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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 catabolism is to supply energy while anabolism is for energy

storagestorage purpose of catabolic pathways is to convert the chemical energy purpose of catabolic pathways is to convert the chemical energy

in food to molecules of ATPin food to molecules of ATP the mitochondria are the sites of catabolic pathways which yield the mitochondria are the sites of catabolic pathways which yield

ATP 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

molecules molecules

= transport membrane proteins abound for transfer of = transport membrane proteins abound for transfer of materials materials

= highly folded = highly folded

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-like chaperone-like translocator inner membrane (TIM) translocator inner membrane (TIM) complexescomplexes

accepts and inserts enzymes into the inner membraneaccepts and inserts enzymes into the inner membrane

enzymes are located only inside the inner membrane, thus, enzymes are located only inside the inner membrane, thus, substrates must pass the 2 membranes ----- products leave the substrates must pass the 2 membranes ----- products leave the same waysame way

matrix is the inner nonmembranous portion of the matrix is the inner nonmembranous portion of the mitochondrion where enzymes for the citric acid cycle are mitochondrion where enzymes for the citric acid cycle are locatedlocated

the cristae (infoldings) project into the matrix and is the locale the cristae (infoldings) project into the matrix and is the locale of enzymes involved in the oxidative phosphorylation of enzymes involved in the oxidative phosphorylation

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 by ADP --- sugar joined together by N-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/mole AMP = 3.4 kcal/mole ATP molecules in the cells do not normally last longer than about 1 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 minute, thus, a high turnover rate (40 kg ATP/day is manufactured and degraded degraded

B. Agents for transfer of electrons in biological B. Agents for transfer of electrons in biological redox reactionsredox reactions– coenzymes, NADcoenzymes, NAD++ and FAD, both contain an ADP core and FAD, both contain an ADP core

in the structure which is the link of the coenzyme to in the structure which is the link of the coenzyme to the apoenzymethe apoenzyme

NADNAD++= +charge is due to the nitrogen= +charge is due to the nitrogen

=operative part is the nicotinamide part which =operative part is the nicotinamide part which gets gets reducedreduced

FAD=operative part is the flavin part which gets FAD=operative part is the flavin part which gets reducedreduced

reduced forms are NADH AND FADHreduced forms are NADH AND FADH22

H+ and e- transporting molecules

C. Agent for transfer of acetyl groupsC. Agent for transfer of acetyl groups– CoA is the acetyl-transporting molecules linked via a CoA 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 and CoA contain ADP linked to pantothenic acid and

mercaptoethylaminemercaptoethylamine– active part is mercaptoethylamine active part is mercaptoethylamine

oo

CHCH33 - c - s - CoA - c - s - CoA

Citric acid cycleCitric acid cycle

Common catabolism of carbohydrates and Common catabolism of carbohydrates and lipids begins when they are broken down into lipids begins when they are broken down into 2-carbon products (acetyl units)2-carbon 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

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 isocitrate is oxidized to produce oxalosuccinate and

decarboxylated at the same time to produce a Cdecarboxylated at the same time to produce a C55 --ketoglutarate (can be made into glutamic acid)ketoglutarate (can be made into glutamic acid)

enzyme used is ICDenzyme used is ICD required NADrequired NAD++

Steps 4 and 5Steps 4 and 5 removal of another COremoval of another CO22 from from -KG to produce -KG to produce

succinate (Csuccinate (C44) ) uses a complex enzyme systemuses a complex enzyme system production of a high energy compound, GTPproduction of a high energy compound, GTP

Step 6 Step 6 succinate is oxidized by FAD to produce fumarate succinate is oxidized by FAD to produce fumarate

(by removal of 2 hydrogen)(by removal of 2 hydrogen) fumarate has a trans-double bondfumarate has a trans-double bond enzyme used is succinate dehydrogenaseenzyme used is succinate dehydrogenase

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 to

give oxaloacetate give oxaloacetate enzyme used is malate dehydrogenaseenzyme used is malate dehydrogenase

An acetyl unit enters the TCA cycle and 2 COAn acetyl unit enters the TCA cycle and 2 CO2 2 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 convert most of the energy is produced via reactions that convert

NADNAD++ to NADH and FAD to FADH to NADH and FAD to FADH22

– NADH and FADHNADH and FADH22 carries the e carries the e-- and H and H++ that will produce that will produce ATP in mitochondrionATP in mitochondrion

Stepwise degradation and oxidation of acetate in the TCA Stepwise degradation and oxidation of acetate in the TCA cycle for cycle for most efficientmost efficient extraction of energy extraction of energy

Other advantages of the TCA cycleOther advantages of the TCA cycle

1. By-products provide raw materials for 1. By-products provide raw materials for amino acid amino acid synthesissynthesis as per need as per need

2. The many-component cycle provides an excellent method 2. The many-component cycle provides an excellent method for for regulating the speed of catabolic reactionsregulating the speed of catabolic reactions

In summary, the In summary, the overall reactions in the TCA overall reactions in the TCA cyclecycle::GDP + Pi + CHGDP + Pi + CH33 - CO - S - CoA + 2H - CO - S - CoA + 2H22O + 3NADO + 3NAD++ + FAD + FAD

(exhaled)(exhaled)

CoA + GTD + 2COCoA + GTD + 2CO22 + 3NADH + FADH + 3NADH + FADH22 + 3H + 3H++

feedback mechanism occurs whenfeedback mechanism occurs whenNADH + HNADH + H++ accumulates - inhibit steps 1, 3 and accumulates - inhibit steps 1, 3 and 44

ATP accumulates - inhibit steps 1, 3 ATP 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

ELECTRON and HELECTRON and H++ TRANSPORT TRANSPORT

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 e and e--, thus, have the potential to yield , thus, have the potential to yield energy when these combine with oxygen to form waterenergy when these combine with oxygen to form water

EXO EXO 4 H4 H++ + 4e + 4e-- + O + O22 2H 2H22O + energyO + energy

involves a number of enzymes embedded in the inner involves a number of enzymes embedded in the inner membrane of mitochondria arranged in an (assembly membrane of mitochondria arranged in an (assembly line) increasing affinity for eline) increasing affinity for e--

The sequence of the electron - carrying enzyme systems starts The sequence of the electron - carrying enzyme systems starts withwith

Complex I Complex I largest complexlargest complex some 40 subunits, among them a flavoprotein some 40 subunits, among them a flavoprotein

and several FeS clustersand several 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 oxidizes the NADH produced in the citric acid

cycle and reduces the CoQcycle and reduces the CoQ

NADH + HNADH + H++ + CoQ -- + CoQ -- NAD NAD++ + CoQH + CoQH22

some of the energy released in this reaction is some of the energy released in this reaction is used to move 2Hused to move 2H++ across the membrane across the membrane (matrix to intermembrane space)(matrix to intermembrane space)Soluble in lipid, thus, can move laterally within the membrane

Complex IIComplex II also catalyzes the transfer of ealso catalyzes the transfer of e-- to CoQ to CoQ

from the oxidation of succinate in the from the oxidation of succinate in the TCA cycle, producing FADHTCA cycle, producing FADH22

energy derived from this is not enough energy derived from this is not enough to pump two protons across the to pump two protons across the membrane nor a channel for such membrane nor a channel for such transfer is possibletransfer is possible

Complex IIIComplex III an integral membrane complex contains 11 subunits, including an integral membrane complex contains 11 subunits, including

cytochrome b, cytochrome Ccytochrome b, cytochrome C11 and FeS clusters and FeS clusters

delivers the edelivers the e-- from CoQH from CoQH22 to cytochrome c to cytochrome c

the complex has 2 channels through which two Hthe complex has 2 channels through which two H++ are pumped from are pumped from CoQHCoQH22 into the intermembrane space into the intermembrane space

since each cyt c can pick up only electron, 2 cytochrome c’s are since each cyt c can pick up only electron, 2 cytochrome c’s are needed: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 each cytochrome has an iron-ion-containing heme center embedded in its own protein and the letters used to designate them were given in its own protein and the letters used to designate them were given in order of their discoveryin order of their discovery

Complex IVComplex IV known as cytochrome oxidase, contains 13 subunits-most known as cytochrome oxidase, contains 13 subunits-most

importantly, cyt importantly, cyt 33, 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 from moves from cyt ccyt c cyt acyt a cyt cyt 33 cleavage of O-O bond cleavage 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 from the matrix for each oxygen atom forming Heach oxygen 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 are pumped out of the matrix and into the intermembrane space (energy driving this process and into the intermembrane space (energy driving this process comes from the energy of water formation)comes from the energy of water formation)

this final pumping into the intermembrane space makes a total this final pumping into the intermembrane space makes a total of of 6H6H++/NADH + H/NADH + H++ and and 4H4H++/FADH/FADH22 molecules molecules

PHOSPHORYLATION AND THE CHEMIOSOMOTIC PUMPPHOSPHORYLATION AND THE CHEMIOSOMOTIC PUMP

CHEMIOSMOTIC THEORY by MitchellCHEMIOSMOTIC THEORY by Mitchell

proposed that the electron transport is proposed that the electron transport is accompanied by an accumulation of protons in accompanied by an accumulation of protons in the intermembrane space of the the intermembrane space of the mitochondrion, which in turn, mitochondrion, which in turn,

creates an osmotic pressurecreates an osmotic pressure

protons driven back to mitochondrion under protons driven back to mitochondrion under this pressure generate ATPthis pressure generate ATP

How do the eHow do the e-- and H and H++ transports produce the chemical transports produce the chemical energy of ATP?energy of ATP?

The energy in the eThe energy in the e-- transfer chain creates a proton gradient transfer 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

Proton translocating ATPaseProton translocating ATPase is a complex is a complex “rotor engine” made of 16 different proteins“rotor engine” made of 16 different proteins– has has FFoo sector, embedded in the membrane, contains sector, embedded in the membrane, contains

the proton channel the proton channel – the proton channel composed of 12 subunits rotate the proton channel composed of 12 subunits rotate

every time a proton passes from the cytoplasmic every time a proton passes from the cytoplasmic side (intermembrane) to the matrix side of the side (intermembrane) to the matrix side of the mitochondrionmitochondrion

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 & subunits)• catalytic unit ( & subunits) surrounds the rotor & makes the ATP• stator unit () for stability of the whole complex

INNERINTERMEMBRANE 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

Protons that enter a mitochondrion combine with the electrons Protons that enter a mitochondrion combine with the electrons transported through the electron transport chain and with transported through the electron transport chain and with oxygen to form wateroxygen to form water

the net result of the two processes the 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 FADH and FADH22 to FAD so to FAD so that these molecules can go back and that these molecules can go back and participate in the TCA cycleparticipate in the TCA cycle

2. Provide energy for the conversion of ADP to 2. Provide energy for the conversion of ADP to ATP which is indirectly accomplished ATP which is indirectly accomplished

Electron/H+ transportATP 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 !

The The 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 + + 3ATP + HH22OO

FADHFADH22 + 2ADP + 1/2 O + 2ADP + 1/2 O22 + 2Pi FAD + 2ATP + H + 2Pi FAD + 2ATP + H22OO

THE ENERGY YIELDTHE ENERGY YIELD The energy released during electron transport is now finally built into the ATP The energy released during electron transport is now finally built into the ATP

molecule molecule each pair of protons entering a mitochondrion results in the production of one ATP each pair of protons entering a mitochondrion results in the production of one ATP

moleculemolecule for each for each NADHNADH molecule, we get molecule, we get 3 ATP3 ATP molecules molecules for each for each FADHFADH22 molecule, only 4 protons are pumped out of the mitochondrion, molecule, only 4 protons are pumped out of the mitochondrion,

thus, only thus, only 2 ATP2 ATP molecules are produced for each FADH molecules 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 cycle fragment entering the TCA cycle

A. we obtain A. we obtain 3NADH x 3ATP/NADH = 9ATP3NADH x 3ATP/NADH = 9ATP

1FADH1FADH22 x 2ATP/FADH x 2ATP/FADH2 2 = 2ATP = 2ATP

1GTP = 12ATP1GTP = 12ATP

B. uses up to 2OB. uses up to 2O22 molecules molecules

one cone c22 fragment is oxidized with two molecules of O fragment is oxidized with two molecules of O22 to produce two molecules to produce two molecules

c22 + 2O + 2O22 + 12 ADP + 12 Pi 12 ATP + 2CO + 12 ADP + 12 Pi 12 ATP + 2CO22

COMPARISON OF CHEMICAL ENERGY TO OTHER FORMS OF COMPARISON OF CHEMICAL ENERGY TO OTHER FORMS OF ENERGYENERGY

Activity of many enzymes is controlled and regulated by Activity of many enzymes is controlled and regulated by phosphorylation phosphorylation

Phosphorylase b

Phosphorylase (seryl-PO4)

ATP ADPGlycogen glucose

Body maintains a high conc of KBody maintains a high conc of K++ inside the cells, low outside the inside the cells, low outside the cells cells

– the reverse is true for Nathe reverse is true for Na++

– special transport proteins in the cell membranes constantly special transport proteins in the cell membranes constantly pump Kpump K++ into and Na into and Na++ out of the cells out 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 with this pumping, the charges in and out of the cell are

unequal which generates electrical potentialunequal which generates electrical potential– chemical energy of ATP is transformed into electrical energy chemical energy of ATP is transformed into electrical energy

which operates in neurotransmission which operates in neurotransmission

ATP is the immediate source of energy in muscle ATP is the immediate source of energy in muscle contractioncontraction– as ATP binds to myosin the actin-myosin complex as ATP binds to myosin the actin-myosin complex

(contracted muscle) dissociates and the muscle (contracted muscle) dissociates and the muscle relaxesrelaxes

– when myosin hydrolyses ATP, it interacts with actin when myosin hydrolyses ATP, it interacts with actin once more, and new contraction occurs once more, and new contraction occurs

a molecule of ATP upon hydrolysis to ADP yields 7.3 a molecule of ATP upon hydrolysis to ADP yields 7.3 kcal/molkcal/mol

= some of this energy is released as heat and used to = some of this energy is released as heat and used to maintain body temperature.maintain body temperature.

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