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720
CHAPTER
23 Energyand Life
Fouow-upro rHECRselt Poltr: A mysteriousfatigue
After eiiminating usual causes of fatigue, the medical
researchers who investigated Emily's condition
sought the source of her problem in the biochemical
processes of energy productlon: oxygen del.ivery,formaLion of NADH and FADH2, the respiratory chain,
and oxidative phosphoryiation. They found that oxygen uptake by her tissues was normal. This eliminated
the posslbility of a flawed delivery of oxygen to the tissues. Her body cells' levels of NADH, NAD | , FADH2,
and FAD also were normal, suggesting that enough
reducing power was avarlable to the respiratory chain
and that the respiratory chain was operative. Her cellular ATP levels were considerably lower than norma_l.
The researchers concluded that Emrly was suffering from an exf,remely rare defect of oxidative phosphorylation: The respiratory chain and the production
of ATP were partially uncoupled. In such a situation,
oxygen uptake, cellular respuation, and levels of
NADH, NAD r, FADH2, and FAD would be normal.
However, AIP ievels would be iow, leading to chronic
fatigue. The molecular basis of the defect was noi
determined, but a mutant gene could be responsihle
for the defective expression of the ATP synthase that
couples the respiratory chain to the production of ATP
in oxidative phosphorylation. A flawed AIP synthase
would result in impaired ATP producfion.
2t.7 Cellularwork
AIMS: Todescribethe threemoior typesof work done by cells.
Toshow how coupled reactionsenoble o cell to corry out
chemicolwork.
Focus
Energy conserved inATP drives
cellular processes.
We have seen that cleavageof the phosphoric acid anhydride bonds in the
ATP molecule releasesfree energy that can do cellular work. Cells do three
major kinds of work chemical, osmotic, and mechanical. In this section we
will examine each kind of work and seehowATP is involved.
Chemical
work
ATPoften supplies energy to chemical reactions that need energyto make a
product. Most of these reactionsinvolve AIP as a phosphorylating agent.
That is, becauseof its very reactivephosphoric acid anhydride functional
groups, AIP readily transfers phosphoryl
o
-P-OH
I
OH
oq less commonly, plrophosphoryl
oo
iltl
-P-O-P-OH
groups to other molecules.Justas reducing power is the ability of NADH and
FADH2to transfer electronsin reduction reactions,phosphorylatingpower zs
the ability of ATP to transferphosphorylgroups in phosphorylationreactions.
25.7 CellularWork
721
Some phosphorylated enzyme substrates are activated for subsequent
reactions they would not ordinarily undergo. The process of activation
often involves a coupled reaction-an energeticallyunfauorable reaction is
made to occur by being linked to a reaction that is energetically ueryfauorable (uery exergonic).In a coupled reaction, the net energy change for the
linked reactions is favorable (exergonic).For example,liver cells need to use
ammonia and carbon dioxide to make citrulline from the amino acid
ornithine. (This reaction is important in the urea cycle, and we will return
to it in Chapter 26.)A hypothetical equation for this reaction can be written:
o- c
H
I
NHO
ll
CHT+C
l-l
+
NH3
+
,/
\
NH,
NH
9H,
+ H2O
I
CH,
CH,
O
t-
I
CHr
CHr
I
I
H2N-CH
H2N-CH
I
I
co2H
c02H
omithine
Ammonia
Citrulline
Water
:rT:::
Figure
25.12
Thedirectconversion
of ammonia
to citrullineis not a favorable
process(a).Whenthe reaction
is coupledwith the breakdown
of ATBhowever,it is exergonic
(favorable)
(b).
This hypothetical reaction is energetically unfavorable (Fig. 23.12a).The
equilibrium position greatly favors the reactants over the product. lVhat
about using an enzJrmeto catalyze the reaction? This would not make the
reaction exergonic.As catalysts, enzymes only speed up reactions that are
already exergonic; they do not alter the position of equilibrium. Cells are
not stymied by this state of affaits, however,becausethey have AIP on their
side. They carry out an exergonic reaction instead, forming a molecule of
carbamoyl phosphate by using one molecule of ammonia, one of carbon
Citrulline (product)
Energyreleasedby conversionofATP
to ADP makes formation of carbamoyl
phosphate energeticallyfavorable {exergonic).
bo
Freeenergy change is unfavorable.
Formation of citrulline does not occur.
m
0)
o
q)
0
oo
il[
NH2-c-o-1-oH+6$tr
I
OH
Carbamoyl phosphate
Formation of citnrlline from
carbamoyiphosphate and
ornithine is energetically
favorable (exergonic).
Ornithine + CO2+ NH3 (reactants)
I
f +Omithine
I
i
Citrulline
f
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CHAPTER
25 Energyand Life
dioxide,and two ofAIP (Fig.23.12b).An enzymespeedsup the reaction.
oo
E*"'so'i",
NH3+ CO2+ 2ATp
NU2-a-O-J-O"
I
+ 2ADp+ p'
OH
;ilxlHJj
The structure of carbamoyl phosphate contains a mixed anhydride linkage,
one formed from a carboxylic acid and phosphoric acid. This linkage is very
energetic. Carbamoyl phosphate readily reacts with ornithine to produce
citrulline in another exergonic enzyme- cata\rzed reaction (Fig. 23.I 2b).
Mived
anhridride
_t*fq_
oo
tl
NH,-C-O-P-OH
,rN''t
O:C
.*"
NH,
T
OH
Exergonic
l,,
UHr+CH,*P'
t-t-
CH,
tl
CHI
tl
H2N-CH
co2H
Carbamoyl
phosphate
Ornithine
I
CHI
CH'
H2N-CH
co2H
Citrulline
ATP appearsin the equation for the overall reaction for the formation of
citrulline, and it looks as if it were used up, as it is in hydrolysis.
ornithine + co2 + NH3 + 2ATp
Exergonic,
citrulline + 2ADp + zpi + HzO
The reality is quite different. The free energy stored in the energetic anhydride bonds of two AIP molecules was unleashed by breaking these bonds,
but some was consewed in the anhydride bond of carbamoyl phosphate.
By expending the phosphorylating power of AIP to make carbamoyl phosphate, liver cells boosted the reactivity of ammonia and carbon dioxide and
achieved the synthesis of citrulline. In our example, an energetically unfavorable reaction-the formation of citrulline from ammonia, carbon dioxide, and ornithine-could not occur without coupling the reaction to the
favorable breakdor,rmof ATP Sometimesthe route to energetically activated
molecules requires several chemical steps, but the principle is the same.
The inevitable result of substrate phosphorylation is the production of a
more reactive molecule.
Like substrates,some enzyrnesare also phosphorylated by ATP Phosphorylation often makes the difference between an active'and inactive
enzyrne.A good example of enzyme activation caused by phosphoq4ation
comes from catabolism and involves phosphorylase, the errzyrnethat catalyzesthe breakdor,rmof stored glycogen.The inactive form of phosphorylase (phosphorylase b) is a dimer consisting of identical protein subunits.
23.7 CellularWork
PO.z-,
t:
o
Figure25.15
Phosphorylase
is convertedfrom
an inactiveto an activeform upon
phosphorylation.
Inactive
phosphorylase b
dimers
72t
Po:zl'
o
Active
phosphorylase a
The active form of phosphorylase (phosphorylase a) is a tetramer of these
identical subunits.
PhosphoryIation of the hydroxyl groups of a single serine residue in the
amino acid sequenceof each subunit causestwo inactive phosphorylase b
dimers to form the active phosphorylase a tetramer (Fig. 23.L3).The phosphorylase a can now go about the work nature intended: the breakdor.nrn
of
glycogen.It may appear that the phosphorylation of phosphorylase, a catabolic enzSrme,
violates the rule that catabolism produces ATP However,one
molecule of phosphorylase acatalyzes the cleavageof glycogen into many
molecules of glucose.And aswe will seein Chapter 24, the complete oxidation of only one glucosemolecule freed by the action of phosphorylase a on
glycogen gives a return of ATP many times greater than the four molecules
of AIP it takes to phosphorylate the en4rrne.
Osmotic work
Cellscontain molecularpumps that transportions and moleculesthrough
cell membranes. Thesepumps work against the normal concentration gradient-the transport is from a lower to a higher concentration of the substance being transported-and require the expenditure of energy in the
form of ATP Such pumps often require the phosphorylation of transport
proteins embeddedin the cell membrane.
Mechanical
work
At this point we understand that AIP is a phosphorylating agent in the
chemical and osmotic work done by cells.But in mechanical work-that is,
cellular movements including muscle contraction-ATP is hydrolyzed
rather than acting as a phosphorylating agent. The sliding-filament model
is the generally accepted depiction of muscle contraction. In this model,
muscles contract when thick and thin filaments slide past each otherffth
AIP providing the energy of propulsion (Fig. 23.141.
Muscle contraction requires so much ATP that muscle cells cannot
keep enough on hand. Nature usesATPto transmit energy,not to store it. In
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23 Energyand Life
CHAPTER
Thick filament (myosin)
Thin filament (actin)
Baseplate
(a) Restingmuscle
Figure25.14
Musclefibers contractwhen thick
filamentsmade of myosinand thin
filamentsmade of actin slide past
each other,propelledby energy
releasedin the hydrolysisof ATP.
(b) Contractedmuscle
resting muscle, the phosphorylating power ofAIP is stored in another highenergy compound called creatine phosphate, or phosphocreatine. On
demand, the phosphoryl groups of creatine phosphate are transferred back
to ADP
NHr
I
I
T
.C
+/\
HzN
T-t"'
cH2co2H
ATD
ntr
-
fot'
I
NH
Resting
muscle
Active
muscle
I
+ ADP
C
+/\
H
-"Nl
N-CH"
cH2co2H
creatine
of;:".XtiT"
The enz].,rneinvolved in this reversible reaction is creatine phosphokinase.
(Enzymesthat catalyze the transfer of a phosphoryl group to or from AIP
are called kinases.)As soon as the demand forAIP exceedsthe supply, as in
heavy exercise,muscles become tired and weak.
,.
-:
PRACIICE
EXERCISE
2I.8
Outline the steps to showwhy the body's need for oxygen incrgdes as
,' physical activity increases.\Mhathappens to muscleswhen the demand
,i: forAIP exceedsthe supply?