunit in the L conformation will be converted into the T conformation, allowing the transition of bound ADP + Pi into ATP. Finally, the subunit in the O conformation will be converted into the L conformation, trapping the bound ADP and Pi so that they cannot escape.
  26. 26. Rotational catalysis: The γ subunit rotates in 120-degree increments, with each step corresponding to the hydrolysis of a single ATP molecule.
  27. 27. Proton Motion Across the Membrane Drives Rotation of the C Ring • The c subunit consists of two a helices with an aspartate at 61 position. • The a subunit contains two proton half channels. • A proton enters from the intermembrane space into the cytosolic half- channel to neutralize the charge on an aspartate residue in a c subunit. • With this charge neutralized, the c ring can rotate clockwise by one c subunit, moving an aspartic acid residue out of the membrane into the matrix half-channel. • This proton can move into the matrix, resetting the system to its initial state. • Each proton enters the cytosolic half-channel, follows a complete rotation of the c ring, and exits through the other half-channel into the matrix.