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2. BioenergeticsBioenergetics
Living cells are in a dynamic state maintained by metabolismLiving cells are in a dynamic state maintained by metabolism
catabolism is to supply energy while anabolism is for energy storagecatabolism is to supply energy while anabolism is for energy storage
purpose of catabolic pathways is to convert the chemical energy in foodpurpose of catabolic pathways is to convert the chemical energy in food
to molecules of ATPto molecules of ATP
the mitochondria are the sites of catabolic pathways which yield ATPthe mitochondria are the sites of catabolic pathways which yield ATP
it is made of 2 membranesit is made of 2 membranes
outer = permeable to small molecules and ionsouter = permeable to small molecules and ions
= no transporting membrane proteins= no transporting membrane proteins
= not folded= not folded
inner = resistant to penetration of any ions and most unchargedinner = resistant to penetration of any ions and most uncharged
moleculesmolecules
= transport membrane proteins abound for transfer of materials= transport membrane proteins abound for transfer of materials
= highly folded= highly folded

3. All mitochondrial enzymes are synthesized in the cytosolAll mitochondrial enzymes are synthesized in the cytosol
translocator outer membrane (TOM) channelstranslocator outer membrane (TOM) channels
where enzymes cross into the intermembrane spacewhere enzymes cross into the intermembrane space
chaperone-likechaperone-like translocator inner membrane (TIM) complexestranslocator inner membrane (TIM) complexes
accepts and inserts enzymes into the inner membraneaccepts and inserts enzymes into the inner membrane
enzymes are located only inside the inner membrane, thus, substratesenzymes are located only inside the inner membrane, thus, substrates
must pass the 2 membranes ----- products leave the same waymust pass the 2 membranes ----- products leave the same way
matrix is the inner nonmembranous portion of the mitochondrionmatrix is the inner nonmembranous portion of the mitochondrion
where enzymes for the citric acid cycle are locatedwhere enzymes for the citric acid cycle are located
the cristae (infoldings) project into the matrix and is the locale ofthe cristae (infoldings) project into the matrix and is the locale of
enzymes involved in the oxidative phosphorylationenzymes involved in the oxidative phosphorylation

4. THE COMMON CATABOLIC PATHWAYTHE COMMON CATABOLIC PATHWAY
Has 2 partsHas 2 parts
1. Citric acid cycle (TCA cycle or Krebs cycle)1. Citric acid cycle (TCA cycle or Krebs cycle)
2. Oxidative phosphorylation (electron transport chain, phosphorylation)2. Oxidative phosphorylation (electron transport chain, phosphorylation)
A. Agents for storage of energy and transfer of phosphate groupsA. Agents for storage of energy and transfer of phosphate groups
AMP --- contain heterocyclic amine adenine and D-riboseAMP --- contain heterocyclic amine adenine and D-ribose
ADP --- sugar joined together byADP --- sugar joined together by αβαβN-glycosidic bondN-glycosidic bond
ATP --- to form adenosine; further linked to PiATP --- to form adenosine; further linked to Pi
when one phosphate group is hydrolyzed from each of these…when one phosphate group is hydrolyzed from each of these…
ATP = 7.3 kcal/molATP = 7.3 kcal/mol
ADP = 7.3 kcal/molADP = 7.3 kcal/mol
AMP = 3.4 kcal/moleAMP = 3.4 kcal/mole
ATP molecules in the cells do not normally last longer than about 1ATP molecules in the cells do not normally last longer than about 1
minute, thus, a high turnover rate (40 kg ATP/day is manufactured andminute, thus, a high turnover rate (40 kg ATP/day is manufactured and
degradeddegraded

5. B. Agents for transfer of electrons in biological redoxB. Agents for transfer of electrons in biological redox
reactionsreactions
– coenzymes, NADcoenzymes, NAD++
and FAD, both contain an ADP core in theand FAD, both contain an ADP core in the
structure which is the link of the coenzyme to the apoenzymestructure which is the link of the coenzyme to the apoenzyme
NADNAD++
= +charge is due to the nitrogen= +charge is due to the nitrogen
=operative part is the nicotinamide part which gets=operative part is the nicotinamide part which gets
reducedreduced
FAD=operative part is the flavin part which gets reducedFAD=operative part is the flavin part which gets reduced
reduced forms are NADH AND FADHreduced forms are NADH AND FADH22
H+
and e-
transporting
molecules

6. C. Agent for transfer of acetyl groupsC. Agent for transfer of acetyl groups
– CoA is the acetyl-transporting molecules linked via aCoA is the acetyl-transporting molecules linked via a
thioester bond (high energy bond) 7.51 kcal/molthioester bond (high energy bond) 7.51 kcal/mol
– CoA contain ADP linked to pantothenic acid andCoA contain ADP linked to pantothenic acid and
mercaptoethylaminemercaptoethylamine
– active part is mercaptoethylamineactive part is mercaptoethylamine
oo
CHCH33 - c - s - CoA- c - s - CoA

7. Citric acid cycleCitric acid cycle
Common catabolism of carbohydrates and lipidsCommon catabolism of carbohydrates and lipids
begins when they are broken down into 2-carbonbegins when they are broken down into 2-carbon
products (acetyl units)products (acetyl units)
transported by CoA as acetylCoAtransported by CoA as acetylCoA
Step 1
•acetylCoA enters the cycle by combining with a
C4 compound called oxaloacetate to produce
citrate
• addition of -
CH3 group of acetylCoA to the
C=O of the oxaloacetate
• hydrolysis of the thioester to produce the C6
compound citrate
• enzyme used is citrate synthase
C6
CO2
C5
C4
C4
C2
C2
Carbon balance

8. Step 2Step 2
citrate ion is dehydrated to cis-aconitatecitrate ion is dehydrated to cis-aconitate
cis-aconitate is hydrated back to isocitratecis-aconitate is hydrated back to isocitrate
enzyme used is aconitaseenzyme used is aconitase
Step 3Step 3
isocitrate is oxidized to produce oxalosuccinate and decarboxylatedisocitrate is oxidized to produce oxalosuccinate and decarboxylated
at the same time to produce a Cat the same time to produce a C55 αα-ketoglutarate (can be made into-ketoglutarate (can be made into
glutamic acid)glutamic acid)
enzyme used is ICDenzyme used is ICD
required NADrequired NAD++

9. Steps 4 and 5Steps 4 and 5
removal of another COremoval of another CO22 fromfrom αα-KG to produce succinate-KG to produce succinate
(C(C44))
uses a complex enzyme systemuses a complex enzyme system
production of a high energy compound, GTPproduction of a high energy compound, GTP
Step 6Step 6
succinate is oxidized by FAD to produce fumarate (bysuccinate is oxidized by FAD to produce fumarate (by
removal of 2 hydrogen)removal of 2 hydrogen)
fumarate has a trans-double bondfumarate has a trans-double bond
enzyme used is succinate dehydrogenaseenzyme used is succinate dehydrogenase

10. Step 7Step 7
fumarate is hydrated to give the malate ion (Cfumarate is hydrated to give the malate ion (C44))
enzyme used is fumaraseenzyme used is fumarase
Step 8Step 8
final step is the oxidation of malate by NADfinal step is the oxidation of malate by NAD++
to giveto give
oxaloacetateoxaloacetate
enzyme used is malate dehydrogenaseenzyme used is malate dehydrogenase

11. An acetyl unit enters the TCA cycle and 2 COAn acetyl unit enters the TCA cycle and 2 CO22 molecules are
given off
How does the TCA cycle produce energy?How does the TCA cycle produce energy?
– Production of GTPProduction of GTP
– most of the energy is produced via reactions that convertmost of the energy is produced via reactions that convert
NADNAD++
to NADH and FAD to FADHto NADH and FAD to FADH22
– NADH and FADHNADH and FADH22 carries the ecarries the e--
and Hand H++
that will produce ATPthat will produce ATP
in mitochondrionin mitochondrion
Stepwise degradation and oxidation of acetate in the TCA cycleStepwise degradation and oxidation of acetate in the TCA cycle
forfor most efficientmost efficient extraction of energyextraction of energy
Other advantages of the TCA cycleOther advantages of the TCA cycle
1. By-products provide raw materials for1. By-products provide raw materials for amino acidamino acid
synthesissynthesis as per needas per need
2. The many-component cycle provides an excellent method2. The many-component cycle provides an excellent method
forfor regulating the speed of catabolic reactionsregulating the speed of catabolic reactions

12. In summary, theIn summary, the overall reactions in the TCAoverall reactions in the TCA
cyclecycle::
GDP + Pi + CHGDP + Pi + CH33 - CO - S - CoA + 2H- CO - S - CoA + 2H22 O + 3NADO + 3NAD++
+ FAD+ FAD
(exhaled)(exhaled)
CoA + GTD + 2COCoA + GTD + 2CO22 + 3NADH + FADH+ 3NADH + FADH22 + 3H+ 3H++
feedback mechanism occurs whenfeedback mechanism occurs when
NADH + HNADH + H++
accumulates - inhibit steps 1, 3 andaccumulates - inhibit steps 1, 3 and
44
ATP accumulates - inhibit steps 1, 3ATP accumulates - inhibit steps 1, 3
and 4and 4
acetylCoA is in abundance - cycle acceleratesacetylCoA is in abundance - cycle accelerates
presence of ADP and NADpresence of ADP and NAD++
- stimulates ICD- stimulates ICD

13. ELECTRON and HELECTRON and H++
TRANSPORTTRANSPORT
The reduced coenzymes, NADH and FADHThe reduced coenzymes, NADH and FADH22, are end, are end
products of the TCA cycleproducts of the TCA cycle
they carry Hthey carry H++
and eand e--
, thus, have the potential to yield energy, thus, have the potential to yield energy
when these combine with oxygen to form waterwhen these combine with oxygen to form water
EXOEXO 4 H4 H++
+ 4e+ 4e--
+ O+ O22 2H2H22O + energyO + energy
involves a number of enzymes embedded in the innerinvolves a number of enzymes embedded in the inner
membrane of mitochondria arranged in an (assembly line)membrane of mitochondria arranged in an (assembly line)
increasing affinity for eincreasing affinity for e--

14. The sequence of the electron - carrying enzyme systems starts withThe sequence of the electron - carrying enzyme systems starts with
Complex IComplex I
largest complexlargest complex
some 40 subunits, among them a flavoprotein andsome 40 subunits, among them a flavoprotein and
several FeS clustersseveral FeS clusters
CoQ or ubiquinone is associated with complex ICoQ or ubiquinone is associated with complex I
oxidizes the NADH produced in the citric acid cycleoxidizes the NADH produced in the citric acid cycle
and reduces the CoQand reduces the CoQ
NADH + HNADH + H++
+ CoQ --+ CoQ -- NADNAD++
+ CoQH+ CoQH22
some of the energy released in this reaction is usedsome of the energy released in this reaction is used
to move 2Hto move 2H++
across the membrane (matrix toacross the membrane (matrix to
intermembrane space)intermembrane space)
Soluble in lipid,
thus, can move
laterally within
the membrane

15. Complex IIComplex II
also catalyzes the transfer of ealso catalyzes the transfer of e--
to CoQ fromto CoQ from
the oxidation of succinate in the TCA cycle,the oxidation of succinate in the TCA cycle,
producing FADHproducing FADH22
energy derived from this is not enough toenergy derived from this is not enough to
pump two protons across the membrane norpump two protons across the membrane nor
a channel for such transfer is possiblea channel for such transfer is possible

16. Complex IIIComplex III
an integral membrane complex contains 11 subunits, including cytochrome b,an integral membrane complex contains 11 subunits, including cytochrome b,
cytochrome Ccytochrome C11 and FeS clustersand FeS clusters
delivers the edelivers the e--
from CoQHfrom CoQH22 to cytochrome cto cytochrome c
the complex has 2 channels through which two Hthe complex has 2 channels through which two H++
are pumped from CoQHare pumped from CoQH22 intointo
the intermembrane spacethe intermembrane space
since each cyt c can pick up only electron, 2 cytochrome c’s are needed:since each cyt c can pick up only electron, 2 cytochrome c’s are needed:
CoQHCoQH22 + 2 cyt c (reduced)+ 2 cyt c (reduced)
CoQ + 2HCoQ + 2H++
+ 2 cytochrome c (oxid)+ 2 cytochrome c (oxid)
each cytochrome has an iron-ion-containing heme center embedded in its owneach 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 theirprotein and the letters used to designate them were given in order of their
discoverydiscovery

17. Complex IVComplex IV
known as cytochrome oxidase, contains 13 subunits-most importantly,known as cytochrome oxidase, contains 13 subunits-most importantly,
cytcyt αα33, a heme that has an associated copper center, a heme that has an associated copper center
an integral membrane protein complexan integral membrane protein complex
ee--
moves frommoves from cyt ccyt c  cyt acyt a  cytcyt αα33  cleavage of O-O bondcleavage of O-O bond
oxidized form of the enzyme takes up two Hoxidized form of the enzyme takes up two H++
from the matrix for eachfrom the matrix for each
oxygen atom forming Hoxygen atom forming H22O which is released into the matrixO which is released into the matrix
1/2 O1/2 O22 + 2H+ 2H++
+ 2e+ 2e--
-- H-- H22OO
during this process, two more Hduring this process, two more H++
are pumped out of the matrix and intoare pumped out of the matrix and into
the intermembrane space (energy driving this process comes from thethe intermembrane space (energy driving this process comes from the
energy of water formation)energy of water formation)
this final pumping into the intermembrane space makes a total ofthis final pumping into the intermembrane space makes a total of
6H6H++
/NADH + H/NADH + H++
andand 4H4H++
/FADH/FADH22 moleculesmolecules

18. PHOSPHORYLATION AND THE CHEMIOSOMOTIC PUMPPHOSPHORYLATION AND THE CHEMIOSOMOTIC PUMP
CHEMIOSMOTIC THEORY by MitchellCHEMIOSMOTIC THEORY by Mitchell
proposed that the electron transport is accompaniedproposed that the electron transport is accompanied
by an accumulation of protons in the intermembraneby an accumulation of protons in the intermembrane
space of the mitochondrion, which in turn,space of the mitochondrion, which in turn,
creates an osmotic pressurecreates an osmotic pressure
protons driven back to mitochondrion under thisprotons driven back to mitochondrion under this
pressure generate ATPpressure generate ATP

19. How do the eHow do the e--
and Hand H++
transports produce the chemicaltransports produce the chemical
energy of ATP?energy of ATP?
The energy in the eThe energy in the e--
transfer chain creates a proton gradienttransfer chain creates a proton gradient
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 + H2O
A continuous variation in the
H+
conc along a given region
 H+
conc in intermembrane
space than matrix

20. Proton translocating ATPaseProton translocating ATPase is a complex “rotoris a complex “rotor
engine” made of 16 different proteinsengine” made of 16 different proteins
– hashas FFoo sector, embedded in the membrane, contains thesector, embedded in the membrane, contains the
proton channelproton channel
– the proton channel composed of 12 subunits rotate everythe proton channel composed of 12 subunits rotate every
time a proton passes from the cytoplasmic sidetime a proton passes from the cytoplasmic side
(intermembrane) to the matrix side of the mitochondrion(intermembrane) to the matrix side of the mitochondrion
rotation is transmitted to the Frotation is transmitted to the F11 sector “rotor”sector “rotor”
- F1 sector contains 5 kinds of
polypeptides
- the F1 catalytic unit converts the
mechanical energy of the rotor to
chemical energy of the ATP
molecule
• Rotor (γ & ε subunits)
• catalytic unit (α & β subunits)
surrounds the rotor & makes the
ATP
• stator unit (δ) for stability of the
whole complex

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
• ONLY when the two parts of the proton translocating ATPase, F1
and Fo, are linked is energy production possible
• disruption of the interaction between F1 and Fo is disrupted –
energy transduction is lost

22. Protons that enter a mitochondrion combine with the electronsProtons that enter a mitochondrion combine with the electrons
transported through the electron transport chain and with oxygen totransported through the electron transport chain and with oxygen to
form waterform water
the net result of the two processesthe net result of the two processes
The oxygen has two functionsThe oxygen has two functions
1. Oxidize NADH to NAD1. Oxidize NADH to NAD++
and FADHand FADH22 to FAD so thatto FAD so that
these molecules can go back and participate in thethese molecules can go back and participate in the
TCA cycleTCA cycle
2. Provide energy for the conversion of ADP to ATP2. Provide energy for the conversion of ADP to ATP
which is indirectly accomplishedwhich is indirectly accomplished
Electron/H+
transport
ATP formed
Each O2 molecule
we breathe in
2H2O Combines with 4H+
ions & 4 e-
Coming from the
NADH and FADH2
molecules (TCA
cycle
ATP formation is driven by the entrance of H+
into the mitochondrion
HOH from O2 ------- increase in H2O depleted the H+
conc
O2 is not utilized but is needed for cell’s survival !

23. TheThe overall reactions in oxidative phosphorylationoverall reactions in oxidative phosphorylation isis
NADH + 3ADP + 1/2 ONADH + 3ADP + 1/2 O22 + 3Pi + H+ 3Pi + H++
NADNAD++
+ 3ATP + H+ 3ATP + H22OO
FADHFADH22 + 2ADP + 1/2 O+ 2ADP + 1/2 O22 + 2Pi FAD + 2ATP + H+ 2Pi FAD + 2ATP + H22OO

24. THE ENERGY YIELDTHE ENERGY YIELD
The energy released during electron transport is now finally built into theThe energy released during electron transport is now finally built into the
ATP moleculeATP molecule
each pair of protons entering a mitochondrion results in the production ofeach pair of protons entering a mitochondrion results in the production of
one ATP moleculeone ATP molecule
for eachfor each NADHNADH molecule, we getmolecule, we get 3 ATP3 ATP moleculesmolecules
for eachfor each FADHFADH22 molecule, only 4 protons are pumped out of themolecule, only 4 protons are pumped out of the
mitochondrion, thus, onlymitochondrion, thus, only 2 ATP2 ATP molecules are produced for each FADHmolecules are produced for each FADH22
combining the TCA cycle and oxidative phosphorylation:combining the TCA cycle and oxidative phosphorylation:
– for each cfor each c22 fragment entering the TCA cyclefragment entering the TCA cycle
A. we obtainA. we obtain 3NADH x 3ATP/NADH = 9ATP3NADH x 3ATP/NADH = 9ATP
1FADH1FADH22 x 2ATP/FADHx 2ATP/FADH22 = 2ATP= 2ATP
1GTP = 12ATP1GTP = 12ATP
B. uses up to 2OB. uses up to 2O22 moleculesmolecules
one cone c22 fragment is oxidized with two molecules of Ofragment is oxidized with two molecules of O22 to produce twoto produce two
moleculesmolecules
c22 + 2O+ 2O22 + 12 ADP + 12 Pi 12 ATP + 2CO+ 12 ADP + 12 Pi 12 ATP + 2CO22

25. COMPARISON OF CHEMICAL ENERGY TO OTHER FORMS OFCOMPARISON OF CHEMICAL ENERGY TO OTHER FORMS OF
ENERGYENERGY
Activity of many enzymes is controlled and regulated byActivity of many enzymes is controlled and regulated by
phosphorylationphosphorylation
Phosphorylase b Phosphorylase (seryl-PO4)
ATP ADP
Glycogen glucose
Body maintains a high conc of KBody maintains a high conc of K++
inside the cells, low outside the cellsinside the cells, low outside the cells
– the reverse is true for Nathe reverse is true for Na++
– special transport proteins in the cell membranes constantly pump Kspecial transport proteins in the cell membranes constantly pump K++
into and Nainto and Na++
out of the cellsout of the cells
– pumping requires energy via hydrolysis of ATP to ADPpumping requires energy via hydrolysis of ATP to ADP
– with this pumping, the charges in and out of the cell are unequal whichwith this pumping, the charges in and out of the cell are unequal which
generates electrical potentialgenerates electrical potential
– chemical energy of ATP is transformed into electrical energy whichchemical energy of ATP is transformed into electrical energy which
operates in neurotransmissionoperates in neurotransmission

26. ATP is the immediate source of energy in muscle contractionATP is the immediate source of energy in muscle contraction
– as ATP binds to myosin the actin-myosin complexas ATP binds to myosin the actin-myosin complex
(contracted muscle) dissociates and the muscle relaxes(contracted muscle) dissociates and the muscle relaxes
– when myosin hydrolyses ATP, it interacts with actin oncewhen myosin hydrolyses ATP, it interacts with actin once
more, and new contraction occursmore, and new contraction occurs
a molecule of ATP upon hydrolysis to ADP yields 7.3 kcal/mola molecule of ATP upon hydrolysis to ADP yields 7.3 kcal/mol
= some of this energy is released as heat and used to maintain= some of this energy is released as heat and used to maintain
body temperature.body temperature.

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