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  1. 1. Online practice tests, live classes, tutoring, study guides Q&A, premium content and more .
  2. 2. Bioenergetics <ul><li>Living cells are in a dynamic state maintained by metabolism </li></ul><ul><li>catabolism is to supply energy while anabolism is for energy storage </li></ul><ul><li>purpose of catabolic pathways is to convert the chemical energy in food to molecules of ATP </li></ul><ul><li>the mitochondria are the sites of catabolic pathways which yield ATP </li></ul><ul><li>it is made of 2 membranes </li></ul><ul><li>outer = permeable to small molecules and ions </li></ul><ul><li> = no transporting membrane proteins </li></ul><ul><li> = not folded </li></ul><ul><li>inner = resistant to penetration of any ions and most uncharged </li></ul><ul><li> molecules </li></ul><ul><li>= transport membrane proteins abound for transfer of materials </li></ul><ul><li>= highly folded </li></ul>
  3. 3. <ul><li>All mitochondrial enzymes are synthesized in the cytosol </li></ul><ul><li>translocator outer membrane (TOM) channels </li></ul><ul><ul><li>where enzymes cross into the intermembrane space </li></ul></ul><ul><li>chaperone-like translocator inner membrane (TIM) complexes </li></ul><ul><ul><li>accepts and inserts enzymes into the inner membrane </li></ul></ul><ul><li>enzymes are located only inside the inner membrane, thus, substrates must pass the 2 membranes ----- products leave the same way </li></ul><ul><li>matrix is the inner nonmembranous portion of the mitochondrion where enzymes for the citric acid cycle are located </li></ul><ul><li>the cristae (infoldings) project into the matrix and is the locale of enzymes involved in the oxidative phosphorylation </li></ul>
  4. 4. THE COMMON CATABOLIC PATHWAY <ul><li>Has 2 parts </li></ul><ul><li>1. Citric acid cycle (TCA cycle or Krebs cycle) </li></ul><ul><li>2. Oxidative phosphorylation (electron transport chain, phosphorylation) </li></ul><ul><li>A. Agents for storage of energy and transfer of phosphate groups </li></ul><ul><li>AMP --- contain heterocyclic amine adenine and D-ribose </li></ul><ul><li>ADP --- sugar joined together by  N-glycosidic bond </li></ul><ul><li>ATP --- to form adenosine; further linked to Pi </li></ul><ul><li>when one phosphate group is hydrolyzed from each of these… </li></ul><ul><li>ATP = 7.3 kcal/mol </li></ul><ul><li>ADP = 7.3 kcal/mol </li></ul><ul><li>AMP = 3.4 kcal/mole </li></ul><ul><li>ATP molecules in the cells do not normally last longer than about 1 minute, thus, a high turnover rate (40 kg ATP/day is manufactured and degraded </li></ul>
  5. 5. <ul><li>B. Agents for transfer of electrons in biological redox reactions </li></ul><ul><ul><li>coenzymes, NAD + and FAD, both contain an ADP core in the structure which is the link of the coenzyme to the apoenzyme </li></ul></ul><ul><li> NAD + = +charge is due to the nitrogen </li></ul><ul><li>=operative part is the nicotinamide part which gets reduced </li></ul><ul><li> FAD=operative part is the flavin part which gets reduced </li></ul><ul><li>reduced forms are NADH AND FADH 2 </li></ul>H + and e - transporting molecules
  6. 6. <ul><li>C. Agent for transfer of acetyl groups </li></ul><ul><ul><li>CoA is the acetyl-transporting molecules linked via a thioester bond (high energy bond) 7.51 kcal/mol </li></ul></ul><ul><ul><li>CoA contain ADP linked to pantothenic acid and mercaptoethylamine </li></ul></ul><ul><ul><li>active part is mercaptoethylamine </li></ul></ul><ul><ul><li>o </li></ul></ul><ul><ul><li>CH 3 - c - s - CoA </li></ul></ul>
  7. 7. Citric acid cycle <ul><li>Common catabolism of carbohydrates and lipids begins when they are broken down into 2-carbon products (acetyl units) </li></ul><ul><li>transported by CoA as acetylCoA </li></ul><ul><li>Step 1 </li></ul><ul><li>acetylCoA enters the cycle by combining with a C 4 compound called oxaloacetate to produce citrate </li></ul><ul><li>addition of - CH 3 group of acetylCoA to the </li></ul><ul><li>C=O of the oxaloacetate </li></ul><ul><li>hydrolysis of the thioester to produce the C 6 </li></ul><ul><li>compound citrate </li></ul><ul><li>enzyme used is citrate synthase </li></ul>C 6 CO 2 C 5 C 4 C 4 C 2 C 2 Carbon balance
  8. 8. <ul><li>Step 2 </li></ul><ul><li>citrate ion is dehydrated to cis-aconitate </li></ul><ul><li>cis-aconitate is hydrated back to isocitrate </li></ul><ul><li>enzyme used is aconitase </li></ul><ul><li>Step 3 </li></ul><ul><li>isocitrate is oxidized to produce oxalosuccinate and decarboxylated at the same time to produce a C 5  -ketoglutarate (can be made into glutamic acid) </li></ul><ul><li>enzyme used is ICD </li></ul><ul><li>required NAD + </li></ul>
  9. 9. <ul><li>Steps 4 and 5 </li></ul><ul><li>removal of another CO 2 from  -KG to produce succinate (C 4 ) </li></ul><ul><li>uses a complex enzyme system </li></ul><ul><li>production of a high energy compound, GTP </li></ul><ul><li>Step 6 </li></ul><ul><li>succinate is oxidized by FAD to produce fumarate (by removal of 2 hydrogen) </li></ul><ul><li>fumarate has a trans-double bond </li></ul><ul><li>enzyme used is succinate dehydrogenase </li></ul>
  10. 10. <ul><li>Step 7 </li></ul><ul><li>fumarate is hydrated to give the malate ion (C 4 ) </li></ul><ul><li>enzyme used is fumarase </li></ul><ul><li>Step 8 </li></ul><ul><li>final step is the oxidation of malate by NAD + to give oxaloacetate </li></ul><ul><li>enzyme used is malate dehydrogenase </li></ul>
  11. 11. <ul><li>An acetyl unit enters the TCA cycle and 2 CO 2 molecules are given off </li></ul><ul><li>How does the TCA cycle produce energy? </li></ul><ul><ul><li>Production of GTP </li></ul></ul><ul><ul><li>most of the energy is produced via reactions that convert NAD + to NADH and FAD to FADH 2 </li></ul></ul><ul><ul><li>NADH and FADH 2 carries the e - and H + that will produce ATP in mitochondrion </li></ul></ul><ul><li>Stepwise degradation and oxidation of acetate in the TCA cycle for most efficient extraction of energy </li></ul><ul><li>Other advantages of the TCA cycle </li></ul><ul><ul><li>1. By-products provide raw materials for amino acid synthesis as per need </li></ul></ul><ul><ul><li>2. The many-component cycle provides an excellent method for regulating the speed of catabolic reactions </li></ul></ul>
  12. 12. <ul><li>In summary, the overall reactions in the TCA cycle : </li></ul><ul><li>GDP + Pi + CH 3 - CO - S - CoA + 2H 2 O + 3NAD + + FAD </li></ul><ul><li>(exhaled) </li></ul><ul><li>CoA + GTD + 2CO 2 + 3NADH + FADH 2 + 3H + </li></ul><ul><li>feedback mechanism occurs when </li></ul><ul><li>NADH + H + accumulates - inhibit steps 1, 3 and 4 </li></ul><ul><li>ATP accumulates - inhibit steps 1, 3 and 4 </li></ul><ul><li>acetylCoA is in abundance - cycle accelerates </li></ul><ul><li>presence of ADP and NAD + - stimulates ICD </li></ul>
  13. 13. ELECTRON and H + TRANSPORT <ul><li>The reduced coenzymes, NADH and FADH 2 , are end products of the TCA cycle </li></ul><ul><li>they carry H + and e - , thus, have the potential to yield energy when these combine with oxygen to form water </li></ul><ul><li>EXO 4 H + + 4e - + O 2 2H 2 O + energy </li></ul><ul><li>involves a number of enzymes embedded in the inner membrane of mitochondria arranged in an (assembly line) increasing affinity for e - </li></ul>
  14. 14. The sequence of the electron - carrying enzyme systems starts with <ul><li>Complex I </li></ul><ul><li>largest complex </li></ul><ul><li>some 40 subunits, among them a flavoprotein and several FeS clusters </li></ul><ul><li>CoQ or ubiquinone is associated with complex I </li></ul><ul><li>oxidizes the NADH produced in the citric acid cycle and reduces the CoQ </li></ul><ul><li> NADH + H + + CoQ --  NAD + + CoQH 2 </li></ul><ul><li>some of the energy released in this reaction is used to move 2H + across the membrane (matrix to intermembrane space) </li></ul>Soluble in lipid, thus, can move laterally within the membrane
  15. 15. <ul><li>Complex II </li></ul><ul><li>also catalyzes the transfer of e - to CoQ from the oxidation of succinate in the TCA cycle, producing FADH 2 </li></ul><ul><li>energy derived from this is not enough to pump two protons across the membrane nor a channel for such transfer is possible </li></ul>
  16. 16. <ul><li>Complex III </li></ul><ul><li>an integral membrane complex contains 11 subunits, including cytochrome b, cytochrome C 1 and FeS clusters </li></ul><ul><li>delivers the e - from CoQH 2 to cytochrome c </li></ul><ul><li>the complex has 2 channels through which two H + are pumped from CoQH 2 into the intermembrane space </li></ul><ul><li>since each cyt c can pick up only electron, 2 cytochrome c’s are needed: </li></ul><ul><li>CoQH 2 + 2 cyt c (reduced) </li></ul><ul><li> CoQ + 2H + + 2 cytochrome c (oxid) </li></ul><ul><li>each cytochrome has an iron-ion-containing heme center embedded in its own protein and the letters used to designate them were given in order of their discovery </li></ul>
  17. 17. <ul><li>Complex IV </li></ul><ul><li>known as cytochrome oxidase, contains 13 subunits-most importantly, cyt  3 , a heme that has an associated copper center </li></ul><ul><li>an integral membrane protein complex </li></ul><ul><li>e - moves from cyt c  cyt a  cyt  3  cleavage of O-O bond </li></ul><ul><li>oxidized form of the enzyme takes up two H + from the matrix for each oxygen atom forming H 2 O which is released into the matrix </li></ul><ul><li>1/2 O 2 + 2H + + 2e - -- H 2 O </li></ul><ul><li>during this process, two more H + are pumped out of the matrix and into the intermembrane space (energy driving this process comes from the energy of water formation) </li></ul><ul><li>this final pumping into the intermembrane space makes a total of 6H + /NADH + H + and 4H + /FADH 2 molecules </li></ul>
  18. 18. PHOSPHORYLATION AND THE CHEMIOSOMOTIC PUMP <ul><li>CHEMIOSMOTIC THEORY by Mitchell </li></ul><ul><li>proposed that the electron transport is accompanied by an accumulation of protons in the intermembrane space of the mitochondrion, which in turn, </li></ul><ul><li>creates an osmotic pressure </li></ul><ul><li>protons driven back to mitochondrion under this pressure generate ATP </li></ul>
  19. 19. <ul><li>How do the e - and H + transports produce the chemical energy of ATP? </li></ul><ul><li>The energy in the e - transfer chain creates a proton gradient </li></ul>Spontaneous flow of ions from a region of high concentration to a region of low concentration results in a driving force that propels the protons back to the mitochondrion through the proton translocating ATPase in the inner membrane of mitochondrion catalyzing ATPase ADP + Pi ATP + H 2 O A continuous variation in the H + conc along a given region  H + conc in intermembrane space than matrix
  20. 20. <ul><li>Proton translocating ATPase is a complex “rotor engine” made of 16 different proteins </li></ul><ul><ul><li>has F o sector, embedded in the membrane, contains the proton channel </li></ul></ul><ul><ul><li>the proton channel composed of 12 subunits rotate every time a proton passes from the cytoplasmic side (intermembrane) to the matrix side of the mitochondrion </li></ul></ul><ul><ul><li>rotation is transmitted to the F 1 sector “rotor” </li></ul></ul>- F 1 sector contains 5 kinds of polypeptides - the F 1 catalytic unit converts the mechanical energy of the rotor to chemical energy of the ATP molecule <ul><li>Rotor ( γ &  subunits) </li></ul><ul><li>catalytic unit (  &  subunits) surrounds the rotor & makes the ATP </li></ul><ul><li>stator unit (  ) for stability of the whole complex </li></ul>
  21. 21. INNER INTERMEMBRANE SPACE OUTER Accumulated H + Pump H + out A molecule of ATP synthesized / pair of translocated H + storage of electrical energy (due to flow of charges) in the form of chemical energy Hydrolysis of ATP <ul><li>ONLY when the two parts of the proton translocating ATPase, F 1 and F o , are linked is energy production possible </li></ul><ul><li>disruption of the interaction between F 1 and F o is disrupted – </li></ul><ul><li>energy transduction is lost </li></ul>
  22. 22. <ul><li>Protons that enter a mitochondrion combine with the electrons transported through the electron transport chain and with oxygen to form water </li></ul><ul><li>the net result of the two processes </li></ul><ul><li>The oxygen has two functions </li></ul><ul><li>1. Oxidize NADH to NAD + and FADH 2 to FAD so that these molecules can go back and participate in the TCA cycle </li></ul><ul><li>2. Provide energy for the conversion of ADP to ATP which is indirectly accomplished </li></ul>Electron/H + transport ATP formed Each O 2 molecule we breathe in 2H 2 O Combines with 4H + ions & 4 e - Coming from the NADH and FADH 2 molecules (TCA cycle ATP formation is driven by the entrance of H + into the mitochondrion HOH from O 2 -------  increase in H 2 O depleted the H + conc O 2 is not utilized but is needed for cell’s survival !
  23. 23. <ul><li>The overall reactions in oxidative phosphorylation is </li></ul><ul><li>NADH + 3ADP + 1/2 O 2 + 3Pi + H + NAD + + 3ATP + H 2 O </li></ul><ul><li>FADH 2 + 2ADP + 1/2 O 2 + 2Pi FAD + 2ATP + H 2 O </li></ul>
  24. 24. THE ENERGY YIELD <ul><li>The energy released during electron transport is now finally built into the ATP molecule </li></ul><ul><li>each pair of protons entering a mitochondrion results in the production of one ATP molecule </li></ul><ul><li>for each NADH molecule, we get 3 ATP molecules </li></ul><ul><li>for each FADH 2 molecule, only 4 protons are pumped out of the mitochondrion, thus, only 2 ATP molecules are produced for each FADH 2 </li></ul><ul><li>combining the TCA cycle and oxidative phosphorylation: </li></ul><ul><ul><li>for each c 2 fragment entering the TCA cycle </li></ul></ul><ul><ul><li>A. we obtain 3NADH x 3ATP/NADH = 9ATP </li></ul></ul><ul><ul><li>1FADH 2 x 2ATP/FADH 2 = 2ATP </li></ul></ul><ul><ul><li>1GTP = 12ATP </li></ul></ul><ul><ul><li>B. uses up to 2O 2 molecules </li></ul></ul><ul><ul><li>one c 2 fragment is oxidized with two molecules of O 2 to produce two molecules </li></ul></ul><ul><ul><li>c 2 + 2O 2 + 12 ADP + 12 Pi 12 ATP + 2CO 2 </li></ul></ul>
  25. 25. COMPARISON OF CHEMICAL ENERGY TO OTHER FORMS OF ENERGY <ul><li>Activity of many enzymes is controlled and regulated by phosphorylation </li></ul>Phosphorylase b Phosphorylase (seryl-PO 4 ) ATP ADP Glycogen glucose <ul><ul><li>Body maintains a high conc of K + inside the cells, low outside the cells </li></ul></ul><ul><ul><li>the reverse is true for Na + </li></ul></ul><ul><ul><li>special transport proteins in the cell membranes constantly pump K + into and Na + out of the cells </li></ul></ul><ul><ul><li>pumping requires energy via hydrolysis of ATP to ADP </li></ul></ul><ul><ul><li>with this pumping, the charges in and out of the cell are unequal which generates electrical potential </li></ul></ul><ul><ul><li>chemical energy of ATP is transformed into electrical energy which operates in neurotransmission </li></ul></ul>
  26. 26. <ul><li>ATP is the immediate source of energy in muscle contraction </li></ul><ul><ul><li>as ATP binds to myosin the actin-myosin complex (contracted muscle) dissociates and the muscle relaxes </li></ul></ul><ul><ul><li>when myosin hydrolyses ATP, it interacts with actin once more, and new contraction occurs </li></ul></ul><ul><li>a molecule of ATP upon hydrolysis to ADP yields 7.3 kcal/mol </li></ul><ul><li>= some of this energy is released as heat and used to maintain body temperature. </li></ul>
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