Cellular Respiration.pptx

8/20/2019 Cellular Respiration.pptx

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CellularRespirationDoreen Alexis VillanuevaIntroduction to Physiology


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ATP provides the energy for cellular work


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The ATP Cycle


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ATP powers cellular work by coupling energy releasing toenergy using reactions

ATP + !" ADP + P


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ATP and Cellular Work


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Relationship of Cellular Respiration to Breathing


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Overall Equation for Cellular Respiration


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Cellular respiration breaks down organic #olecules toyield energy$


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!alling Electrons as an Energy "ource

%ood represents a source o& high energy electrons si#ilar to thepotential energy o& being on top o& a slide$

'hen the electrons pass &ro# the high potential state o& &ood tooxygen( released energy is converted to other &or#s o& energy$

#ow does $urning

co%pare to cellularrespiration&


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Burning Co%pared to Cell Respiration) The energy release iscontrolled by en*y#es and carrier #olecules in a series o& steps$


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Electron Transport Chains

Co#pared with burning( cellular respiration is a #ore controlled$nergy is released &ro# glucose in s#all a#ounts that cells canput to productive use,the &or#ation o& ATP #olecules$


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'n Eukaryotic Cells( the reaction of Aero$ic Respirationoccur 'nside )'TOC#O*+R'A,


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"tructure of )itochondria

-itochondria are &ound in al#ost all eukaryotic cells$ Its structure iskey to its role in cellular respiration$

Its co#plex &olding pattern o& #e#branes and spaces allows &or

#any sites where reactions can occur$


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Respiration involves glycolysis( the -re$s cycle(and electron transport


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"tage '. /lycolysis

The .rst stage in breaking down a glucose #olecule( called glycolysis/splitting sugar0( takes place outside the #itochondria in thecytoplas# o& the cell$


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1lycolysis harvests che#ical energy by oxidi*ing glucoseto pyruvate

The energy input andoutput o& glycolysis$

Concentrate on thetotals( not thedetails2

1lycolysis #ovie

http://var/www/apps/conversion/tmp/scratch_4/Ch09VideosandAnimations%5C09-09-Glycolysis.movhttp://var/www/apps/conversion/tmp/scratch_4/Ch09VideosandAnimations%5C09-09-Glycolysis.mov


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/lycolysis takes place in the cytosol o& cells$

1lucose enters the 1lycolysis pathway byconversion to glucose010phosphate$

Initially there is energy input corresponding tocleavage o& two 3P bonds o& ATP$

H O

OH

H

OHH

OH

CH2OPO32−

H

OH

H

1

6

5

4

3 2

glucose-6-phosphate


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2, #e3okinase cataly*es)

/lucose 4 ATP glucose010P 4 A+P

The reaction involves nucleophilic attack o&the C4 hydroxyl " o& glucose on P o& theter#inal phosphate o& ATP$

ATP binds to the en*y#e as a co#plex with

)g44$

H O

OH

H

OHH

OH

CH2OH

H

OH

H H O

OH

H

OHH

OH

CH2OPO32−

H

OH

H

23

4

5

6

11

6

5

4

3 2

ATP ADP

Mg2+

glucose glucose-6-phosphate

Hexokinase


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)g44 interacts with negatively chargedphosphate oxygen ato#s( providing chargeco#pensation 5 pro#oting a &avorablecon&or#ation o& ATP at the active site o& the

exokinase en*y#e$

N

NN

N

NH2

O

OHOH

HH

H

CH2

H

OPOPOPO

O

O

O

O O

O

adenine

ribose

ATP

adenosine triphosphate


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The reaction cataly*ed by exokinase is highly spontaneous$

A phosphoanhydride bond o& ATP /5P0 iscleaved$

The phosphate ester &or#ed in glucose646

phosphate has a lower ∆1 o& hydrolysis$

H O

OH

H

OHH

OH

CH2OH

H

OH

H H O

OH

H

OHH

OH

CH2OPO32−

H

OH

H

23

4

5

6

1 1

6

5

4

3 2

ATP ADP

Mg2+


Hexokinase

2


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the C1 hydro3yl o& thebound glucose is close to the ter#inal phosphate o&

ATP( pro#oting catalysis$

water is e3cluded &ro# the active site$

This prevents the en*y#e &ro# cataly*ing ATP hydrolysis(rather than trans&er o& phosphate to glucose$

'nduced 6t.

/lucose $inding toexokinasestabili*es aconfor%ation inwhich)

glucose

Hexokinase

H O

OH

H

OHH

OH

CH2OH

H

OH

H H O

OH

H

OHH

OH

CH2OPO32−

H

OH

H

23

4

5

6

1 1

6

5

4

3 2

ATP ADP

Mg2+


Hexokinase


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It is a co%%on %otif &or an en*y#e activesite to be located at an inter&ace betweenprotein do#ains that are connected by a8exible hinge region$

The structural 7e3i$ility allows access tothe active site( while per#itting precisepositioning o& active site residues( and inso#e cases exclusion o& water( as substratebinding pro#otes a particular con&or#ation$

glucose

Hexokinase


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8, Phosphoglucose 'so%erase cataly*es)

glucose010P /aldose0 fructose010P /ketose0

The #echanis# involves acid9base catalysis( withring opening( iso#eri*ation via an enediolateinter%ediate( and then ring closure$ A si#ilarreaction cataly*ed by Triosephosphate Iso#erase willbe presented in detail$

H O

OH

H

OHH

OH

CH2OPO32−

H

OH

H

1

6

5

4

3 2

CH2OPO32−

OH

CH2OH

H

OH H

H HO

O

6

5

4 3

2

1

glucose-6-phosphate fructose-6-phosphate

Phosphoglucose Isomerase


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9, Phosphofructokinase cataly*es)

fructose010P 4 ATP fructose02(10$isP4 A+P

This highly spontaneous reaction has a#echanis# si#ilar to that o& exokinase$

The Phospho&ructokinase reaction is the rate0li%iting step o& 1lycolysis$

The en* #e is hi hl re ulated as will be

CH2OPO32−

OH

CH2OH

H

OH H

H HO

O

6

5

4 3

2

1 CH2OPO32−

OH

CH2OPO32−

H

OH H

H HO

O

6

5

4 3

2

1

ATP ADP

Mg2

fructose-6-phosphate fructose-1!6-bisphosphate

Phosphofructokinase

2


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:, Aldolase cataly*es) fructose02(10

$isphosphate dihydro3yacetone0P 4

glyceraldehyde090P

The reaction is an aldol cleavage( the reverseo& an aldol condensation$

6

5

4

3

2

1CH2OPO32−

C

C

C

C

CH2OPO32−

O

HO H

H OH

H OH

3

2

1

CH2OPO32−

C

CH2OH

O

C

C

CH2OPO32−

H O

H OH

1

2

3

fructose-1!6- bisphosphate

"ldolase

dih#drox#acetone gl#ceraldeh#de-3- phosphate phosphate

$riosephosphate Isomerase


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A lysine residue at the active site &unctions

in catalysis$ The keto group o& &ructose6;(46bisphosphatereacts with the ε6a#ino group o& the activesite lysine( to &or# a protonated "chi; $ase

inter#ediate$

CH OPO2


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cataly*es) dihydro3yacetone0P glyceraldehyde090P

1lycolysis continues &ro# glyceraldehyde6s ? &avors dihydroxyacetone6P$ Re#oval o&

6

5

4

3

2

1CH2OPO32−

C

C

C

C

CH2OPO32−

O

HO H

H OH

H OH

3

2

1

CH2OPO32−

C

CH2OH

O

C

C

CH2OPO32−

H O

H OH

1

2

3

fructose-1!6- bisphosphate

"ldolase

dih#drox#acetone gl#ceraldeh#de-3- phosphate phosphate



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The ketose9aldose conversion involves

acid?$ase catalysis( and is thought to proceedvia an enediol inter#ediate( as withPhosphoglucose Iso#erase$

Active site 1lu and is residues are thought toextract and donate rotons durin catal sis$

C

C

CH2OPO32−

O

C

C

CH2OPO32−

H O

H OH

C

C

CH2OPO32−

H OH

OH

H

H OH

H+

H+

H+

H+

dih#drox#acetone enediol gl#ceraldeh#de- phosphate intermediate 3-phosphate



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80Phosphoglycolate is a transition stateanalog that binds tightly at the active site o&

Triose Phosphate Iso#erase /TI-0$

This inhibitor o& catalysis by TI- is si#ilar instructure to the proposed enediolateinter#ediate$

TI- is udged a Bper&ect en*y#e$B Reactionrate is li#ited onl b the rate that substrate

C

CH2OPO32−

OO−

C

CH2OPO32−

HC O−

OH

proposedenediolate

intermediate

phosphogl#colatetransition state

analog


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TriosephosphateIso#erase structure isan αβ $arrel( or TI-

barrel$

In an αβ barrel there are parallel β6

strands surrounded by α6helices$

hort loops connectalternating β6strands 5

α6helices$

$I%


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T') $arrels serve asscaEolds &or active site

residues in a diversearray o& en*y#es$

Residues o& the activesite are always at thesa#e end o& the barrel(on C6ter#inal ends o& β6strands 5 loopsconnecting these to α6helices$

There is debate whether the #any diEerent

en*y#es with TI- barrel structures areevolutionarily related$

In spite o& the structural si#ilarities there is

tre#endous diversity in catalytic

$I%


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E3plore the structure o& the TriosephosphateIso#erase /TI-0 ho#odi#er( with thetransition state inhibitor !6phosphoglycolate bound to one o& the TI-#ono#ers$

*ote the structure o& the TI- barrel( and the

$I%

C

CH2OPO32−

OO−

C

CH2OPO32−

HC O−

OH

proposedenediolate

intermediate

phosphogl#colatetransition state

analog


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1, /lyceraldehyde090phosphate+ehydrogenase cataly*es)

glyceraldehyde090P 4 *A+4 4 Pi

2(90$isphosphoglycerate4

C

C

CH2OPO32−

H O

H OH

C

C

CH2OPO32−

O OPO32−

H OH Pi

+ H+NAD

+ NADH

1

2

3

2

3

1

gl#ceraldeh#de- 1!3-bisphospho-3-phosphate gl#cerate

&l#ceraldeh#de-3-phosphate'eh#drogenase


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xergonic oxidation o& the aldehyde in

glyceraldehyde6


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A cysteine thiol at the active site o&

1lyceraldehyde6


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The “high energy” acyl thioester isattacked by P

i to yield the acyl phosphate

/5P0 product$

"xidation to acarboxylicacid /in a 3

thioester0occurs( as:AD+ isreduced to

*A+#$

CH CH2OPO32−

OHEnz-Cys SH

Enz-Cys S CH CH CH2OPO32−

OHOH

Enz-Cys S C CH CH2OPO32−

OHO

HC

NAD+

NADH

Enz-Cys SH

Pi

C CH CH2OPO32−

OHO

O3PO2−

O

gl#ceraldeh#de-3- phosphate

1!3-bisphosphogl#cerate

thiohemiacetalintermediate

ac#l-thioesterintermediate


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Recall that :AD+ accepts ! e− plus one + /a

hydride0 in going to its reduced &or#$

N

R

H

CNH2

O

N

R

CNH2

OH H

2e− + H

+

"' ("'H

Phosphogl#cerate )inase


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@, Phosphoglycerate -inase cataly*es)

2(90$isphosphoglycerate 4 A+P

90

phosphoglycerate 4 ATP This phosphate trans&er is reversible /low ∆10(since one 5P bond is cleaved 5 anothersynthesi*ed$

6

C

CCH2OPO3

2−

O OPO32−

H OH

C

CCH2OPO3

2−

O O−

H OH

ADP ATP

1

22

3 3

1

Mg2+

1!3-bisphospho- 3-phosphogl#cerategl#cerate



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, Phosphoglycerate )utase cataly*es)

90phosphoglycerate

80phosphoglyceratePhosphate is shi&ted &ro# the " onC< to the " on C!$

C

C

CH2OH

O O−

H OPO32−

2

3

1C

C

CH2OPO32−

O O−

H OH2

3

1

3-phosphogl#cerate 2-phosphogl#cerate

Phosphogl#cerate %utase



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An active site histidine side6chain participates in Pi

trans&er( by donating 5accepting phosphate$

The process involves a8(90$isphosphate

inter#ediate$View an ani#ation o& the

Phosphoglycerate -utasereaction$

C

C

CH2OH

O O−

H OPO3

2−

2

3

1C

C

CH2OPO32−

O O−

H OH2

3

1

3-phosphogl#cerate 2-phosphogl#cerate


C

C

CH2OPO32−

O O−

H OPO32−

2

3

1


+nolase

http://var/www/apps/conversion/tmp/scratch_4/glycolysis.htm%23pglymutasehttp://var/www/apps/conversion/tmp/scratch_4/glycolysis.htm%23pglymutase


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, Enolase cataly*es)80phosphoglycerate

phosphoenolpyruvate 4 #8O

This dehydration reaction is )g440dependent$8 )g44 ions interact with oxygen ato#s o& thesubstrate car$o3yl group at the active site$

The -g

++

ions help to stabili*e the enolateanion inter#ediate that &or#s when a F s

C

C

CH2OH

O O−

H OPO32−

C

C

CH2OH

−O O

−

OPO32−

C

C

CH2

O O−

OPO32−

OH−

2

3

1

2

3

1

H+

2-phosphogl#cerate enolate intermediate phosphoenolp#ru*ate

+nolase


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P ru*ate )inase


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$his phosphate transfer from P+P to "'P is spontaneous,

P+P has a larger ∆& of phosphate h#drol#sis than "$P,

emo*al of Pi from P+P #ields an unstable enol! .hichspontaneousl# con*erts to the keto form of p#ru*ate,

e/uired inorganic cations ) and %g bind to anionic

residues at the acti*e site of P#ru*ate )inase,

C

C

CH3

O O−

O2

3

1

ADP ATPC

C

CH2

O O−

OPO32−

2

3

1

C

C

CH2

O O−

OH2

3

1

phosphoenolp#ru*ate enolp#ru*ate p#ru*ate

P ru*ate )inase

glucose Glycolysis


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Hexokinase

Phosphofructokinase

glucose Glycolysis

"$P

"'P

glucose-6-phosphate

Phosphoglucose Isomerase

fructose-6-phosphate

"$P

"'P

fructose-1!6-bisphosphate

"ldolase

gl#ceraldeh#de-3-phosphate dih#drox#acetone-phosphate

$riosephosphateIsomerase

&l#col#sis continued

gl#ceraldeh#de-3-phosphate


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1lycolysiscontinue

d$

Recallthat

there are! 1APperglucose$

&l#ceraldeh#de-3-phosphate'eh#drogenase


+nolase

P#ru*ate )inase

gl#ceraldeh#de-3-phosphate

("' Pi

("'H H


"'P

"$P

3-phosphogl#cerate


2-phosphogl#cerate

H20 phosphoenolp#ru*ate

"'P

"$P

p#ru*ate

B l h & P b d & ATP


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Balance sheet &or 5P bonds o& ATP) ! ATP expended = ATP produced /! &ro# each o& two


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They %ust reo3idiDe *A+# produced in1lycolysis through so#e other reaction(because *A+4 is needed &or the

1lyceraldehyde6


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$g$( actate +ehydrogenase cataly*esreduction o& the keto in pyruvate to ahydroxyl( yielding lactate( as :AD isoxidi*ed to :AD+$

actate( in addition to being an end6producto& &er#entation( serves as a %o$ile &or# o&nutrient energy( 5 possibly as a signal #olecule in #a##alian organis#s$

Cell #e#branes contain carrier roteins that

C

C

CH3

O−

O

O

C

HC

CH3

O−

OH

O

NADH + H+ NAD+

actate 'eh#drogenase

p#ru*ate lactate



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"keletal %uscles &er#ent glucose to lactate during exercise( when the exertion is brie& andintense$

actate released to the $lood #ay be takenup by other tissues( or by skeletal #uscle a&terexercise( and converted via FactateDehydrogenase back to pyruvate( which #ay

be oxidi*ed in -re$s Cycle or /in liver0

C

C

CH3

O−

O

O

C

HC

CH3

O−

OH

O

NADH + H+ NAD+


p#ru*ate lactate


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actate serves as a fuel source &or cardiac%uscle as well as $rain neurons$

Astrocytes( which surround and protectneurons in the brain( fer%ent glucose tolactate and release it$

actate taken up by adacent neurons is

converted to pyruvate that is oxidi*ed via

C

C

CH3

O−

O

O

C

HC

CH3

O−

OH

O

NADH + H+ NAD+


p#ru*ate lactate


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o#e anaerobic organis#s #etaboli*e

pyruvate to ethanol( which is excretedas a waste product$

*A+# is converted to *A+4 in the

reaction cataly*ed by Alcohol

C

C

CH3

O−

O

O

C

CH3

OHC

CH3

OH H

H

NADH + H+ NAD

+CO2

P#ru*ate "lcohol

'ecarbox#lase 'eh#drogenase

p#ru*ate acetaldeh#de ethanol


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/lycolysis( o#itting +)glucose 4 8 *A+4 4 8 A+P 4 8 P

i

8 pyruvate 4 8

*A+# 4 8 ATP!er%entation( &ro# glucose to lactate)

glucose 4 8 A+P 4 8 Pi 8 lactate 4

8 ATPAnaero$ic cata$olis% o& glucose yieldsonly ! “high energy” bonds o& ATP$

&l#col#sis +n#meeaction ∆&o ∆&


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# # # ∆&kmol

∆&kmol

Hexokinase -2,7 -28,2

Phosphoglucose Isomerase 2,2 -1,4

Phosphofructokinase -18,2 -25,7

"ldolase 22,9 -5,7

$riosephosphate Isomerase 8,7 negati*e

&l#ceraldeh#de-3-P 'eh#drogenase: Phosphogl#cerate )inase

-16,8 -1,1

Phosphogl#cerate %utase 4,8 -,6+nolase -3,2 -2,4

P#ru*ate )inase -23, -13,7

Values in this table &ro# D$ Voet 5 J$ 1$ Voet /!KK=0 Lioche#istry(


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!lu3 through the 1lycolysis pathway isregulated by control o& < en*y#es thatcataly*e spontaneous reactions)

#e3okinase( Phosphofructokinase 5Pyruvate -inase$

ocal control o& #etabolis# involves regulatory eEects o&varied concentrations o& pathway su$strates orinter%ediates( to bene.t the cell$

/lo$al control is &or the bene.t o& the whole organis#( 5o&ten involves hor%one0activated signal cascades$

iver cells have #aor roles in #etabolis#( including

#aintaining blood levels various o& nutrients such as glucose$ Thus global control especially involves liver$

o#e aspects o& global control by hor#one6activated signal

cascades will be discussed later$

CH2OH CH2OPO32−6 6

ATP ADP


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#e3okinase is inhi$ited by product glucose010phosphate) by co%petition at the active site by allosteric interaction at a separate en*y#e site$

Cells trap glucose by phosphorylating it(

preventing exit on glucose carriers$

Product inhi$ition o& exokinase ensures thatcells will not continue to accu#ulate glucose

&ro# the blood( i& Nglucose646phosphateO within

H O

OH

H

OHH

OHH

OH

H H O

OH

H

OHH

OHH

OH

H

23

4

5

1 1

5

4

3 2

ATP ADP

Mg2+


Hexokinase

CH2OH CH2OPO32−6 6

ATP ADP


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/lucokinase has a high - ) &or glucose$It is active only at high FglucoseG$

"ne eEect o& insulin( a hor#one producedwhen blood glucose is high( is activation inliver o& transcription o& the gene thatencodes the /lucokinase en*y#e$

1lucokinase is not su$Hect to product

inhi$ition by glucose646phosphate$ Fiver

/lucokina

se is avariant o&exokinase&ound in

liver$

H O

OH

H

OHH

OHH

OH

H H O

OH

H

OHH

OHH

OH

H

23

4

5

1 1

5

4

3 2

ATP ADP

Mg2+


Hexokinase


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1lucokinase is subect to inhi$ition byglucokinase regulatory protein //-RP0$

The ratio o& 1lucokinase to 1?RP in liverchanges in diEerent #etabolic states(providing a #echanis# &or #odulatingglucose phosphorylation$

&l#cogen &lucose


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/lucose010phosphatase cataly*es hydrolyticrelease o& Pi &ro# glucose646P$ Thus glucose is

released &ro# the liver to the blood asneeded to #aintain blood NglucoseO$

The en*y#es 1lucokinase 5 1lucose646phosphatase( both &ound in liver but not in

#ost other body cells( allow the liver to control

/lucokinase(with high ? -

&or glucose(allows liver

to storeglucose

as glycogen inthe &ed

statewhen blood

NglucoseO is high$

# g

Hexokinase or &lucokinase

&lucose-6-Pase

&lucose-1-P &lucose-6-P &lucose Pi &l#col#sis Path.a#

P#ru*ate

&lucose metabolism in li*er,


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#igh FglucoseG within liver cells causes atranscription &actor car$ohydrate responsiveele%ent $inding protein /ChREBP0 to be

trans&erred into the nucleus( where it activatestranscription o& the gene &or Pyruvate ?inase$

This &acilitates converting e3cess glucose topyruvate( which is #etaboli*ed to acetyl0CoA( the #ain recursor &or s nthesis o& fatt

Pyruvate -inase(

the last step1lycolysis( iscontrolled in liver partly by

#odulation o& thea%ount o& enDy%e$

C

C

CH3

O O−

O2

3

1

ADP ATPC

C

CH2

O O−

OPO32−

2

3

1

phosphoenolp#ru*ate p#ru*ate

P ru*ate )inase

Phosphofructokinase


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Phosphofructokinase is usually the rate0li%iting step o& the 1lycolysis pathway$

Phospho&ructokinase is allosterically

inhi$ited $y ATP$ At low concentration( the substrate ATP binds only at the

active site$

At high concentration( ATP binds also at a low6anityregulatory site( pro#oting the tense con&or#ation$

CH2OPO32−

OH

CH2OH

H

OH H

H HO

O

6

5

4 3

2

1 CH2OPO32−

OH

CH2OPO32−

H

OH H

H HO

O

6

5

4 3

2

1

ATP ADP

Mg2

fructose-6-phosphate fructose-1!6-bisphosphate

p

60


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The tense con&or#ation o& P%?( at high FATPG(has lower anity &or the other substrate(&ructose646P$ "ig%oidal dependence o& reactionrate on N&ructose646PO is seen$

A)P( present at signi.cant levels only when

0

10

20

30

40

50

0 05 1 15 2

[Fructose-6-phosphate] mM

P F K

A c

t i v i t y

high ;"$P<

lo. ;"$P<

&l#cogen &lucose


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Inhibition o& the 1lycolysis en*y#e

Phospho&ructokinase when NATPO is highprevents breakdown o& glucose in a pathwaywhose #ain role is to #ake ATP$

It is #ore use&ul to the cell to store glucose as

glycogen when ATP is plenti&ul$

&l#cogen &lucose

Hexokinase or &lucokinase

&lucose-6-Pase &lucose-1-P &lucose-6-P &lucose Pi

&l#col#sis Path.a#

P#ru*ate&lucose metabolism in li*er,

"tage 8. The -re$s Cycle


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The ?rebs cycle .nishes the breakdown o& pyruvic acid #olecules tocarbon dioxide( releasing #ore energy in the process$ The en*y#es&or the ?rebs cycle are dissolved in the 8uid #atrix within a

#itchondrion>s inner #e#brane$


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?reb!s Cycle)

'here does this

occurQIdenti&y the products$

?reb!s Cycle #ovie

Citric Acid cycle or Tricar$o3ylic Acid cycle or -re$s

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y y yCycleOverview and $rief history

•Pyruvate +ehydrogenase Co%ple3 =P+C> and its control

•Reactions of TCA cycle or CAC

•A%phi$olic nature of TCA cycle

•Regulation of TCA cycle

•Reactions of /lycolysis are localiDed in Cytosol( and do notrequire any o3ygen,

whereas pyruvate dehydrogenase and TCA cycle reactionstake place in %itochondria where o3ygen is utiliDed togenerate ATP $y o3ydative phosphorylation,

Consu%ption of o3ygen =respiration> depends on the rate of

P+C and TCA reactions,


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'n)itochondria

'n Cytosol


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Re"#$i%ns %& Ci$'i# A#i( Cy#)e


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y

1. Citrate sythase! Formatio o" Citroy# CoA iterme$iate.

2. %i$i& o" O'a#oacetate to the e(yme resu#ts i co"ormatioa# cha&e

)hich "aci#itates the *i$i& o" the e't su*strate+ the acety# Coe(yme A.

,here is a "urther co"ormatioa# cha&e )hich #ea$s to "ormatio o"

pro$ucts. ,his mechaism o" reactio is re"erre$ as i$uce$ "it mo$e#.

8, Aconitase. This enDy%e catalyses the iso%eriDationreaction $y re%oving and then adding $ack the water = #


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reaction $y re%oving and then adding $ack the water = #and O# > to cis0aconitate in at di;erent positions,'socitrate is consu%ed rapidly $y the ne3t step thusderiving the reaction in forward direction,

9, 'socitrate dehydrogenase. There are two isofor%s of thisenDy%e one uses *A+4 and other uses *A+P4 as electron


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enDy%e( one uses *A+ and other uses *A+P as electronacceptor,

:, α0-etoglutarate dehydrogenase. This is a co%ple3 ofdi;erent enDy%atic activities si%ilar to the pyruvate


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di;erent enDy%atic activities si%ilar to the pyruvatedyhdogenase co%ple3, 't has the sa%e %echanis% ofreaction with E2( E8 and E9 enDy%e units, *A+4 is anelectron acceptor,


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has a thioester $ond with very negative free energy ofhydrolysis, 'n this reaction( the hydrolysis of thethioester $ond leads to the for%ation of phosphoester$ond with inorganic phosphate, This phosphate is

transferred to #istidine residue of the enDy%e and thishigh energy( unsta$le phosphate is 6nally transferred to/+P resulting in the generation of /TP,


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1, "uccinate +ehydrogenase. O3idation of succinate tofu%arate, This is the only citric acid cycle enDy%e that is


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fu%arate, This is the only citric acid cycle enDy%e that istightly $ound to the inner %itochondrial %e%$rane, 't is an!A+ dependent enDy%e,

)alonate has si%ilar structure to "uccinate( and itco%petitively inhi$its "+#,

@, !u%arase. #ydration of !u%arate to %alate. 't is a highlystereospeci6c enDy%e, Cis0)aleate =the cis for% of


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stereospeci6c enDy%e, Cis )aleate =the cis for% offu%arate is not recogniDed $y this enDy%e,

, 0)alate dehydrogenase. O3idation of %alate too3aloacetate. 't is an *A+4dependent enDy%e, Reaction is


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p ypulled in forward direction $y the ne3t reaction =citratesynthase reaction> as the o3aloacetate is depleted at a veryfast rate,

Conservation of energy of o3idation in the CAC. The twocar$on acetyl group generated in P+C reaction enter the CAC( and


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y g p gtwo %olecules of CO8 are released in on cycle, Thus there isco%plete o3idation of two car$ons during one cycle, Althoughthe two car$ons which enter the cycle $eco%e the part of

o3aloacetate( and are released as CO8 only in the third round ofthe cycle, The energy released due to this o3idation is conservedin the reduction of 9 *A+4( 2 !A+ %olecule and synthesis of one/TP %olecule which is converted to ATP,

Regulation o& CAC)


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Rate controlling enDy%es.

Citrate synthatase

'socitrate dehydrogenaseα0keoglutaratedehydrogenase

Regulation of activity $y.

"u$strate availa$ility

Product inhi$ition

Allosteric inhi$ition oractivation $y other

inter%ediates

"tage 9. Electron Transport Chain and ATP "ynthase ActionThe .nal stage occurs in the inner #e#branes o& #itochondria$ This


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The .nal stage occurs in the inner #e#branes o& #itochondria$ Thisstage has two parts) an electron transport chain and ATP productionby ATP synthase

ATP % i Th hATP % ti Th h


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ATP %or#ation Through-itochondrial lectron6Transport

/Chapter ;0

ATP %or#ation Through-itochondrial lectron6Transport

/Chapter ;0

* Co#ponents o& the lectron6Transport Chain

* "xidative Phosphorylation

* Recycling o& Cytoplas#ic :AD

* Co#ponents o& the lectron6Transport Chain

* "xidative Phosphorylation

* Recycling o& Cytoplas#ic :AD


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* A&ter glycolysis and TCA cycle( ;K :ADand ! %AD! are generated &ro# theoxydation o& one glucose #olecule$

S

* A! + :AD+ A +

:AD + +

"r

* L! + %AD L +

dehydrogenase

dehydrogenase

lectron transport( also known as aerobicrespiration( is the last stage o& aerobic#etabolis#$


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hen there is sucient "! supply( :AD and

AD! enter electron transport chain to becoeoxidi*edS

arge a#ount o& energy is recovered( when

lectrons are passed &ro# :AD and %AD!o "!$

his is acco#plished by a series o& carrier pron the inner #itochondrial #e#brane $


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-itochondrial lectron Transport-itochondrial lectron Transport

* %olding in the #itochondria inner #e#brane providesa large sur&ace area$

* lectron6transport chain co#ponents are arranged inpackages called respiratory asse#blies$

l t T t d " id ti


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lectron Transport and "xidativeosphorylation)

T( electrons are trans&erred &ro# :ADd %AD! to "! step by step$

the #ean ti#e( energy released &ro# electrw is coupled to ATP synthesis$

ere( phosphorylation o& ADP is coupled withe oxidation o& :AD or %AD!$


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:AD + + + ;9! "! :AD+ + !"

%AD! + ;9! "! %AD + !"

ADP + PiATP

ADP + Pi ATP

•

The energy released during the electron flow iscoupled to ATP synthesis.

ATP synthase

ATP synthase

Co#position o& the lectron TransportCo#position o& the lectron Transport


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p pChainChain

* %our large protein co#plexes$

* Co#plex I 6 :AD6Coen*y#e reductase

* Co#plex II 6 uccinate6Coen*y#e

reductase

* Co#plex III 6 Cytochro#e c reductase

* Co#plex IV 6 Cytochro#e c oxidase

* -any o& the co#ponents are proteins with prostheticgroups to #ove electrons$

Co#plex Co#plex Co#plex


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#atrix

Co#plexI

Co#plexIII

Co#plexIV

Co

cytb

cyt

c

cyt

c;/Cu0cyt

a9a<

:AD "!

%AD!

Co#plex II

!e

"


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* I#portant characteristic o& the electron6

transport chain)

* lectron carriers are arranged in order o& increasingelectron anity( &ro# low to high$

* This results in the spontaneous 8ow o&

electrons &ro# carrier to carrier$

! t d d d ti t ti l


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o!( standard reduction potentials$

The #ore positive the o! value a #olecule has(thebetter it serves as an electron acceptor$

"! has the highest o! /K$!V0( 6 highest anity

&or electrons and is located in the end o& thechain$

o! &or :AD is U K$

beginning$

K =


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cyt c

Co#plex I

Co#plex II Co#plex III

Co#plex IV

6K$=

6K$!

K$K

K$!

K$=

K$4

K$

;$K

:AD

:AD+

succinate

&u#arate

"!

;9! " + ! !

+

Path o& lectrons

/%AD!0 /K$;0

/6K$

/K$!0

/K$!0 Table ;$! 2

Co#ponents o& theCo#ponents o& the


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Co#ponents o& theelectron transport chain

Co#ponents o& theelectron transport chain

* Co#plex I

* lectrons pass &ro#

* :AD %-: %e6 cluster ubi@uinone

• %e6 cluster) iron cycles between


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%-: %-:!

:AD :AD+

! +

!e0"

! +

!

Co#plex I

+

! electrons! electrons


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* Co U ubi@uinone

* ighlighted region serves as an anchor to inner#itochondrial #e#brane$

O

O

CH3H3CO

H3CO CH C

CH3

CH210,CH2 H

Reduction o& CoReduction o& Co


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Reduction o& CoReduction o& Co

OH

OH

CHHCO

HCO

O

O

CHHCO

HCO

"xidi*ed &or#Hbi@uinone /Co0

Reduced &or#Hbi@uinol /Co!0

!e 6

!+


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* Co#plex II

* ntry point &or %AD!$

* uccinate dehydrogenase /&ro# the citric acidcycle0 directs trans&er o& electrons &ro#

succinate to Co via %AD!$* Acyl6CoA dehydrogenase /&ro# β6oxidation o&

&atty acids0 also trans&ers electrons to Covia %AD!$


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* All electrons &ro# %AD! and :AD #ust pass throughCo$

!e0"

!)*

*A+# *A+4

'

''

"uccinate

!A+

!e0"

!atty acylCoA

!A+

%atri3

inner%e%$ranespace

CoJ


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* Co#plex III /cytochro#es b( c; and c0$

* lectron trans&er &ro# ubi@uinol tocytochro#e c$

cytochro#e c

he#e prosthetic group


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tochro#es are electron6trans&er proteins tha

ntain a he#e prosthetic group$

e iron ato# in he#e also cycles through

duced &or# /%e!+

0 and the oxidi*ed &or# /%e<

d #uscles are rich in #itochondria( whichntains electron transport syste# andtochro#es$

* Co#plex IV


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* Co#bination o& cytochro#es a and a


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cyt c

Co#plex I

Co#plex II Co#plex III

Co#plex IV

6K$!

K$K

K$!

K$=

K$4

K$

;$K

:AD

:AD+

succinate

&u#arate

"!

;9! " + ! ! +

Path o& lectrons

/%AD!0

nergy is not released at once( but in incre#en

a#ounts at each step$


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• The a#ount o& energy can becalculated in

ter#s o& ∆1o! $

• /o/ K 0 n! Eo/

n W electron nu#ber(% W &araday constant W X4$kJ9volt

$#ole

∆o

! W o

!acceptor 6 o

!donor

nergy Mield

nergy Mieldnergy Mield


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* :AD + + + ;9! "! :AD+ + !"

∆1o! W 6 !!K kJ9#ol

%AD! + ;9! "! %AD + !"

∆1o! W 6 ;! kJ9#ol

* *ote. ADP + Pi ATP ∆1o! W +


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"xidative phosphorylation"xidative phosphorylation

* The electron6transport chain #oveselectrons &ro# :AD and %AD! to "!$

* In the #ean ti#e( ADP is phosphorylated toATP$

* The two processes are dependent on eachother$ATP cannot be synthesi*ed unless there isenergy &ro# electron transport /∆1o!W +


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ATP are generated when two electronsre transported &ro# :AD to "!$

he oxidation o& %AD! only produces ! ATP$

C li & l t t tCoupling o& electron transport


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Coupling o& electron6transportwith ATP synthesis

Coupling o& electron6transportwith ATP synthesis* Che#ios#otic coupling #echanis#* lectron6transport causes unidirectional

#ove#ent o& + into the inner#e#brane space$

* The results in a + gradient being produced$

* The gradient then drives the synthesis o& ATP$


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Inner mitochondrial membrane

Outer mitochondrial membrane

H+ H+

H+

H+

H+

H+

H+

H+H+

H+

H+

H+

H

+

H+

H+

ADP + Pi ATP

lectron Transport

Chain

ATPsynthaseco#plex


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Co#ponents o& ATP synthaseCo#ponents o& ATP synthase


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Co#ponents o& ATP synthaseCo#ponents o& ATP synthase

-atrix

Cytosole

ADP + Pi ATP

α β

γ

δ

ε

#4

#4#4

#4

#4

#4

#4#4#4

#4

!

!2


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TP is transported &ro# the #atrix o& #itochondriao cytosole by ATP6ADP translocase$

TP and ADP cannot diEuse through the #itochondre#brane &reely$

he exit o& ATP is coupled with the entry o& Anto #itochondria$

Regulation o& oxidativeRegulation o& oxidative


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phosphorylationphosphorylation

* lectrons do not 8ow unless ADP is present &orphosphorylation

* Increased ADP levels cause an increase in the activity o&various en*y#es including)

* glycogen phosphorylase

* phospho&ructokinase

* citrate synthase

Hncoupling o& electron6transportHncoupling o& electron6transport


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Hncoupling o& electron transportand oxidative phosphorylation

H coup g o e ec o a spoand oxidative phosphorylation

* In so#e special cases( the coupling o& thetwo processes can be disrupted$

* Farge a#ounts o& "! are consu#ed but no

ATP is produced$* Hsed by newborn ani#als and hibernating

#a##als$

* "ccurs in -brown &at!6 which contain

ther#ogenin /uncoupling protein0$* Ther#ogenin allows the release o& energy as

heat instead o& ATP$

nergy production &ro#glucosenergy production &ro#glucose


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glucoseglucose* 1lycolysis

* ! ATP ! ATP

* ! :AD < ATP9:AD 4 ATP

* Citric Acid Cycle

* ! 1TP ; ATP91TP ! ATP* 4 :AD < ATP9:AD ; ATP

* ! %AD! ! ATP9%AD! = ATP

*


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Glycolysis

Glucose 2 Pyruvate

Oxidativephosphorylation

6 NADH+2 FADH2

2 NADH2 NADH

2 ATP 2 ATP32-34 ATP

2 Acetyl CoA

2 GTP


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1lucose6


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1lucose < phosphate shuttlep p

:AD+ :AD + +

cytoplas#ic

glycerol6


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F6aspartate

-atrix

α6ketoglutarate

F6gluta#ate

F6aspartate

α6ketoglutarate

F6gluta#ate

oxaloacetate

#itochondrial

aspartatea#inotrans&erase

F6#alate F6#alate

oxaloacetate

:AD+

< ATP

:AD+

:AD

+ +

:AD+ +

1lycolysis

#itochondrial

#alatedehydrogenase

cytoplas#ic

aspartatea#inotrans&erase

cytoplas#ic #alate dehydrogenase

The inner #itochondrial #e#brane couples electrontransport to ATP synthesis$


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The Pathway o& lectron

Transport

This energy change isused to “pu#p” hydrogen to the inner

#e#brane spacecreating a gradientwhich can power cellprocesses$

$

Che#ios#osis couples the electron transport chain toATP synthesis


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Che%ios%osis. The Energy0Coupling )echanis%


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ATP synthase proteinco#plex &unctions as a #ill(

powered by the 8ow o&hydrogen ions$

This co#plex resides in#itochondrial and

chloroplast #e#branes o&eukaryotes and in theplas#a #e#branes o&prokaryotes$$

The gradient o& hydrogenions “pushes” the ATPsynthesis$

Ani#ation o& ATP synthesis in -itochondria


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Copyright ;XX$ Tho#as-$ Terry( The Hniversityo& Connecticut

Cellular respiration generates #any ATP #olecules &or each sugar#olecule it oxidi*es

D i i ti t 8 i thi


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During respiration( #ost energy 8ows in this se@uence)

1lucose:AD electron transport chain proton#otive

&orce ATP

#arvesting Energy without O3ygen!er%entation in #u%an )uscle Cells

'hen your lungs and bloodstrea# can>t supply oxygen &ast enough to


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'hen your lungs and bloodstrea# can>t supply oxygen &ast enough to#eet your #uscles> need &or ATP$ Mour #uscle cells use &er#entation(to #ake ATP without using oxygen$

ow does the energy production o& Factic Acid &er#entationco#pare to aerobic respirationQ

tic Acid &er#entation occurs in ani#al cells de.cient in oxy


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Factic Acid %er#entation #ovie

!er%entation in )icroorganis%s

Meast /a #icroscopic &ungus0 is capable o& both cellular respirationand &er#entation

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and &er#entation$

%er#entation in yeast produces ethyl alcohol$ The carbon dioxide thatis released during &er#entation creates bubbles and pockets that#ake bread rise$ The alcohol evaporates during baking$

%er#entation enables so#e cells to produce ATP withoutthe help o& oxygen$ Alcoholic &er#entation occurs inyeast


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yeast$

Alcoholic %er#entation #ovie

Pyruvate as a key uncture in catabolis#$ 1lycolysis isco##on to &er#entation and respiration$

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ow does the net gain o&ATP co#pare in aerobicvs$ &er#entationQ

The catabolis# o& various&ood #olecules


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&ood #olecules$Carbohydrates( &ats( and

proteins can all be usedas &uel &or cellularrespiration$

"u%%ary


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y1lucose

ATP

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