Download how cells obtain energy from food

88
Chapter2: CellChemistryand Biosynthesis
HOWCELLS
OBTAIN
ENERGY
FROMFOOD
The constant supply of energy that cells need to generate and maintain the biological order that keeps them alive comes from the chemical bond energy in
food molecules, which thereby serve as fuel for cells.
The proteins, lipids, and polysaccharidesthat make up most of the food we
eat must be broken down into smaller molecules before our cells can use themeither as a source of energy or as building blocks for other molecules. EnzFnatic
digestion breaks down the large polymeric molecules in food into their
monomer subunits-proteins into amino acids, polysaccharides into sugars,
and fats into fatty acids and glycerol. After d^igestion, the small orginic
molecules derived from food enter the cltosol of cells, where their gradual oxidation begins.
Sugars are particularly important fuel molecules, and they are oxidized in
small controlled steps to carbon dioxide (coz) and water (Figure 2-69). In this
section we trace the major steps in the breakdor.tm,or catabolism, of sugarsand
show how they produce ATB NADH, and other activated carrier molecules in
animal cells. A very similar pathway also operates in plants, fungi, and many
bacteria. As we shall see, the oxidation of fatty acids is equally important for
cells. other molecules, such as proteins, can also serve as energy sourceswhen
they are funneled through appropriate enzymatic pathways.
Glycolysis
ls a CentralATP-Producing
Pathway
The major process for oxidizing sugars is the sequence of reactions known as
verted into two molecules of pyruuate, each of which contains three carbon
atoms. For each glucose molecule, two molecules of ATp are hydrolyzed to provide energy to drive the early steps, but four molecules of Arp are produced in
the later steps.At the end of glycolysis,there is consequently a nef gain of two
molecules of AIP for each glucose molecule broken down.
The glycolltic pathway is outlined in Figure 2-zo and shown in more detail
in Panel 2-8 (pp. I?}-IZL). Glycolysis involves a sequence of l0 separate reac_
tions, each producing a different sugar intermediate and each caialvzed bv a
(A) stepwiseoxidation of sugar in cells
I
a
q
o
E
( B ) d i r e c tb u r n i n go f s u g a r
s m a l la c t i v a t i o ne n e r g i e s
o v e r c o m ea t b o d y
t e m p e r a t u r eo w i n g t o t h e
presence
of enzymes
S U G A R+ O ,
q
activated
c ar n e r
molecules
store
energy
1w
allfree
energy rs
reteaSed
as heat;
none rs
stored
&
C O ,+ H r O
CO, + HrO
Figure2-69 Schematicrepresentation
of the controlled stepwiseoxidation of
sugarin a cell,comparedwith ordinary
burning,(A)In the cell,enzymescatalyze
oxidationvia a seriesof smallsteosin
whichfreeenergyis transferred
in
conveniently
sizedpacketsto carrier
molecules-mostoftenATPand NADH.
At eachstep,an enzymecontrolsthe
reactionby reducingthe activation
energybarrierthat hasto be surmounted
beforethe specificreactioncan occur.
The total free energyreleasedis exactly
the samein (A)and (B).But if the sugar
wereinsteadoxidizedto CO2and H2Oin
a singlestep,as in (B),it would release
an
amountof energymuch largerthan
could be capturedfor usefulpurposes.
89
HOWCELLSOBTAINENERGY.FROM
FOOD
one molecule
of glucose
energy
investment
to be
recoupeo
later
Figure2-70 An outlineof glycolysis'
Eachofthe 10 stepsshownis
<GGGC>
catalyzedby a differentenzyme.Note
sugar
a six-carbon
that step4 cleaves
so that the
sugars,
into two three-carbon
at everystageafter
numberof molecules
step6 begins
this doubles.As indicated,
the energygenerationphaseof
of ATP
two molecules
glycolysis.
Because
in the early,energY
arehydrolyzed
resultsin the
investmentphase,glycolysis
of 2 ATPand 2 NADH
net synthesis
moleculesper moleculeof glucose(see
alsoPanel2-B).
fructose 1,6bisphosphate
I
I
CHO
CHOH
CHOH
I
two moleculesof
glyceraldehyde
3-phosphate
i
cH2o P
I
@
I
a
|
I
I
I
<
two molecules
of pyruvate
srres
CHO
COO
C:o
I
CHr
srEPT
,',r,
e
srEP
c l e a v a g eo f
s i x - c rab o n
sugarto two
th ree-carbon
s u g ar s
I
I
t---*
I
I
I
I
t
I
energy
generation
sTEP1O
l-
cooI
I
CH:
different enzyrne. Like most enzymes, these have names ending in ase--such as
isomerase and dehydro genase-,lo indicate the type of reaction they catalyze.
Although no molecular oxygen is used in glycolysis,oxidation occurs, in that
electrons are removed by NAD+ (producing NADH) from some of the carbons
derived from the glucose molecule. The stepwise nature of the process releases
the energy of oxidation in small packets,so that much of it can be stored in activated carrier molecules rather than all of it being released as heat (see Figure
2-69). Thus, some of the energy releasedby oxidation drives the direct slmthesis
of ATP molecules from ADP and Pi, and some remains with the electrons in the
high-energy electron carrier NADH.
TWomolecules of NADH are formed per molecule of glucosein the course of
glycolysis. In aerobic organisms (those that require molecular oxygen to live),
these NADH molecules donate their electrons to the electron-transport chain
described in Chapter 14, and the NAD+ formed from the NADH is used again for
glycolysis (see step 6 in Panel 2-8, pp. 120-l2I).
ProduceATPin the Absenceof Oxygen
Fermentations
For most animal and plant cells, glycolysis is only a prelude to the final stage of the
breakdo'ornof food molecules. In these cells, the p],'ruvateformed by glycolysis is
90
Chapter2: CellChemistryand Biosynthesis
rapidly transported into the mitochondria, where it is converted into co2 plus
acetyl CoA, which is then completely oxidized to CO2and H2O.
In contrast, for many anaerobic organisms-which do not utilize morecular
oxygen and can grow and divide without it-glycolysis is the principal source of
the cell'sArP This is also true for certain animal tissues,such as skeletalmuscle,
that can continue to function when molecular oxygen is limiting. In these anaerobic conditions, the pyruvate and the NADH electrons stay in the cytosol. The
pyruvate is converted into products excreted from the cell-for example, into
ethanol and co2 in the yeastsused in brewing and breadmaking, or into lactate
in muscle. In this process,the NADH gives up its electrons and is converted back
into NAD+. This regeneration of NAD+ is required to maintain the reactions of
glycolysis (Figure 2--7l).
Anaerobic energy-yielding pathways like these are called fermentations.
process.The piecing together of the complete glycolltic pathway in the 1930swas
a major triumph of biochemistry, and it was quickly followed by the recognition of
the central role of ArP in cell processes.Thus, most of the fundamentalioncepts
discussed in this chapter have been understood for manv vears.
(A) FERMENTATION
LEADINGTO EXCRETION
OF LACTATE
grucose
2 ADF-
.r -2l|{4q:
\ E/
--E
-E-;
2 x pyruvate
oo\,,
o.
o\./
I
I
H- C-OH
C
C
I
I
cH:r
CH:
2 x lactate
( B ) F E R M E N T A T I OLN
EADING
T O E X C R E T I OONFA L C O H O L
ANDCO.
grucose
-
^-'
........._.\
'6
t->I
=-
/.-'
EDlr
2 x pyruvate
o.
o\//
C
I
HC:O
I
CH:
I
CH:
2 x acetaldehyde
H-, C
l -OH
CH:
2x
COz
2 x ethanol
Figure2-71 Two pathwaysfor the
anaerobicbreakdownof pyruvate.
(A)Whenthereis inadequate
oxygen,for
example,in a musclecellundergoing
vigorouscontraction,
the pyruvate
producedby glycolysisis convertedto
lactateas shown.Thisreactton
regenerates
the NADt consumedin step
6 of glycolysis,but the whole pathway
yieldsmuch lessenergyoverallthan
completeoxidation.(B)In some
organisms
that can grow anaerobically,
suchasyeasts,pyruvateis convertedvia
acetaldehyde
into carbondioxideand
ethanol.Again,this pathwayregenerates
NAD+from NADH,as requiredto enable
glycolysis
to continue.Both(A)and (B)
are exampfes of fermentations.
HOWCELLS
OBTAIN
ENERGY
FROMFOOD
Glycolysis
lllustrates
HowEnzymes
CoupleOxidationto Energy
Storage
Returning to the paddle-wheel analogy that we used to introduce coupled reactions (see Figure 2-56), we can now equate enzymes with the paddle wheel.
Enzymes act to harvest useful energy from the oxidation of organic molecules
by coupling an energetically unfavorable reaction with a favorable one. To
demonstrate this coupling, we examine a step in glycolysis to see exactly how
such coupled reactions occur.
TWo central reactions in glycolysis (steps 6 and 7) convert the three-carbon
sugar intermediate glyceraldehyde3-phosphate (an aldehyde) into 3-phosphoglycerate(a carboxylic acid; seePanel2-8, pp. 120-121).This entails the oxidation
of an aldehyde group to a carboxylic acid group in a reaction that occurs in two
steps.The overall reaction releasesenough free energy to convert a molecule of
ADP to AIP and to transfer two electrons from the aldehyde to NAD* to form
NADH, while still releasing enough heat to the environment to make the overall
reaction energeticallyfavorable (AG for the overall reaction is -3.0 kcal/mole).
Figure 2-72 otttlines the means by which this remarkable feat of energy harvesting is accomplished. The indicated chemical reactions are precisely guided
by two enzymes to which the sugar intermediates are tightly bound. In fact, as
detailed in Figure 2-72, the first enzyme (glyceraldehyde 3-phosphate dehydrogenase) forms a short-lived covalent bond to the aldehyde through a reactive -SH group on the enzyme, and catalyzes its oxidation by NAD+ in this
attached state. The reactive enzyme-substrate bond is then displaced by an
inorganic phosphate ion to produce a high-energy phosphate intermediate,
which is released from the enzyme. This intermediate binds to the second
enzyme (phosphoglycerate kinase), which catalyzesthe energetically favorable
transfer of the high-energy phosphate just created to ADB forming AIP and
completing the process of oxidizing an aldehyde to a carboxylic acid.
We have shown this particular oxidation process in some detail because it
provides a clear example of enzyme-mediated energy storage through coupled
reactions (Figure 2-73). Steps 6 and 7 are the onlyreactions in glycolysis that
create a high-energy phosphate linkage directly from inorganic phosphate. As
such, they account for the net yield of two AIP molecules and two NADH
molecules per molecule of glucose (seePanel 2-8, pp.l20-I2l).
As we have just seen,AIP can be formed readily from ADP when a reaction
intermediate is formed with a phosphate bond of higher-energy than the phosphate bond in AIP Phosphatebonds can be ordered in energy by comparing the
standard free-energy change (AGl for the breakage of each bond by hydrolysis.
Figure 2-74 compares the high-energy phosphoanhydride bonds in ATP with
the energy of some other phosphate bonds, several of which are generated during glycolysis.
in SpecialReservoirs
StoreFoodMolecules
Organisms
All organisms need to maintain a high ATP/ADP ratio to maintain biological
order in their cells. Yet animals have only periodic accessto food, and plants
need to survive overnight without sunlight, when they are unable to produce
sugar from photosynthesis. For this reason, both plants and animals convert
sugars and fats to special forms for storage (Figure 2-75).
To compensate for long periods of fasting, animals store fatty acids as fat
droplets composed of water-insoluble triacylglycerols,largely in the cytoplasm
of specialized fat cells, called adipocltes. For shorter-term storage, sugar is
stored as glucose subunits in the large branched polysaccharide glycogen,
which is present as small granules in the cltoplasm of many cells,including liver
and muscle. The synthesis and degradation of glycogen are rapidly regulated
according to need. \.A/hencells need more AIP than they can generate from the
food molecules taken in from the bloodstream, they break down glycogen in a
reaction that produces glucose 1-phosphate,which is rapidly converted to glucose 6-phosphate for glycolysis.
91
92
Chapter2: CellChemistryand Biosynthesis
(A)
HO
\ /(_
/
I
H-C-OH
glyceraldehyde
3-phosphate
SH
A covalent bond is formed between
glyceraldehyde3-phosphate(the
substrate)and the -5H group of a
cysteineside chain of the enzyme
glyceraldehyde3-phosphate
d e h y d r o g e n a s ew,h i c h a l s ob i n d s
noncovalentlyto NAD+.
t-? I
H -C-OH
I
H_C_OH
I
Oxidation of glyceraldehyde
3-phosphateoccurs,as two
electronsplus a proton (a hydride
ion, see Figure2-60) are
transferredfrom glyceraldehyde
3-phosphateto the bound NAD+,
forming NADH.Part of the energy
releasedby the oxidation of the
a l d e h y d ei s t h u s s t o r e di n N A D H ,
and part goes into convertingthe
bond between the enzymeand its
substrateglyceraldehyde
3-phosphateinto a high-energy
thioester bond
cH2oo
(o
c
r
F
I
H-C-OH
HO-
A m o l e c u l eo f i n o r g a n i cp h o s p h a t e
displacesthe high-energybond to
the enzymeto create 1,3-bisphosphoglycerate,which contains
a high-energyacyl-anhydride
bond.
PIO
ti
rU- iAL J
1,3-bisphosphoglycerate
C:O
I
H-C-OH
l^
cH2o(L)
@@o
F
4
H
r fr_A-r,
C
I
H- C-OH
l^
cH2o(L)
(B)
3 - p h o s p h olgy c e r a t e
The high-energybond to phosphate
is transferredto ADP to form ATP.
SUMMARYOF STEPS
6 AND 7
Much of the energy of oxidation
has been stored in the activateo
carriersATPand NADH.
Figure2-72 Energystoragein steps6
and 7 of glycolysis.In thesestepsthe
oxidationof an aldehydeto a carboxylic
acidis coupledto the formationof ATP
and NADH.(A)Step6 beginswith the
formationof a covalentbond between
the substrate(glyceraldehyde
3-phosphate)
and an -5H groupexposed
on the surfaceof the enzyme
(glyceraldehyde
3-phosphate
dehydrogenase).
Theenzymethen
catalyzestransferof hydrogen(asa
hydrideion-a protonplustwo
electrons)
from the bound
glyceraldehyde
3-phosphate
to a
moleculeof NAD+.Partof the energy
released
in this oxidationis usedto form
a moleculeof NADHand part is usedto
convertthe originallinkagebetweenthe
enzymeand its substrate
to a highenergythioesterbond (shownin red.).
A moleculeof inorganicphosphatethen
displaces
this high-energy
bond on the
enzyme,creatinga high-energy
sugarphosphatebond instead(red).At this
point the enzymehas not only stored
energyin NADH,but alsocoupledthe
energetically
favorableoxidationof an
aldehydeto the energetically
unfavorable
formationof a high-energy
phosphate
bond.Thesecondreactionhasbeen
drivenby the first,therebyactinglikethe
"paddle-wheel"
couplerin Figure2-56.
In reactionstep7, the high-energy
just made,
sugar-phosphate
intermediate
1,3-bisphosphoglycerate,
bindsto a
secondenzyme,phosphoglycerate
kinase.The
reactivephosphateis
transferredto ADP,forming a moleculeof
ATPand leavinga freecarboxylic
acid
groupon the oxidizedsugar.
(B)Summaryof the overallchemical
changeproducedby reactions6 and 7.
93
HOWCELLSOBTAINENERGY
FROMFOOD
o
ME
o
c
o
a
o
o
Figure 2-73 Schematicview of the
coupledreactionsthat form NADHand
ATPin steps 6 and 7 of glycolysis.The
C-H bond oxidationenergydrivesthe
formationof both NADHand a highenergyphosphatebond.The breakageof
bond then drivesATP
the high-energy
formation.
\,/
C
I
\,,
C
I
C-H bond
oxidation
energy
+
STEP6
7
STEP
t o t a l e n e r g yc h a n g ef o r s t e p6 f o l l o w e d b y s t e p 7 i s a f a v o r a b l e- 3 k c a l / m o l e
o-o
\//
CO
enol phosphate
bond
rll
H'' C : C - O - . P
Hro
-O-
/ ,/lo-
p h o s p h o e n oply r u v a t e
isee ianel Z-8,'pp. 120-121)
- 14'6
(-61 e)
oo
tltl
c-c-o y'P o-
anhydride
bondto carbon
o
Hro/
phosphate
bond in
creaTtne
phosphate
anhydride
bondto
phosphate
(phosphoanhydride
bond)
a._a)-
ooo
ililtl
i-"-i-o7i-"o-
o-
Hzo
c r e a t i n eo h o s p h a t e
( a c t i v a t e dc a r r i e rt h a t
storesenergy in muscle)
(-43.0)
for example,
ATPwhen hydrolyzed
tOADP
-7.3
(-306)
-10.3
/o-
HO
phosphoester
bond
for example,
1,3-bisphosphoglycerate
(seePanel2-8)
lll
, -i-"vP-o-
for example,
g l u c o s e6 - p h o s p h a t e
(seePanel2-8)
",/o-
Hzo
type of phosphatebond
specificexamplesshowing the
standardfree-energychange (AG')
for hydrolysisof phosphatebond
Figwe 2-74 Phosphatebonds have different energies.Examplesof differenttypes of phosphatebondswith their sitesof hydrolysisare
shown in the moleculesdepictedon the left.Thoseitarting with a gray catbonatom show only part of a molecule.Examplesof molecules
(kilojoules
transfer
in parentheses)'The
in kilocalories
changefor hydrolysis
containingsuchbondsaregivenon the right,with the free-energy
of a phosfhate group from one moleculeto anotheris energeticallyfavorableif the standardfree-energychange(AG')for hydrolysisof the
Thus,a phosphategroup
of the phosphatebond in the second.
phosphatebond of the firstmoleculeis more negativethan that for hydrolysis
to ADPto form ATPThe hydrolysisreactioncan be viewedas the transferof the phosphate
is readilytransferredfrom 1,3-bisphosphoglycerate
group to water.
94
Chapter2: CellChemistyand Biosynthesis
9rycogen
g r a n u l e isn
the cytoplasm
o f a l i v e rc e l l
b r a n c hp o i n t
g l u c o s es u b u n i t s
1pm
ql
a 1,4-glycosidic
bond in backbone
,,-
Figure2-75 The storageof sugarsand
fats in animaland plant cells.(A)The
structures
of starchand glycogen,
the
storageform of sugarsin plantsand
animals,respectively.
Botharestorage
polymersof the sugarglucoseand differ
only in the frequencyof branchpoints
(theregioninyellowisshownenlarged
below).Therearemanymore branchesin
glycogenthan in starch.(B)An electron
micrographshowsglycogengranulesin
the cytoplasmof a livercell.(C)A thin
sectionof a singlechloroplast
from a
plantcell,showingthe starchgranules
and lipid(fatdroplets)that have
accumulated
asa resultof the
biosyntheses
occurringthere.(D)Fat
droplets(stainedred)beginningto
accumulate
in developingfat cellsof an
animal.(8,courtesyof RobertFletterick
and DanielS.Friend;C,courtesyof
K.Plaskitt;
D,courtesyof RonaldM. Evans
and PeterTotonoz.)
o 1 , 6 - 9 l y c o s i dbi co n d
at branch point
/
o-cH2
OH
l;------.,
Quantitatively, fat is far more important than glycogen as an energy store for
animals, presumably becauseit provides for more efficient storage.The oxidation
of a gram of fat releasesabout twice as much energy as the oxidation of a gram
of glycogen. Moreover, glycogen differs from fat in binding a great deal of water,
producing a sixfold difference in the actual mass of glycogen required to store
the same amount of energy as fat. An averageadult human stores enough glycogen for only about a day of normal activities but enough fat to last for nearly a
month. If our main fuel reservoir had to be carried as glycogen instead of fat,
body weight would increase by an averageof about 60 pounds.
Although plants produce NADPH and Arp by photosynthesis,this important
process occurs in a specialized organelle, called a chloroplast, which is isolated
from the rest of the plant cell by a membrane that is impermeable to both types
of activated carrier molecules. Moreover, the plant contains many other cellssuch as those in the roots-that lack chloroplasts and therefore cannot produce
their or,rmsugars.Therefore, for most of its ATP production, the plant relies on an
50u.
HOWCELLSOBTAINENERGY
FROMFOOD
.95
Figure 2-76 How the ATPneeded for
most plant cell metabolismis made.In
plants,the chloroplasts
and mitochondria
to supplycellswith
collaborate
metabolitesand ATP.(Fordetails,see
Chapter14.)
light
chloroplast
metabolites
export of sugars from its chloroplasts to the mitochondria that are located in all
cells of the plant. Most of the AIP needed by the plant is synthesized in these
mitochondria and exported from them to the rest of the plant cell, using exactly
the same pathways for the oxidative breakdor,rrnof sugars as in nonphotosynthetic organisms (Figure 2-76).
During periods of excessphotosynthetic capacity during the day, chloroplasts convert some of the sugars that they make into fats and into starch, a
polgner of glucose analogous to the glycogen of animals. The fats in plants are
triacylglycerols, just like the fats in animals, and differ only in the types of fatty
acids that predominate. Fat and starch are both stored in the chloroplast as
reservoirs to be mobilized as an energy source during periods of darkness (see
Figure 2-75C).
The embryos inside plant seedsmust live on stored sources of energy for a
prolonged period, until they germinate to produce leaves that can harvest the
energy in sunlight. For this reason plant seeds often contain especially large
amounts of fats and starch-which makes them a malor food source for animals,
including ourselves (Figare 2-7 7),
MostAnimalCellsDeriveTheirEnergyfrom FattyAcidsBetween
Meals
After a meal, most of the energy that an animal needs is derived from sugars
derived from food. Excesssugars,if any, are used to replenish depleted glycogen
stores,or to synthesizefats as a food store. But soon the fat stored in adipose tissue is called into play, and by the morning after an overnight fast, fatty acid oxidation generatesmost of the ATP we need.
Low glucose levels in the blood trigger the breakdown of fats for energy production. As illustrated in Figure 2-78, the triacylglycerols stored in fat droplets
in adipocl'tes are hydrolyzed to produce fatty acids and glycerol, and the fatty
acids released are transferred to cells in the body through the bloodstream.
\.\hile animals readily convert sugars to fats, they cannot convert fatty acids to
sugars.Instead, the fatty acids are oxidized directly.
Figure2-77 SomePlant seedsthat
serveas important foods for humans.
Corn,nuts,and Peasall containrich
storesof starchand fat that providethe
youngplantembryoin the seedwith
energyand buildingblocksfor
(Courtesy
of the JohnInnes
biosynthesis.
Foundation.)
96
Chapter
2:CellChemistry
and Biosynthesis
stored fat
bloodstream
glycerol
MUSCLE
CELL
fatty acids
o x i d a t i o ni n
mitochondria
Figure 2-78 How stored fats are
mobilized for energy production in
animals.Low glucoselevelsin the blood
triggerthe hydrolysisof the
triacylglycerolmoleculesin fat droplets
to free fatty acidsand glycerol,as
illustrated.Thesefatty acidsenter the
bloodstream,wherethey bind to the
abundantblood protein,serumalbumin.
Specialfatty acidtransportersin the
plasmamembraneof cellsthat oxidize
fatty acids,suchas musclecells,then pass
thesefatty acidsinto the cytosol,from
whichthey aremovedinto mitochondria
for energyproduction(seeFigure2-80).
)
Sugarsand FatsAre Both Degradedto AcetylCoAin
Mitochondria
The fatty acids imported from the bloodstream are moved into mitochondria, where all of their oxidation takes place
). Each molecule of
fatty acid (as the activated molecule /a tty acyl coA) is broken down completely
by a cycle of reactions that trims two carbons at a time from its carboxyl end,
generating one molecule of acetyl coA for each turn of the cycle. A molecule of
NADH and a molecule of FADH2 are also produced in this proces
Sugars and fats are the major energy sources for most nonorganisms, including humans. However, most of the useful ene
8 t r i m e r so f
lipoamide reductasetransacetylase
+6 dimersof
dihydrolipoyl
dehydrogenase
+ 1 2 d i m e r so f
pyruvatedecarboxylase
o
,//
cH.c
si*ht{iiii
acetyl coA
(B)
Figure 2-79 The oxidation of pyruvate
to acetylCoA and COz.(A)The structure
of the pyruvatedehydrogenase
complex,
whichcontains60 polypeptidechains.
Thisis an exampleof a large
multienzymecomplexin which reaction
intermediatesare passeddirectlyfrom
one enzymeto another.In eucaryotic
cellsit is locatedin the mitochondrion.
(B)The reactionscarriedout by the
pyruvatedehydrogenase
complex.The
complexconvertspyruvateto acetylcoA
in the mitochondrial
matrix;NADHis also
producedin this reaction.A, B,and C are
the three enzymespyruvate
decarboxylase,Iipoam ide reductasetronsacetylose,and dihydrolipoyI
dehydrogenase,respectively.These
enzymesareillustrated
in (A);their
activities
arelinkedas shown.
97
HOWCELL5OBTAINENERGY
FROMFOOD
S u g a r sa n d
polysaccharides
Fats+fatty acids
CYTOSOL
Figure2-80 Pathwaysfor the production of acetyl CoAfrom sugarsand fats.The mitochondrionin
lt is
eucaryotic
cellsis the placewhereacetylCoAis producedfrom both typesof majorfood molecules.
occurand wheremostof its ATPis made.
thereforethe olacewheremostof the cell'soxidationreactions
in detailin Chapter14.
arediscussed
Thestructureand functionof mitochondria
extracted from the oxidation of both types of foodstuffs remains stored in the
acetyl CoA molecules that are produced by the two t)?es of reactions just
described. The citric acid cycle of reactions, in which the acetyl group in acetyl
CoA is oxidized to CO2and H2O,is therefore central to the energy metabolism of
aerobic organisms. In eucaryotesthese reactions all take place in mitochondria.
We should therefore not be surprised to discover that the mitochondrion is the
place where most of the ATP is produced in animal cells. In contrast, aerobic
bacteria carry out all of their reactions in a single compartment, the cytosol, and
it is here that the citric acid cycle takes place in these cells.
TheCitricAcidCycleGenerates
NADHby OxidizingAcetylGroups
to COz
In the nineteenth century, biologists noticed that in the absence of air (anaerobic conditions) cells produce lactic acid (for example, in muscle) or ethanol (for
example, in yeast), while in its presence (aerobic conditions) they consume 02
and produce CO2and H2O.Efforts to define the pathways of aerobic metabolism
Figure2-81 The oxidation of fatty acids
to acetyl CoA.(A)Electronmicrographof
a lipid droplet in the cytoplasm(top),and
the structureof fats (bottom).Fatsare
The glycerolportion,to
triacylglycerols.
whichthreefattyacidsarelinked
throughesterbonds,is shownherein
areinsolublein waterand form
blue.Fats
fat
largelipiddropletsin the specialized
in whichthey are
cells(calledadipocytes)
stored.(B)The fatty acid oxidationcycle.
The cycleis catalyzedby a seriesof four
Each
enzymesin the mitochondrion.
turn of the cycleshortensthe fattyacid
chain by two carbons(shownin red)and
generatesone moleculeof acetylCoA
and one moleculeeachof NADHand
The structureof FADHzis
FADHz.
presentedin Figure2-838.(4, courtesy
of Daniel5. Friend.)
(B)
fatty acyl CoA
Rr,-CH2-CH2-
CH2-C
hydrocarbontail
fatty acyl CoA
shortenedby .:fl,- CH2 - C
two carDons
//
o
\s-coA
/
C H'?\ S
-C
1pm
o
C-
acetylCoA
hydrirclrrbohtail
o
tlC
e s t e rb o n d
6it
Hzo
o
C-
@
//o
-c
i$tct-tr-cu: cH 's
hydrocarbon
tail
\?
R-CH2-C-CH2-C.
,,o
OHH
r$,-CHr- Ct l- C HH
hydrocarbontail
C
2
o
.5{6A
98
Chapter2:CellChemistryand Biosynthesis
eventually focused on the oxidation ofpyruvate and led in 1937to the discovery
of the citric acid cycle, also knoum as the tricarboxylic acid cycle or the Krebs
cycle.Thecitric acid cycle accounts for about two-thirds of the total oxidation of
carbon compounds in most cells, and its major end products are CO2and highenergy electrons in the form of NADH. The CO2 is released as a waste product,
while the high-energy electrons from NADH are passed to a membrane-bound
electron-transport chain (discussedin Chapter 14), eventually combining with
02 to produce H2O. Although the citric acid cycle itself does not use 02, it
requires 02 in order to proceed because there is no other efficient way for the
NADH to get rid of its electrons and thus regeneratethe NAD+ that is needed to
keep the cycle going.
The citric acid cycle takes place inside mitochondria in eucaryotic cells. It
results in the complete oxidation of the carbon atoms of the acetyl groups in
acetyl CoA, converting them into CO2. But the acetyl group is not oxidized
directly. Instead, this group is transferred from acetyl CoA to a larger, four-carbon molecule, oxaloacetate,to form the six-carbon tricarboxylic acid, citric acid,
for which the subsequent cycle of reactions is named. The citric acid molecule is
then gradually oxidized, allowing the energy of this oxidation to be harnessedto
produce energy-rich activated carrier molecules. The chain of eight reactions
forms a cycle because at the end the oxaloacetate is regenerated and enters a
new turn of the cycle, as shown in outline in Figure 2-82.
we have thus far discussed only one of the three types of activated carrier
molecules that are produced by the citric acid cycle, the NAD+-NADH pair (see
Figure 2-60). In addition to three molecules of NADH, each turn of the cycle also
produces one molecule of FADH2 (reduced flavin adenine dinucleotide) from
FAD and one molecule of the ribonucleotide GTP (guanosine triphosphate)
from GDP The structures of these two activated carrier molecules are illustrated
in Figure 2-83. GTP is a close relative of ATB and the transfer of its terminal
phosphate group to ADP produces one ATP molecule in each cycle. Like NADH,
FADHz is a carrier of high-energy electrons and hydrogen. As we discussshortly,
the energy that is stored in the readily transferred high-energy electrons of
NADH and FADH2will be utilized subsequently for Arp production through the
process of oxidatiue phosphorylation, the only step in the oxidative catabolism
of foodstuffs that directly requires gaseousoxygen (oz) from the atmosphere.
Panel 2-9 (pp. 122-123)presents the complete citric acid cycle.Water, rather
than molecular oxygen, supplies the extra oxygen atoms required to make co2
from the acetyl groups entering the citric acid cycle.As illustrated in the panel,
o
-t
- s-coA
Hrc
acetylCoA
2C
t
oxd toacelale
4C
+H*
/
I
4C
STEP1
*{
srEP2
-)l
u4lllil-,,/
./
V
srEP8
5C
\
srEP
3
r*E!E-f.-
co,
I
5C
N E TR E S U L O
T N ET U R NO FT H EC Y C L E
P R O D U C ETSH R E EN A D H ,O N EG T BA N D
O N EF A D H 2A, N D R E L E A S E
TS
W O M O L E C U L EOSF C O I
Figure2-82 Simpleoverviewof the
citric acid cycle.<TAGT>The reactionof
acetylcoA with oxaloacetatestartsthe
cycleby producingcitrate(citricacid).In
eachturn of the cycle,two molecules
of
CO2are producedas wasteproducts,plus
threemolecules
of NADH,one molecule
of GTP,
and one moleculeof FADH2.
The
numberof carbonatomsin each
intermediateis shown in a yellowbox.
Fordetails,see Panel2-9 (pp. 122-123).
guanine
o-
o
ll
c
2H-
???\'.,-i
2e
OH
ill
- N - - c- t - r n
c
llrtll
HrC-9
t-r-t--N-C\O
H3C-C
OH
OH
tl
,rN '' c,.
,rC'-N.'
n
CH,
I'
H-C -OH
I
H-C-OH
I
H-C-OH
(B)
three moleculesof water are split in each cycle,and the orygen atoms of some
of them are ultimately used to make CO2.
In addition to pyruvate and fatty acids, some amino acids pass from the
cytosolinto mitochondria, where they are alsoconvertedinto acetylCoAor one
of the other intermediatesof the citric acid cycle.Thus,in the eucaryoticcell,the
mitochondrion is the center toward which all energy-yieldingprocesseslead,
whether they begin with sugars,fats,or proteins.
Both the citric acid cycle and glycolysisalso function as starting points for
important biosynthetic reactionsby producing vital carbon-containing intermediates,such as oxaloacetateand a-ketoglutarate.Someof these substances
produced by catabolism are transferredback from the mitochondrion to the
cytosol,where they servein anabolicreactionsasprecursorsfor the synthesisof
many essentialmolecules,such as amino acids (Figure244).
H2C-O-
-O-
Figure2-83 The structuresof GTPand
FADHz.(A)GTPand GDPare close
relativesof ATPand ADP,respectively.
(B)FADH2is a carrierof hydrogensand
high-energyelectrons,like NADHand
NADPH.lt is shown here in its oxidized
form (FAD)with the hydrogen-canying
atoms h ighlightedin yellow.
nucleotides
glucose6-phosp nur. /
amrno
sugars
+
fructose
6-phosphate
'
glycolipids
glycoproteins
+
/\
I
+
+
+
serine
d i h y d r o x y a c e t o n+e
PhosPhate
3-phosphoglycerate
lipids
a m i n oa c i d s
pyrimidines
phosphoenolpyruvate
alanine .*-
.-
orrrlura"
andthe citric
Figure2-84Glycolysis
acidcycleprovidethe precursors
manyimportant
neededto synthesize
Theaminoacids,
biologicalmolecules.
andother
lipids,sugars,
nucleotides,
hereasproducts-in
molecules-shown
for the many
turnserveasthe precursors
the cell.Eachb/ack
macromoleculesof
arrowinthisdiagramdenotesa single
thered
reaction;
enzyme-catalyzed
with
arrowsgenerallyrepresentpathways
to produce
manystepsthatarerequired
products.
the indicated
100
Chapter2:CellChemistryand Biosynthesis
ElectronTransportDrivesthe Synthesis
of the Majorityof the ATP
in MostCells
Most chemical energy is released in the last step in the degradation of a food
molecule. In this final process the electron carriers NADH and FADH2 transfer
the electrons that they have gained when oxidizing other molecules to the electron-transport chain, which is embedded in the inner membrane of the mitochondrion (seeFigure 14-10).As the electrons pass along this long chain of specialized electron acceptor and donor molecules, they fall to successivelylower
energy states.The energy that the electrons release in this process pumps H+
ions (protons) across the membrane-from the inner mitochondrial compartment to the outside-generating a gradient of H+ ions (Figure 2-85). This gradient servesas a source of energy,being tapped like a battery to drive a variety of
energy-requiring reactions.The most prominent of these reactions is the generation of ATP by the phosphorylation of ADP
At the end of this series of electron transfers, the electrons are passed to
molecules of oxygen gas (Oz) that have diffused into the mitochondrion, which
simultaneously combine with protons (H*) from the surrounding solution to
produce water molecules. The electrons have now reached their lowest energy
Ievel, and therefore all the available energy has been extracted from the oxidized
food molecule. This process, termed oxidative phosphorylation (Figure 2-86),
also occurs in the plasma membrane of bacteria. As one of the most remarkable
achievements of cell evolution, it is a central topic of Chapter 14.
In total, the complete oxidation of a molecule of glucose to H2O and CO2is
used by the cell to produce about 30 molecules of ATP In contrast, only 2
molecules of ATP are produced per molecule of glucose by glycolysis alone.
AminoAcidsand Nucleotides
ArePartof the NitrogenCycle
So far we have concentrated mainly on carbohydrate metabolism and have not
yet considered the metabolism of nitrogen or sulfur. These two elements are
important constituents of biological macromolecules. Nitrogen and sulfur
atoms pass from compound to compound and between organisms and their
environment in a seriesof reversible cycles.
Although molecular nitrogen is abundant in the Earth's atmosphere, nitrogen is chemically unreactive as a gas.Only a few living speciesare able to incorporate it into organic molecules, a process called nitrogen fixation. Nitrogen
fixation occurs in certain microorganisms and by some geophysical processes,
such as lightning discharge.It is essentialto the biosphere as a whole, for without it life could not exist on this planet. Only a small fraction of the nitrogenous
compounds in today's organisms, however, is due to fresh products of nitrogen
fixation from the atmosphere. Most organic nitrogen has been in circulation for
pyruvatefrom
gl y c o l y s i s
I
Coz
I
N A D Hf r o m
glycolysis
I
Oz
I
pyruvate
:*Hl * P
II
t
acetyl CoA
ctTRtc
ACID
CYCLE
CoA
MITOCHONDRION
2eI
--
u^rDAilvE
PHOSPHORYLATION
t
Hzo
Figure2-85 The generationof an
H+gradientacrossa membraneby
electron-transportreactions.
A high-energy
electron(derived,
for
example,from the oxidationof a
metabolite)
is passedsequentially
by
carriers
A, B,and C to a lowerenergy
state.In this diagramcarrierB is arranged
in the membranein sucha way that it
takesup H+from one sideand releases
it
to the otherasthe electronpasses.
The
resultis an H+gradient.As discussed
in
Chapter14,this gradientis an important
form of energythat is harnessed
by other
membraneoroteinsto drivethe
formationof ATP.
Figure2-86 Thefinal stagesof oxidation
of food molecules.Molecules
of NADH
(FADHz
and FADH2
is not shown)are
producedby the citricacidcycle.These
activatedcarriers
donatehigh-energy
electrons
that areeventuallyusedto
reduceoxygengasto water.
A majorportionof the energyreleased
duringthe transferof theseelectrons
alongan electron-transfer
chainin the
mitochondrial
innermembrane(or in the
plasmamembraneof bacteria)
is
harnessed
to drivethe synthesis
of ATPhencethe nameoxidative
(discussed
phosphorylation
in Chapter14).
101
HOW CELLSOBTAINENERGY
FROMFOOD
some time, passing from one living organism to another. Thus present-day
nitrogen-fixing reactions can be said to perform a "topping-up" function for the
total nitrogen supply.
Vertebrates receive virtually all of their nitrogen from their dietary intake of
proteins and nucleic acids. In the body these macromolecules are broken down
to amino acids and the components of nucleotides, and the nitrogen they contain is used to produce new proteins and nucleic acids-or utilized to make
other molecules. About half of the 20 amino acids found in proteins are essential amino acids for vertebrates (Figure 2-87), which means that they cannot be
synthesizedfrom other ingredients of the diet. The others can be so synthesized,
using a variety of raw materials, including intermediates of the citric acid cycle
as described previously.The essentialamino acids are made by plants and other
organisms, usually by long and energeticallyexpensivepathways that have been
lost in the course of vertebrate evolution. Roshanl(eab 02l-66950639
The nucleotides needed to make RNA and DNA can be synthesized using
specializedbiosynthetic pathways. All of the nitrogens in the purine and pyrimidine bases (as well as some of the carbons) are derived from the plentiful
amino acids glutamine, aspartic acid, and glycine, whereas the ribose and
deoxyribose sugars are derived from glucose. There are no "essential
nucleotides" that must be provided in the diet.
Amino acids not used in biosynthesis can be oxidized to generatemetabolic
energy.Most of their carbon and hydrogen atoms eventually form COz or HzO,
whereas their nitrogen atoms are shuttled through various forms and eventually
appear as urea, which is excreted.Each amino acid is processeddifferently, and
a whole constellation of enzymatic reactions exists for their catabolism.
Sulfur is abundant on Earth in its most oxidized form, sulfate (SOaz-).To convert it to forms useful for life, sulfate must be reduced to sulfide (S2-),the oxidation state of sulfur required for the synthesis of essential biological molecules.
These molecules include the amino acids methionine and cysteine,coenzymeA
(seeFigure 2-62), and the iron-sulfur centers essentialfor electron transport (see
Figure 14-23). The process begins in bacteria, fungi, and plants, where a special
group of enzymes use ATP and reducing power to create a sulfate assimilation
pathway. Humans and other animals cannot reduce sulfate and must therefore
acquire the sulfur they need for their metabolism in the food that they eat.
Metabolismls Organized
and Regulated
One gets a sense of the intricacy of a cell as a chemical machine from the relation of glycolysis and the citric acid cycle to the other metabolic pathways
sketched out in Figure 2-88. This type of chart, which was used earlier in this
chapter to introduce metabolism, represents only some of the enzymatic pathways in a cell. It is obvious that our discussion of cell metabolism has dealt with
only a tiny fraction of cellular chemistry.
All these reactions occur in a cell that is less than 0.1 mm in diameter, and
each requires a different enzyme. As is clear from Figure 2-88, the same
molecule can often be part of many different pathways. Pyruvate,for example, is
a substrate for half a dozen or more different enzymes,each of which modifies it
chemically in a different way. One enzyme converts pyruvate to acetyl CoA,
another to oxaloacetate;a third enzyrne changespyruvate to the amino acid alanine, a fourth to lactate, and so on. All of these different pathways compete for
the same pyruvate molecule, and similar competitions for thousands of other
small molecules go on at the same time.
The situation is further complicated in a multicellular organism. Different
cell tlpes will in general require somewhat different sets of enzymes. And different tissues make distinct contributions to the chemistry of the organism as a
whole. In addition to differences in specialized products such as hormones or
antibodies, there are significant differences in the "common" metabolic pathways among various types of cells in the same organism.
Although virtually all cells contain the enzymes of glycolysis, the citric acid
cycle, lipid synthesis and breakdown, and amino acid metabolism, the levels of
THEESSENTIAL
AMINOACIDS
Figure?-87The nine essentialamino
by
acids.Thesecannotbe synthesized
humancellsand so mustbe suppliedin
the diet.
102
Chapter2:CellChemistryand Biosynthesis
Figure2-88 Glycolysisand the citric
acid cycleare at the center of
metabolism.Some500 metabolic
reactions
of a typicalcellareshown
with the reactions
schematically
of
glycolysis
and the citricacidcyclein red.
Otherreactions
eitherleadinto these
two centralpathways-delivering
small
molecules
to be catabolized
with
productionof energy-or they lead
outwardand therebysupplycarbon
compoundsfor the purposeof
biosynthesis.
these processes required in different tissues are not the same. For example,
nerve cells, which are probably the most fastidious cells in the body, maintain
almost no reservesof glycogen or fatty acids and rely almost entirely on a constant supply of glucose from the bloodstream. In contrast, liver cells supply glucose to actively contracting muscle cells and recycle the lactic acid produced by
muscle cells back into glucose.All types of cells have their distinctive metabolic
traits, and they cooperate extensivelyin the normal state, as well as in response
to stressand starvation. One might think that the whole system would need to
be so finely balanced that any minor upset, such as a temporary change in
dietary intake, would be disastrous.
In fact, the metabolic balance of a cell is amazingly stable.\.A/henever
the balance is perturbed, the cell reacts so as to restore the initial state. The cell can
adapt and continue to function during starvation or disease.Mutations of many
kinds can damage or even eliminate particular reaction pathways, and yet-provided that certain minimum requirements are met-the cell survives.It does so
because an elaborate network of control mechanismsregulates and coordinates
the rates of all of its reactions.These controls rest, ultimately, on the remarkable
abilities of proteins to change their shape and their chemistry in response to
changesin their immediate environment. The principles that underlie how large
molecules such as proteins are built and the chemistry behind their regulation
will be our next concern.
END-OF-CHAPTER
PROBLEMS
103
Sum mar y
Glucoseand otherfood moleculesare broken down by controlled stepwiseoxidation to
prouide chemical energy in the form of ATP and NADH. Thereare three main setsof
reactions that act in series-the products of each being the starting material for the
next:glycolysis(which occursin the cytosol),the citric acid cycle(in the mitochondrial
matrix), and oxidatiue phosphorylation (on the inner mitochondrial membrane).The
intermediate products of glycolysk and the citric acid cycleare usedboth as sourcesof
metabolic energyand to produce many of the small moleculesusedas the raw materials for biosynthesis.Cellsstore sugar moleculesas glycogenin animals and starch in
plants; both plants and animals also usefats extensiuelyas a food store.Thesestorage
materials in turn serueas a major sourceof food for humans, along with the proteins
that comprisethe majority of the dry massof most of the cellsin thefoods we eet.
PROBLEMS
TableQ2-1 Radioactiveisotopesand someof their
properties(Problem2-12).
Whichstatementsare true?Explainwhy or why not.
2-1
Of the original radioactivityin a sample,only about
1/ 1000will remain after 10 half-lives.
2-2
A 10-BM solution of HCI has a pH of B.
2-3
Most of the interactions between macromolecules
could be mediatedjust aswell by covalentbonds as by noncovalentbonds.
2-4
Animals and plants use oxidation to extract energy
from food molecules.
2-5
If an oxidation occurs in a reaction, it must be
accompaniedby a reduction.
2-6
Linking the energetically unfavorable reaction A -+ B
to a second,favorablereaction B -+ C will shift the equilibrium constantfor the first reaction.
2-7
The criterion for whether a reaction proceedsspontaneouslyis AG not AGo,becauseAG takesinto accountthe
concentrationsof the substratesand products.
2-8
Becauseglycolysis is only a prelude to the oxidation
of glucosein mitochondria, which yields l5-fold more AIB
glycolysisis not really important for human cells.
2-9
The oxygen consumed during the oxidation of glucosein animal cellsis returned as COzto the atmosphere.
Discussthe following problems.
2- 10 The organicchemistryof living cellsis said to be special for two teasons:it occurs in an aqueous environment
and it accomplishessome very complex reactions.But do
you suppose it is really all that much different from the
organic chemistry carried out in the top laboratoriesin the
world? \A/tryor why not?
2-11 The molecular weight of ethanol (CHgCHzOH)is 46
and its density is 0.789g/cm3.
A. \A4ratis the molarity of ethanol in beer that is 5%
ethanol by volume? [Alcohol content of beer varies from
about 4Vo(lite beer) to B% (stout beer).1
B. The legal limit for a driver's blood alcohol content
varies,but 80 mg of ethanol per 100 mL of blood (usually
14c
36
35s
32P
B particle
B particle
B particle
B particle
5730years
12.3years
87.4days
14.3days
0.062
29
1490
9120
referredto as a blood alcohollevel of 0.08)is t)?ical. \ /hat is
the molarity of ethanol in a person at this legal limit?
t. How many l2-oz (355-mL)bottles of 5% beer could a
70-kgpersondrink and remain under the legallimit? A 70-kg
person contains about 40 liters of water. Ignore the
metabolism of ethanol, and assumethat the water content
of the person remains constant.
D. Ethanol is metabolizedat a constant rate of about 120
mg per hour per kg body weight, regardlessof its concentration. If a 70-kg person were at twice the legal limit (160
mg/f 00 mL), how long would it take for their blood alcohol
level to fall below the legal limit?
2-12 Specificactivity refers to the amount of radioactivity per unit amount of substance,usually in biology
expressedon a molar basis,for example,as Ci/mmol. [One
curie (Ci) corresponds to 2.22 x 1012disintegrations per
minute (dpm;.1 As apparent in Table Q2-1, which lists
properties of four isotopes commonly used in biology,
there is an inverserelationship between maximum specific
activity and half-life. Do you suppose this is just a coincidence or is there an underlying reason? Explain your
answer.
2-13 By a convenientcoincidencethe ion product ofwater,
K- = lH+l[OH-],is a nice round number: 1.0x 10-14M2.
A. \AIhyis a solution at pH 7.0 said to be neutral?
B. \A/tratis the H+ concentrationand pH of a I mM solution
of NaOH?
C. If the pH of a solution is 5.0,what is the concentration
of OH- ions?
2-14 Suggesta rank order for the pKvalues (from lowestto
highest)for the carboxylgroup on the aspartateside chain
104
Chapter2:CellChemistryand Biosynthesis
in the following environments in a protein. Explain your
ranking.
1. An aspartateside chain on the surfaceof a protein with
no other ionizable groupsnearby.
2. An aspartateside chain buried in a hydrophobic pocket
on the surlaceof a protein.
3. An aspartateside chain in a hydrophobic pocket adjacent to a glutamateside chain.
4. An aspartateside chain in a hydrophobic pocket adjacent to a lysine side chain.
2-15 A histidine side chain is knol,rrnto play an important
role in the cataly.ticmechanismof an enz).ryne;
however,it is
not clear whether histidine is required in its protonated
(charged)or unprotonated (uncharged)state.To answerthis
question you measureenzyrneactivity over a range of pH,
with the resultssho\^Trin Figure Q2-1. \Ahich form of histidine is required for enz)ryneactivity?
FigureQ2-1 Enzyme
activityasa functionof
pH(Problem
2-15).
c
f
E
o
E
o
,r_ ,_a,
,
!
C- O
FigureQ2-2 Threemolecules
that illustrate
the
sevenmostcommonfunctionalgroupsin
biology(Problem2-17).1,3-Bisphosphoglycerate
and pyruvateareintermediates
in glycolysis
and
cysteineis an aminoacid.
HO-CH
1 , 3 - b i s p h o s p h o g l y c e r a t e pyruvare
SH
cyslerne
Calculatethe instantaneousvelocity of a water molecule
(molecularmass= 1Bdaltons),a glucosemolecule (molecular mass = lB0 daltons),and a myoglobin molecule (molecular mass = 15,000daltons) at 37"C. Just for fun, convert
thesenumbers into kilometers/hour.Beforeyou do any calculations,try to guesswhether the moleculesare moving at
a slow crawl (<1km/hr), an easywalk (5 km/hr), or a recordsettingsprint (40km/hr).
2-19 Polymerization of tubulin subunits into microtubules occurs with an increasein the orderlinessof the
subunits (Figure Q2-3). Yet tubulin polymerization occurs
with an increasein entropy (decreasein order). How can
that be?
o
5
7
2-16 During an all-out sprint, musclesmetabolizeglucose
anaerobically,producing a high concentrationoflactic acid,
which lowers the pH of the blood and of the cytosol and
contributes to the fatigue sprinters experiencewell before
their fuel reservesare exhausted.The main blood buffer
againstpH changesis the bicarbonate/CO2system.
PKr=
PK2=
2.3
38
CO2+CO2 +:
+H*
H2CO3
(gas) (dissolved)
=
PtrG
lo"
+ HCO3-JsH*
POLYMERIZATION
.+
FigureQ2-3Polymerization
of tubulinsubunits
intoa microtubule
(Problem
2-19).The
fatesof onesubunit(shoded)
anditsassociated
(smallspheres)
watermolecules
areshown.
+ CO32-
To improve their performance,would you advisesprinters to
hold their breath or to breatherapidly for a minute immediately before the race?Explain your answer.
2-17 The three molecules in Figure Q2-2 contain the
seven most common reactive groups in biology. Most
moleculesin the cell are built from thesefunctional groups.
Indicate and name the functional groups in these
molecules.
2-18 "Diffusion" sounds slow-and over everyday distancesit is-but on the scaleof a cell it is very fast.The average instantaneousvelocity of a particle in solution, that is,
the velocity betweencollisions,rs
y = (kTlm)h
where k= 1.38x 10-16g cmzlKsecz,T = temperaturein K
(37'Cis 310 K), m = massin g/molecule.
2-2O A 70-kg adult human (154lb) could meet his or her
entire energyneedsfor one day by eating3 moles of glucose
(5a0g). (We don't recommend this.) Each molecule of glucose generates30 AIP when it is oxidizedto CO2.The concentration of AIP is maintained in cellsat about 2 mM, and
a 70-kg adult has about 25 liters of intracellularfluid. Given
that the ATPconcentrationremains constantin cells,calculate how many times per day,on average,eachAIP molecule
in the body is hydrolyzedand reslmthesized.
2-21 Assuming that there are 5 x 1013cells in the human
body and that AIP is turning over at a rate of 10eAIP per
minute in each cell, how many watts is the human body
consuming?(A watt is a joule per second,and there are 4.18
joules/calorie.) Assume that hydrolysis of AIP yields 12
kcal/mole.
2-22 Does a SnickersrMcandy bar (65 g, 325 kcal) provide
enough energyto climb from Zermatt (elevation1660m) to
the top of the Matterhorn (4478m, Figure Q2-4), or might
END-OF-CHAPTER
PROBLEMS
105
FigureQ2-4 The
Matterhorn(Problem
2-22).(Courtesyof
ZermattTourism.)
IAI-^O
fert
a\l-CHr-CH2-CH2-CH2-CH2-CH2-CH2-C
.o,,no'Jrna
ll
\t'
-l
cH2-C
excreted
compound
tt'
work (D = mass (kg)x g (m/sec2;x height gained (m)
where gis accelerationdue to gravity (9.8m/sec2).Onejoule
is 1 kg m2lsec2and there are 4.lB kf per kcal.
\Alhatassumptionsmade here will greatlyunderestimate
how much candy you need?
2-23 At first glance, fermentation of pyruvate to lactate
appearsto be an optional add-on reaction to glycolysis.After
all, could cells growing in the absenceof oxygen not simply
discard pyruvate as a waste product? In the absenceof fermentation, which products derived from glycolysis would
accumulate in cells under anaerobic conditions? Could the
metabolism of glucosevia the glycoll'tic pathway continue in
the absenceof oxygenin cells that cannot carry out fermentation?\.A/hyor why not?
2-24 In the absenceof oxygen,cellsconsumeglucoseat a
high, steadyrate.When oxygenis added,glucoseconsumption drops precipitouslyand is then maintained at the lower
rate.\.Vhyis glucoseconsumedat a high rate in the absence
of oxygenand at a low rate in its presence?
2-25 The liver provides glucose to the rest of the body
betweenmeals.It doesso by breakingdown glycogen,forming glucose6-phosphatein the penultimate step.Glucose6phosphateis convertedto glucoseby splitting offthe phosphate (AG' = -3.3 kcal/mole).\Mhydo you supposethe liver
removesthe phosphateby hydrolysis,rather than reversing
the reactionby which glucose6-phosphate(G6P)is formed
from glucose (glucose + AIP -+ G6P + ADB AG' = -4.0
kcal/mole)?By reversingthis reactionthe liver could generate both glucoseand AIP
//o
\o_
phenylacetate
o
*^^
n'\-cur-cH2-cH2-cH2-cH2-cH2-c
comoound ll
\at
you need to stop at Hdrnli Hut (3260m) to eat another one?
Imagine that you and your gear have a mass of 75 kg, and
that all of your work is done against gravity (that is, you are
just climbing straight up). Rememberfrom your introductory physicscoursethat
-|
o-
seven-carbonchain
o
excreted ri\.
com
-l
' o o u n dl l
\4.
o
benzoate
fattyacid
to analyze
labeling
experiment
FigureQ2-5Theoriginal
(Problem
of an
derivatives
2-26).( ) Fedandexcreted
oxidation
derivatives
of an
fattyacidchain.(B)Fedandexcreted
even-number
fattyacidchain.
odd-number
Can you explainthe reasoningthat led him to concludethat
two-carbon fragments, as opposed to any other number,
were removed, and that degradation was from the carboxylic
acid end, as opposedto the other end?
2-27 Pathways for synthesis of amino acids in microorganismswere worked out in part by cross-feedingexperiments among mutant organisms that were defective for
individual steps in the pathway. Results of cross-feeding
experiments for three mutants defective in the trlptophan
TrpIl, and TrpE-are sholrryt in Figure
parhway-TrpF,
Q2-6. The mutants were streaked on a Petri dish and
allowed to grow briefly in the presence of a very small
amount of tryptophan, producing three pale streaks.As
shown, heavier growth was observed at points where some
streakswere close to other streaks.These spots of heavier
growth indicate that one mutant can cross-feed(supply an
intermediate)to the other one.
From the pattern of cross-feedingshor,trrin Figure Q2-6,
deducethe order ofthe stepscontrolled by the products of
the TrpB, TrpD, and TrpE genes.Explain your reasoning.
C R O S S - F E E D IRNEGS U L T
TrpD-
TrpE-
2-26 In 1904Franz Knoop performed what was probably
the first successfullabeling experiment to study metabolic
pathways. He fed many different fatty acids labeled with a
terminal benzene ring to dogs and analyzedtheir urine for
excreted benzene derivatives.\Alheneverthe fatty acid had
an even number of carbon atoms, phenylacetate was
excreted (Figure Q2-5A). lVhenever the fatty acid had an
odd number of carbon atoms, benzoatewas excreted(Figure Q2-58).
From theseexperimentsKnoop deducedthat oxidation of
fatty acidsto CO2and H2Oinvolved the removalof two-carbon fragments from the carboxylic acid end of the chain.
o-
eight-carbonchain
TrDB'
using
FigureQ2-6 Definingthe pathwayfor tryptophansynthesis
(Problem2-27).Results
of a crossexperiments
cross-feeding
feedingexperimentamongmutantsdefectivefor stepsin the
tryptophan biosyntheticpathway.Darkoreason the Petridish show
regionsof cellgrowth.
CARBONSKELETONS
Carbonhasa unique role in the cell becauseof its
abilityto form strongcovalentbondswith other
carbonatoms.Thuscarbonatomscan ioin to form
chains.
\/
,/
\/
CCCC
"
"
\
\
_ r,,
LLLL
/\
\/
\/
/\
^,..
"\
/\
\,,
\/
-t\
-
-\
^,r-
or branchedtrees
^,,.
/\
also written as
C-C-
-c/
,21
alsowritten
as
./c-
\a /\
X
written
arso
r, al-)
COVALENTBONDS
HYDROCARBONS
A covalent bond forms when two atoms come very close
together and shareone or more of their electrons.In a single
bond one electronfrom eachof the two atoms is shared;in
a double bond a total of four electronsare shared.
Eachatom forms a fixed number of covalentbonds in a
definedspatialarrangement.For example,carbonforms four
singlebondsarrangedtetrahedrally,whereasnitrogenforms
three singlebondsand oxygenforms two singlebondsarranged
as shown below.
Carbonand hydrogencombine
together to make stable
compounds(or chemicalgroups)
calledhydrocarbons.
Theseare
nonpolar,do not form
hydrogenbonds,and are
generallyinsolublein water.
Atomsjoined by two
or more covalentbonds
cannot rotate freely
around the bond axis.
This restriction is a
major influenceon the
three-dimensional
shaoe
of many macromolecules.
HrC.
CH,
ALTERNATING
DOUBLEBONDS
The carbonchain can includedouble
bonds.lf theseare on alternatecarbon
atoms,the bonding electronsmove
within the molecule,stabilizingthe
structureby a phenomenoncalled
reS0nance.
HrC.
Alternatingdouble bonds in a ring
can generate a very stable structure.
CHt
HrC.
CH,
HrC.
CH,
H,C
CH,
Hzc.
the truth is sbmewhereberween
these two structures
9H,
H:C
oftenwritten.,
O
part of the hydrocarbon"tail"
of a fatty acid molecule
C_OCHEMICAL
GROUPS
GROUPS
C-N CHEMICAL
Many biologicalcompoundscontaina carbon
bondedto an oxygen.For example,
Aminesand amidesare two important examplesof
compoundscontaininga carbonlinkedto a nitrogen.
Aminesin water combinewith an H+ ion to become
positivelycharged.
lrHt,H
_ ct_/ l(/
+u* *
_q_n_H*
r\nr\H
Amidesare formed by combiningan acidand an
amine.Unlikeamines,amidesare unchargedin water.
An exampleisthe peptide bond that joins amino acids
in a orotein.
o
-c/
The -COOHis calleda
carboxylgroup. In water
this losesan H+ion to
become-COO-.
esters
Estersare formed by a condensationreaction
betweenacid and an alcohol.
'.Or,O
_[_r/+Ho_l___Lr/
I'
acid
\
|
oH
alcohol
|
\
l+H20
o-c-
ester
I
acid
\o"
+ H"N-J- I
amtne
Nitrogenalsooccursin severalring compounds,including
important constituentsof nucleicacids:purinesand pyrimidines.
)n'
^4rtn
I
o/"C
(a pyrimidine)
ll cytosine
tN-C-H
H
group
the sulfhydryl
group.In the aminoacidcysteine
iscalleda sulfhydryl
form,-t-Sn
mayexistin the reduced
SULFHYDRYL
GROUP
lrl
form, -C-S-S-Cor more rarelyin an oxidized,cross-bridging
PHOSPHATES
Inorganicphosphateis a stableion formed from
phosphoricacid,H3PO4.
lt is often written as Pi.
Phosphateesterscan form between a phosphateand a free hydroxyl group.
Phosphategroups are often attached to proteins in this way.
carboxylgroup, or two or more phosphategroups,givesan acid anhydride.
Hzo
l*
T
Hzo
also written as
high-energyacyl phosphate
bond (carboxylic-phosphoric
acidanhydride)found in
some metabolites
-t_
o
^,
o-P
Hzo
L
T
Hzo
phosphoanhydride-ahighenergybond found in
moleculessuchas ATP
-o
alsowritten as
WATER
WATERSTRUCTURE
Two atoms, connected by a covalent bond, may exert different attractionsfor
the electronsof the bond. In suchcasesthe bond is polar,with one end
slightlynegativelycharged(6-) and the other slightlypositivelycharged(6+).
Moleculesof water join together transiently
in a hydrogen-bondedlattice.Evenat 37oC,
15o/o
oI the water moleculesare joined to
four othersin a short-livedassemblvknown
as a "flickeringcluster."
.:tt:'i
l,::,:
electronegative
regron
Although a water moleculehasan overallneutralcharge(havingthe same
numberof electronsand protons),the electronsare asymmetrically
distributeo,
which makesthe moleculepolar.The oxygennucleusdrawselectronsaway
from the hydrogennuclei,leavingthesenucleiwith a smallnet positivecharge.
The excessof electron density on the oxygen atom createsweakly negative
regionsat the other two cornersof an imaginarytetrahedron.
H Y D R O G EB
NO N D S
Because
they are polarized,two
adjacentH2Omoleculescan form
a linkageknown as a hydrogen
bond. Hydrogenbondshave
only about 1/20the strength
of a covalentbond.
Hydrogenbondsare strongestwhen
the three atoms lie in a straightline.
6-
H
""!,,,
l,u
H
The cohesivenature of water is
responsible
for many of its unusual
properties,suchas high surfacetension,
specificheat, and heat of vaporization.
bond lengths
hydrogenbond
0 . 2 7n m
Q rrrrrrrrrrrrrrrrrrr
H -Oo-.tor'tt
hydrogen bond
covalentbond
H Y D R O P H I LM
I CO L E C U L E S
H Y D R O P H O BM
I CO L E C U L E S
Substances
that dissolvereadilyin water are termed hydrophilic.Theyare
composedof ionsor polar moleculesthat attractwater moleculesthrough
electricalchargeeffects.Water moleculessurroundeachion or polar molecule
on the surfaceof a solidsubstanceand carrvit into solution.
Moleculesthat containa preponderance
of nonpolarbondsare usuallyinsolublein
water and are termed hydrophobic.Thisis
true, especially,
of hydrocarbons,
which
containmany C-H bonds.Water molecules
are not attractedto suchmoleculesand so
have little tendencyto surroundthem and
carrythem into solution.
H
HH
\/
C
.\
\H
-C
lonicsubstances
suchas sodiumchloride
dissolvebecausewater moleculesare
attracted to the positive(Na+)or negative
(Cl) chargeof eachion.
H
/
Polarsubstances
suchas urea
dissolvebecausetheir molecules
form hydrogenbondswith the
surroundingwater molecules.
H
IHH
o\ . H
C
,/\
WATERAS A SOLVENT
Many substances,
suchas householdsugar,dissolvein water. That is,their
moleculesseparatefrom eachother, eachbecomingsurroundedby water molecules.
in a
When a substancedissolves
liquid,the mixture is termed a solution.
The dissolvedsubstance(in this case
sugar)isthe solute,and the liquid that
doesthe dissolving(in this casewater)
is the solvent.Water is an excellent
solvent for many substancesbecause
of its polar bonds.
sugarcrystal
s u g a rm o l e c u l e
ACIDS
ION EXCHANGE
HYDROGEN
Substances
that releasehydrogenionsinto solution
a r e c a l l e da c i d s .
Positivelychargedhydrogenions(H+)can spontaneously
move from one water moleculeto another,therebycreating
two ionic species.
HH
HCI-+Cf
hydrochloric
acid
(strongacid)
hydrogen
ion
ion
chloride
oilililrH-o
Many of the acidsimportant in the cellare only partially
dissociated,
and they are thereforeweak acids-for example,
the carboxylgroup (-COOH),which dissociates
to give a
hydrogenion in solution
,/
n..P, +oo/
-
H
hydroxyl ion
hydronium ion
(water acting as (water acting as
a weak acid)
a weak base)
oftenwrittenas: Hro i
H*
+
-c/
\
H* + oHhydroxyl
nrl:Xn"n
Note that this is a reversible reaction.
hydrogenionsare
israpidlyreversible,
Since
the process
Purewater
shuttlingbetweenwatermolecules.
continually
of hydrogenionsand
concentration
a steady-state
contains
hydroxylions(both10-'M).
pH
BASES
( w e a ka c i d )
pH
The acidityof a
solutionis defined
by the concentration
of H+ ions it possesses.
Forconveniencewe
usethe pH scale,where
1 02
1 03
pH = log,o[H+]
101
1
2
NH:+H*-NHo*
ion
ammonia hydrogen
ion
ammonium
5
1o-4
A
1o-s
5
10-6
6
1o-7
1 08
1 0e
7
8
For pure water
1 o1 0
10
[H+] = 10-7moles/liter
1o-11
1 01 2
11
1013
1014
that reducethe number of hydrogenions in
Substances
solutionare calledbases.Somebases,suchas ammonia,
combinedirectlywith hydrogenions.
9
12
II
14
Other bases,suchas sodiumhydroxide,reducethe number of
H* ionsindirectly,by making OH- ionsthat then combine
directlywith H' ionsto make H2O.
NaOH
s o d i u mh y d r o x i d e
(strong base)
Nasodium
ion
Many basesfound in cellsare partiallydissociatedand are termed
weak bases.Thisis true of compoundsthat containan amino
group (-NH2),which has a weak tendency to reversiblyaccept
an H' ion from water, increasingthe quantity of free OH- ions.
-NHz+H*--NH:*
WEAKCHEMICAL
BONDS
VAN DERWAALSATTRACTIONS
Organicmoleculescan interactwith other moleculesthrough three
types of short-rangeattractive forces known as noncovalentbonds:
van der Waals attractions,electrostaticattractions,and hydrogen
bonds.The repulsionof hydrophobicgroupsfrom water is also
importantfor ordering biologicalmacromolecules.
lf two atoms are too closetogether they repel each other
very strongly. For this reason,an atom can often be
treated as a soherewith a fixed radius.The characteristic
"size" lor eachatom is specifiedby a uniquevan der
Waals radius.The contact distancebetween any two
noncovalentlybondedatoms isthe sum of their van der
Waalsradii.
&
0 . 1 5n m
radius
Weak chemicalbondshave lessthan 1/20the strengthof a strong
covalentbond. Theyare strong enough to providetight binding
only when many of them are formed simultaneously.
H Y D R O G EB
NO N D S
As already describedfor water (seePanel2-2),
hydrogenbondsform when a hydrogenatom is
"sandwiched
" betweentwo electron-attracting
atoms
(usuallyoxygenor nitrogen).
Hydrogenbondsare strongestwhen the three atomsare
i n a s t r a i g h tl i n e :
to-"
nnnro\
N-H
I
I
lt
R-C-H
R-C-H
I
c : o l l l l l l l lH
l t- N
lll
i l i l i l i l i lH - N
FFC-R
I
I
Two bases,G and C, hydrogen-bondedin DNA or RNA.
Fig
H.
N-Hililill
\'
C-C
\\\
.H-. L.
: ///
.NilililililtH\/
N-C.
,/
\\'bllllllltn-N'
,,/
tH
tl
0 . 1 5n m
single-bonded
caroonS
HYDROGEN
BONDSIN WATER
Amino acidsin polypeptidechainshydrogen-bonded
together.
c:o
At very short distancesany two atoms show a weak
bonding interactiondue to their fluctuatingelectrical
charges.The two atomswill be attractedto eachother
in this way until the distancebetweentheir nucleiis
approximatelyequalto the sum of their van der Waals
radii.Although they are individuallyvery weak, van der
Waalsattractionscan becomeimoortant when two
macromolecularsurfacesfit very closetogether,
becausemany atomsare involved.
Note that when two atomsform a covalentbond, the
centersof the two atoms (the two atomic nuclei)are
much closertogether than the sum of the two van der
W a a l sr a d i i .T h u s .
|||||/
Examplesin macromolecules:
I
0 . 1 4n m
radius
Any moleculesthat can form hydrogenbondsto eachother
can alternativelyform hydrogenbondsto water molecules.
Becauseof this competitionwith water molecules,
the
hydrogenbondsformed betweentwo moleculesdissolved
in water are relativelyweak.
HYDROPHOBIC
FORCES
Water forces hydrophobic groups together,
becausedoing so minimizestheir disruptive
effects on the hydrogen-bondedwater
network. Hydrophobicgroupsheld
together in this way are sometimessaid
to be held together by "hydrophobic
bonds,"eventhough the apparentattraction
is actuallycausedby a repulsionfrom the
water.
IN
ATTRACTIONS
ELECTROSTATIC
A Q U E O UsSO L U T I O N S
Chargedgroupsare shieldedby their
interactionswith water molecules.
Electrostaticattractions are therefore
quite weak in water.
Attractive forces occur both between fully charged
groups(ionicbond) and betweenthe partiallycharged
groupson polar molecules.
Similarly,ions in solutioncan clusteraround
chargedgroupsand further weaken
these attractions.
CI
o
o
,.O
-C
//
Na
Na+
1mm
I
rr.t
,rNa
@
cl-
H
H -.-N -
\],
CI\
[/
In the absenceof water, electrostaticforces are very strong.
They are responsible
for the strengthof suchmineralsas
marbleand agate,and for crystalformation in common
table salt.NaCl.
a crystalof
salt,NaCl
Cl,
^Na
\
The force of attraction between the two charges,6+
and 5-, falls off rapidlyasthe distancebetweenthe
chargesincreases.
.H
H.
N
6+
'.,o.
H
-S
ELECTROSTATIC
ATTRACTIONS
I
H
CI
al\
Despitebeing weakenedby water and salt,
electrostaticattractions are very important in
biologicalsystems.For example,an enzymethat
bindsa positivelychargedsubstratewill often
have a negativelychargedamino acidsidechain
at the appropriateplace.
MONOSACCHARIDES
Monosaccharides
usuallyhavethe generalformula (CH2O)',where n can be 3, 4, 5, 6,7, or 8, and havetwo or more hydroxylgroups.
Theyeither containan aldehydegroup ( -c(l ) and are calledaldosesor a ketone group ( ).:o ) and are calledketoses.
3-carbon(TRIOSES)
S-carbon(PENTOSES)
6-carbon(HEXOSES)
H,O
\^//
L
H,O
ta/
I
I-OH
I
H-C -OH
I
H-C -OH
I
H-C -OH
I
g l y c er a1d e h y d e
nbose
H-C
U
o
/ro
"t
H-C
c'
I-OH
I-OH
H-C
H
H-C
{-OH
I
HO-C-H
I
H-C -OH
H-C
H-C
H
I-OH
I-OH
I
H
g Iu c o s e
H
H
I
I
I
H-C -OH
I
H-C -OH
I
H-C -OH
I
I
I
c:o
H-C -OH
H-C -OH
U
u
Y
H
I
H-C -OH
I
c*-o
I-OH
H-C
I
H
H
ribulose
d i hydroxyacetone
I
HO-C-H
I
H-C -OH
I
H-C -OH
H-C
I -OH
I
H
fructose
RINGFORMATION
ISOMERS
In aqueoussolution,the aldehydeor ketone group of a sugar
moleculetendsto reactwith a hydroxylgroup of the same
molecule,therebyclosingthe moleculeinto a ring.
Many monosaccharides
differ only in the spatialarrangement
of atoms-that is,they are isomers.For example,glucose,
galactose,and mannosehavethe sameformula (C6H,'2Ojbut
differ in the arrangementof groupsaround one or two carbon
atoms.
H'. zro
rc
-OH
2C
HO;C -H
H- C - O H
al
H -sC-OH
H
-CH?OH
I
grucose
cH20H
OH
H'. zo
,f
H -C -OH
mannoSe
-l
H-C -OH
HIC -OH
-CH,OH
OH
OH
Note that eachcarbonatom
hasa number.
Thesesmalldifferencesmake only minor changesin the
chemicalpropertiesof the sugars.But they are recognizedby
enzymesand other proteinsand thereforecan have important
biologicaleffects.
0 A N DB L T N K S
SUGARDERIVATIVES
The hydroxylgroup on the carbonthat carriesthe
aldehydeor ketone can rapidlychangefrom one
positionto the other. Thesetwo positionsare
calleda and B.
The hydroxylgroupsof a simple
can be replaced
monosaccharide
by other groups.Forexample,
glucosamine
cr hydroxyl
B hydroxyl
As soon as one sugaris linkedto another,the o or
B form is frozen.
qH2oH
DISACCHARIDES
The carbonthat carriesthe aldehyde
or the ketone can reactwith any
hydroxylgroup on a secondsugar
m o l e c u l et o f o r m a d i s a c c h a r i d e .
The linkageis calleda glycosidic
bond.
Threecommon disaccharides
are
maltose(glucose+ glucose)
lactose(galactose+ glucose)
sucrose(glucose+ fructose)
The reactionforming sucroseis
shown here.
OLIGOSACCHARIDES
AND POLYSACCHARIDES
Largelinearand branchedmoleculescan be made from simplerepeatingsugar
s u b u n i t sS. h o r tc h a i n sa r e c a l l e do l i g o s a c c h a r i d ewsh,i l e l o n g c h a i n sa r e c a l l e d
polysaccharides.
Glycogen,for example,is a polysaccharide
made entirelyof
glucoseunitsjoined together.
glycogen
COMPLEXOLIGOSACCHARI
DE5
In many casesa sugarsequence
is nonrepetitive.Many different
moleculesare possible.Such
complexoligosaccharides
are
usuallylinkedto proteinsor to lipids,
as is this oligosaccharide,
which is
molecule
oart of a cell-surface
that definesa particularblood group.
COMMON FATTY
ACIDS
Fatty acidsare stored as an energy reserve(fats and
oils)through an esterlinkageto glycerolto form
triacylglycerols,
alsoknown astriglycerides.
Theseare carboxylicacids
with long hydrocarbontails.
COOH
I
COOH
I
I
CH,
f",
CHz
CH,
CH,
CH,
CH,
CH,
CH,
f",
CH,
f*'
CH
CH,
I
I
I
I
I
I
CH,
I
CH"
I
CHr
I
CH,
I
CHt
I
CHt
I
CH,
I
CH,
I
9H,
I
cH.
t"
CH:
CH,
I
lI
I
CHr
I
o
il
),,c
Hundredsof different kindsof fatty acidsexist.Somehaveone or more double bonds in their
hydrocarbontail and are saidto be unsaturated.Fattyacidswith no double bondsare saturated.
-oo
\/
I
fn,
fn,
fn'
CHt
CH
CH:
o
tl
I
9I H ,
CH,
i",
f*,
,r'C
o'C
CHt
I
CHt
tI
CHt
fn,
I
ll (
COOH
L-
I
I
T h i sd o u b l eb o n d
is rigid and creates
. za kinkin the chain.
'
ll rh" restof the chain
is free to rotate
about the other C-C
bonds.
CHt
I
9H,
I
CHt
tI
CH.
I
CH,
I
CH,
I
CH.
3i,'J''''
t'
(Crs)
stear|c
a c i d( C r e )
CH:
oleic
acid (Cre)
space-fillingmodel
carbonskeleton
UNSATURATED
CARBOXYL
GROUP
SATURATED
P H O S P H O L I P I D S P h o s p h o l i pai dr set h e m a j o rc o n s t i t u e n t s
of cellmembranes.
lf free, the carboxylgroup of a
fatty acidwill be ionized.
&c..
,a/
B u t m o r e u s u a l l yi t i s l i n k e dt o
other groupsto form either esters
WC
or amides
o
,1/
C
\
s p a c e - f i l l i nm
g o d e lo f
the phospholipid
p h o s p h a t i d y l c hionle
In phospholipids
two of the -OH groupsin glycerolare
linkedto fatty acids,while the third -OH group is linked
g e n e r a ls t r u c t u r e to phosphoricacid.The phosphateis further linkedto
o f a p h o s p h o l i p i d one of a varietyof smallpolar groups(alcohols).
LIPIDAGGREGATES
POLYISOPRENOIDS
long-chainpolymersof isoprene
ln water they can form a surfacefilm
o r f o r m s m a l lm i c e l l e s .
Their derivativescan form largeraggregatesheld together by hydrophobicforces:
Triglycerides
can form largespherical
fat dropletsin the cell cytoplasm.
O T H E RL I P I D S
ipid
P h o s p h o l i p i dasn d g l y c o l i p i dfso r m s e l f - s e a l i nl g
bilayersthat are the basisfor all cell membranes.
Lioidsare defined asthe water-insoluble
m o l e c u l e isn c e l l st h a t a r e s o l u b l ei n o r g a n i c
solvents.Two other commontypesof lipids
are steroidsand polyisoprenoids.
Both are
made from isopreneunits.
CH.
\ -CH:CHr
.C
,//
Lr 12
isoprene
Steroidshavea common multiple-ringstructure.
cholesterol-found in manv membranes
GLYCOLIPIDS
Likephospholipids,
thesecompoundsare composedof a hydrophobic
- C - NI H
dolicholphosphate-used
to carryactivatedsugars
in the membrane-associated
synthesisof glycoproteins
and somepolysaccharides
NUCLEOTIDES
PHOSPHATES
A nucleotideconsistsof a nitrogen-containing
base,a five-carbonsugar,and one or more
phosphategroups.
The phosphatesare normallyjoined to
the C5 hydroxylof the riboseor
deoxyribosesugar(designated5'). Mono-,
di-, and triphosphatesare common.
BASICSUGAR
LINKAGE
BASE
-o-
-
ililtl
P- o -
I
"
o-o-o
-
P- o -
I
P- . ) - c H ^
l-"
a sI n
l"'ott
The phosphatemakesa nucleotide
negativelycharged.
The baseis linkedto
the samecarbon(C1)
usedin sugar-sugar
bonds.
NH
l2
I
i
HclC\NH
\Hu
I
ll U
HCli\x
"t-'.,-t\
llC
lcvtosine
nt-r-t\
o
luracil
The basesare nitrogen-containingring
c o m p o u n d se, i t h e rp y r i m i d i n eosr p u r i n e s .
H
o
l1
" n,.I
'
\./-\**
3
ll r I
thy
lrl\ - t \
PENTOSE
a five-carbonsugar
Eachnumberedcarbonon the sugarof a nucleotideis
followed by a prime mark;therefore,one speaksof the
" 5 - p r i m ec a r b o n , "e t c .
two kindsare used
bose
B-o-2-deoxyri
usedin deoxvribonucleic
acid
NOMENCLATURE A nucleosideor nucleotideis namedaccordingto its nitrogenousbase.
Singleletter abbreviationsare usedvariouslyas
shorthandfor (1) the basealone,(2) the
nucleoside,
or (3) the whole nucleotidethe contextwill usuallymake clearwhich of
the three entitiesis meant.When the context
is not sufficient,we will add the terms "base", B A S E+ S U G A R= N U C L E O S I D E
"nucleoside","nucleotide",or-as in the
examolesbelow-use the full 3-letternucleotide
cooe.
AMP
dAMP
UDP
ATP
N U C L E IACC I D S
= adenosinemonophosphate
= deoxyadenosine
monophosphate
= u r i d i n ed i p h o s p h a t e
= adenosinetriphosphate
= NUCLEOTIDE
BASE+ SUGAR+ PHOSPHATE
NUCLEOTIDES
HAVEMANY OTHERFUNCTIONS
Nucleotidesare joined together by a
phosphodiester
linkagebetween 5' and
3' carbonatomsto form nucleicacids.
The linearsequenceof nucleotidesin a
nucleicacid chain is commonly
abbreviated by a one-letter code,
A-G-C-T-T-A-C-A,
with the 5'
end of the chain at the left.
bonds.
Theycarrychemicalenergy in their easilyhydrolyzedphosphoanhydride
p h o s p h o a n h y d r i dbeo n d s
-l
ooo
-o- ililtl
-l
- f H,
l- o - P- o - P - o
o-
o-
o-
example:ATP(or
OH
)
OH
Theycombinewith other groupsto form coenzymes.
H
O
H
H
O
H
HS
ttttlllllll
H
t
H
H
H
H
H
O
H CH.H
ll l l'l
il r r
t t
_C _C _N _C _C -C _N_C _C _C -C
ll
-O-
HO CH3H
O
ll
P_O-P-O
O-
- CH
2
O-
example:coenzymeA (CoA)
ooH
5' endof chain
I
O : P- O -
5',
oTheyare usedas specificsignalingmoleculesin the cell'
l)Hz
example:cyclicAMP (cAMP)
o
o
II
I
P_
I
o-
ooH
T H EI M P O R T A N COEF F R E E
E N E R GF
YO RC E L L S
Life is possiblebecauseof the complexnetwork of interacting
chemicalreactionsoccurringin everycell.In viewingthe
metabolicpathwaysthat comprisethis network, one might
suspectthat the cell has had the abilityto evolvean enzymeto
carryout any reactionthat it needs.But this is not so.Although
enzymesare powerful catalysts,
they can speedup only those
reactionsthat are thermodynamically
possible;other reactions
proceedin cellsonly becausethey are coupledto very favorable
reactionsthat drive them. The ouestionof whether a reaction
can occurspontaneously,
or insteadneedsto be coupledto
another reaction,is centralto cell biology. The answeris
obtained by referenceto a quantity calledthe free energy: the
total changein free energyduring a set of reactionsdetermines
whether or not the entire reactionseouencecan occur.ln this
panel we shallexplainsomeof the fundamentalideas-derived
from a specialbranchof chemistryand physicscalledthermodynamics-that are requiredfor understandingwhat free
energy is and why it is so important to cells.
E N E R GR
Y E L E A S EBDY C H A N G EISN C H E M I C ABLO N D I N G
I SC O N V E R T EI N
D T OH E A T
of molecularcollisionsthat heat uo first the walls of the box
and then the outsideworld (representedby the sea in
our example).In the end, the systemreturnsto its initial
temperature,by which time all the chemicalbond energy
releasedin the box has been convertedinto heat energyand
transferredout of the box to the surroundings.
Accordingto
the first law, the changein the energyin the box (AE6o",
which
5EA
we shalldenote as AE) must be equal and oppositeto the
amount of heat energytransferred,which we shalldesignate
as h: that is,AE = -h. Thus,the energy in the box (E) decreases
when heat leavesthe system.
Ealso can changeduring a reactionas a resultof work being
done on the outsideworld. For example,supposethat there is
UNIVERSE
a smallincreasein the volume (Ay) of the box during a reaction.
Sincethe walls of the box must pushagainstthe constant
pressure(P) in the surroundingsin order to expand,this does
An enclosedsystemis defined as a collectionof moleculesthat
work on the outsideworld and requiresenergy.The energy
doesnot exchangematter with the restof the universe(for
usedis P(AV),which accordingto the first law must decrease
example,the "cell in a box" shown above).Any suchsystemwill
the energy in the box (E) by the sameamount. ln most reactions
containmoleculeswith a total energyE. Thisenergywill be
chemicalbond energy is convertedinto both work and heat.
distributedin a varietyof ways:someasthe translationalenergy
Enthalpy (H) is a compositefunction that includesboth of these
of the molecules,someas their vibrationaland rotationalenergies, (H = E + PV).To be rigorous,it is the changein enthalpy
but most asthe bonding energiesbetweenthe individualatoms
(AH) in an enclosedsystem,and not the changein energy,that
that make up the molecules.Supposethat a reactionoccursin
is equal to the heat transferredto the outsideworld during a
the system.The f irst law of thermodynamicsplacesa constraint
reaction.Reactionsin which H decreases
releaseheat to the
on what typesof reactionsare possible:it statesthat "in any
surroundingsand are saidto be "exothermic,"while reactions
process,
the total energyof the universeremainsconstant."
in which H increases
absorbheat from the surroundingsand
Forexample,supposethat reactionA - B occurssomewherein
are saidto be "endothermic."Thus,-h = AH. However,the
the box and releases
a great deal of chemicalbond energy.This
volume changeis negligiblein most biologicalreactions,so to
energywill initiallyincreasethe intensityof molecularmotions
a good approximation
(translational,
vibrational,and rotational)in the system,which
is equivalentto raisingits temperature.However,these increased
motionswill soon be transferredout of the svstembv a series
THESECOND
LAW OFTHERMODYNAMICS
Considera containerin which 1000coinsare all lying headsup.
lf the containeris shakenvigorously,subjectingthe coinsto
the typesof random motionsthat all moleculesexperiencedue
to their frequent collisionswith other molecules,one will end
up with about half the coinsoriented headsdown. The
reasonfor this reorientationis that there is only a singleway in
which the originalorderlystateof the coinscan be reinstated
(everycoin mu{lie headsup), whereasthere are many different
ways (about 102s8)
to achievea disorderlystate in which there is
an equal mixtureof headsand tails;in fact, there are more wavs
to achievea 50-50statethan to achieveany other state.Each
state has a probabilityof occurrencethat is proportionalto the
number of ways it can be realized.The secondlaw of thermodynamicsstatesthat "systemswill changespontaneously
from
statesof lower probabilityto statesof higher probability."
Sincestatesof lower probabilityare more "ordered" than
statesof high probability,the secondlaw can be restated:
"the universeconstantlychangesso as to becomemore
disordered."
THEENTROPY,
5
The secondlaw (but not the first law) allowsone to predictthe
directionof a particularreaction.But to make it usefulfor this
purpose,one needsa convenientmeasureof the probabilityor,
equivalently,the degreeof disorderof a state.The entropy (5)
i s s u c ha m e a s u r el.t i s a l o g a r i t h m i fcu n c t i o no f t h e p r o b a b i l i t y
suchthat the changein entropy (45) that occurswhen the
reactionA - B convertsone mole of A into one mole of B is
A5=RInpB/pA
where p4 and p, are the probabilitiesof the two statesA and B,
R is the gas constant(2 cal deg 1 mole 1),and A5 is measured
i n e n t r o p yu n i t s( e u ) .I n o u r i n i t i a le x a m p l eo f 1 0 0 0c o i n s t, h e
relativeprobabilityof all heads(stateA) versushalf headsand
half tails (stateB) is equal to the ratio of the number of different
waysthat the two resultscan be obtained.One can calculate
t h a t p A = 1 a n d p , = 1 0 0 0 1 ( 5 0 x0 15 0 0 1-) 1 0 2 s eT.h e r e f o r e ,
the entropy changefor the reorientationof the coinswhen their
containeris vigorouslyshakenand an equal mixtureof heads
or about 1370eu per mole of
and tails is obtained is R In (102e8),
We seethat, becauseA5
suchcontainers(6 x 1023containers).
defined above is positivefor the transitionfrom stateA to
state B (ps/p4 > 1), reactionswith a large increasein 5 (that is,
for which A5 > 0) are favoredand will occurspontaneously.
in Chapter2, heat energycausesthe random
As discussed
the transferof heat from an
commotionof molecules.Because
the numberof
enclosedsystemto its surroundingsincreases
different arrangementsthat the moleculesin the outsideworld
their entropy.lt can be shown that the
can have,it increases
releaseof a fixed quantity of heat energyhasa greaterdisordering effect at low temperaturethan at high temperature,and
that the value of A5 for the surroundings.as defined above
(ASr"u),
is preciselyequalto h, the amount of heattransferredto
the surroundingsfrom the system,dividedby the absolute
temperature(f ):
T H EG I B B S
FREE
E N E R G YG,
When dealingwith an enclosedbiologicalsystem,one would
like to have a simpleway of predictingwhether a given reaction
will or will not occurspontaneously
in the system.We have
seenthat the crucialquestionis whether the entropy changefor
the universeis positiveor negativewhen that reactionoccurs.
In our idealizedsystem,the cell in a box, there are two separate
componentsto the entropy changeof the universe-the entropy
changefor the systemenclosedin the box and the entropy
changefor the surrounding"sea"-and both must be added
together before any predictioncan be made.For example,it is
possiblefor a reactionto absorbheat and therebydecreasethe
entropy of the sea (A5r""< 0) and at the sametime to cause
sucha large degreeof disorderinginsidethe box (A56o*
> 0)
= A5r"" + A56o,is greater than 0. In this
that the total A5rn;u"rr"
casethe reactionwill occurspontaneously,
eventhough the
seagivesup heat to the box during the reaction.An exampleof
sucha reactionisthe dissolvingof sodiumchloridein a beaker
containingwater (the "box"), which is a spontaneousprocess
eventhough the temperatureof the water dropsasthe salt
goesinto solution.
Chemistshavefound it usefulto define a number of new
"compositefunctions"that describecombinationsof physical
propertiesof a system.The propertiesthat can be combined
includethe temperature(f), pressure(P), volume (V), energy
(E), and entropy (5). The enthalpy(H) is one suchcomposite
function.But by far the most usefulcompositefunction for
biologistsis the Gibbs free energy, G. lt servesas an accounting
devicethat allowsone to deducethe entropy changeof the
universeresultingfrom a chemicalreactionin the box, while
avoidingany separateconsiderationof the entropychangein
the sea.The definition of G is
G=H-TS
where, for a box of volume V, H is the enthalpydescribedabove
(E + PV), r is the absolutetemperature,and 5 is the entropy.
Eachof thesequantitiesappliesto the insideof the box only. The
changein free energyduring a reactionin the box (the G of the
productsminusthe G of the startingmaterials)is denoted asAG
and, as we shallnow demonstrate,it is a direct measureof the
amount of disorderthat is createdin the universewhen the
reaction occurs.
At constanttemperature the change in free energy (AG)
during a reactionequalsAH - IA5. Rememberingthat AH =
-h, the heat absorbedfrom the sea,we have
But h/f is equal to the entropy change of the sea (A5r""),and
the A5 in the above equation is A56o^.Therefore
We concludethat the free-energychangeis a direct measure
of the entropy changeof the universe.A reactionwill proceed
in the directionthat causesthe changein the free energy(AG)
to be lessthan zero, becausein this casethere will be a positive
entropy changein the universewhen the reactionoccurs.
For a complexset of coupledreactionsinvolvingmany
the total free-energychangecan be comdifferent molecules,
puted simplyby adding up the free energiesof all the different
molecularspeciesafter the reactionand comparingthis value
with the sum of free energiesbefore the reaction;for common
the requiredfree-energyvaluescan be found from
substances
publishedtables.In this way one can predictthe directionof
a reactionand thereby readilycheckthe feasibilityof any
proposedmechanism.
Thus,for example,from the observed
proton gradient
valuesfor the magnitudeof the electrochemical
acrossthe inner mitochondrialmembraneand the AG for ATP
hydrolysisinsidethe mitochondrion,one can be certainthat ATP
synthaserequiresthe passageof more than one proton for each
moleculeof ATPthat it synthesizes.
The value of AG for a reactionis a direct measureof how far
the reactionis from equilibrium.The large negativevaluefor
ATP hydrolysisin a cell merelyreflectsthe fact that cellskeep
the ATP hydrolysisreactionas much as 10 ordersof magnitude
away from equilibrium.lf a reactionreachesequilibrium,
AG = 0, the reactionthen proceedsat preciselyequal rates
in the forward and backward direction. For ATP hydrolysis,
equilibriumis reachedwhen the vast majorityof the ATP
has been hydrolyzed,as occursin a dead cell'
F o r e a c hs t e p ,t h e p a r t o f t h e m o l e c u l et h a t u n d e r g o e sa c h a n g ei s s h a d o w e di n b l u e ,
a n d t h e n a m e o J t h e e n z y m et h a t c a t a l y z etsh e r e a c t i o ni s i n a y e l l o w b o x .
S T E P1
G l u c o s ei s
phosphorylatedby ATPto
f o r m a s u g a rp h o s p h a t e .
T h e n e g a t i v ec h a r g eo f t h e
phosphatepreventspassage
of the sugar
p h o s p h a t et h r o u g h t h e
p r a s m am e m D r a n e ,
t r a p p i n gg l u c o s ei n s i d e
the cell.
o.
.H
\,/
't-
!r
1CH?OH
I
H-C.-OH
l'
f r o m c a r b o n1 t o H O
c a r o o nz , t o r m t n g
a ketosefrom an
a l d o s es u g a r ( S e e
Panel2-4.)
*'-i?
+
H.)-(--H
lH-
OH
H-C-OH
5
|
-CH,OqP(openchainform)
H-C-OH
l5
.CH,OP
( o p e nc h a i nf o r m )
STEP3
The new hydroxyl
.l
g r o u p o n c a r b o n1 ' ,
phosphorylatedby ATP,in
p r e p a r a t i o nf o r t h e f o r m a t i o n
o f t w o t h r e e - c a r b o ns u g a r
phosphates.The entry of sugars
i n t o g l y c o l y s iiss c o n t r o l l e da t t h i s
s t e p ,t h r o u g h r e g u l a t i o no f t h e
enzyme p hosphof ru ctok i nase-
(ringform)
P O H-) |C, " - \o
(
CH,O P
Hr))
rLJ/l
|
+
tt''
OH
f ructose
1,6-bisphosphate
CH,O P
STEP
4
The
s i x - c a r b o sn u g a ri s
c l e a v e dt o p r o d u c e
two three-carbon
m o l e c u l e sO n l y t h e
glyceraldehyde
3-phosphate
can
p r o c e e di m m e d i a t e l y
through glycolysis
I
a-A
I
HO
HO-C-H
I
+C
H-C-OH
I
I
cH2o P
I
H-C-OH
I
cH2o
I
( o p e nc h a i nf o r m )
f r u c t o s e1 , 5 - b i s p h o s p h a t e
CH,OH
\//
I
H-C-OH
cH2o P
S T E P5
Theother
product of step 4,
d i hydroxyacetone
p h o s p h a t ei,s
isomerized
to form
glyceraldehyde
3-phosphate.
ADP
P
glyceraldehyde
?-nhncnh:te
C
,ro
" I
I
H-C-OH
cH2o P
g l y c e r a l d e h y d3e- p h o s p h a t e
t
ovo
+ E E E E +u *
f
H-C-OH
l
cH2o P
F i g u r e2 - 7 3 )
1,3-bisphosphoglycerate
g l y c e r a l d e h y d3e- p h o s p h a t e
S T E P7
T h et r a n s f e r
t o A D Po f t h e
h i g h - e n e r g yp h o s p h a t e
groupthat was
generated in step 6
forms ATP.
C
I
I
+
H-C-OH
cH2o P
1,3-bisphosphoglycerate
o. .o
\//
o. .o\//
'Cl
STEP
8
Theremaining
p h o s p h a t ee s t e rl i n k a g ei n
3-phosphoglycerate,
which has
a relativelylow free energy of
hydrolysis,is moved from
carbon 3 to carbon 2 to form
2-phosphoglycerate.
C
I
H-C-Oi*P
H-C-OH
,l
3-phosphoglycerate
C
C
I
H-C-O
I
P
cH2oH
2 - p h o s p h olgy c e r a t e
P
cHz
p h o s ph o e n oIp y r u v a t e
C
C
C-O
I
C-O
o. .o\./
o. .o\//
I
2-p hosphog lycerate
o. .o
\./
o. .o
\,/
STEP9
The removal of
water from 2-phosphoglycerate
c r e a t e sa h i g h - e n e r g ye n o l
p h o s p h a t el i n k a g e .
STEP10 The transfer to
ADP of the high-energy
p h o s p h a t eg r o u p t h a t w a s
generated in step 9 forms
A T P ,c o m p l e t i n gg l y c o l y s i s .
t-
cH2oH
- C H r O ' .P .
P
cHz
p h o s p h o e n oply r u v a t e
N E TR E S U LO
T FG L Y C O L Y S I S
In addition to the pyruvate,the net productsare
t w o m o l e c u l e so f A T Pa n d t w o m o l e c u l e so f N A D H
I
I
CH:
HS-CoA
pyruvate
The completecitricacidcycle.The two
carbonsfrom acetylCoA that enter this
turn of the cycle(shadowedin
) will
be convertedto CO, in subsequentturns
of the cycle:it is the two carbons
shadowed in blue that are convertedto
CO, in this cycle.
(2c)
acetyl CoA
HS-CoA
eoo
*",
tHO-C-COO-
Step 1
(+a^)
in, \*'ioo\
Po
(6c)
isocitrate
fn,
HC COO
t
citrate(6c)
no-tH
Coo-
fumarate (4C)
(x-ketoglutarate(5C)
€oot
fu
2
'
t'
CH
ffoo-
s u c c i n a t e( 4 C )
,rStep6
GOO-
Hzo
Coz
CH.
succinylCoA (4C)
t'
Ioo-
I
coo-
2
CH,
il*p_:,
t-
C=O
I
S-CoA
coz
HS-CoA
HS-CoA
EE*t-
Detailsof the eight stepsare shown below. For eachstep,the part of the moleculethat undergoesa changeis shadowedin hlue
and the name of the enzymethat catalyzesthe reactionis in a yellow box.
O:C -S-CoA
STEP1
After the enzyme
removesa proton from the
CH, group on acetyl CoA,
t h e n e g a t i v e l yc h a r g e d
C H r - f o r m sa b o n d t o a
carbonylcarbon of
oxaloacetate.The
s u b s e q u e nlto s sb y
h y d r o l y s ios f t h e c o e n z y m e
A (CoA)drivesthe reaction
strongly forward.
S T E P2
An isomerization
reaction,in which water is
f i r s t r e m o v e da n d t h e n
added back, movesthe
hydroxyl group from one
c a r b o na t o m t o i t s n e i g h b o r
I
CH,
cooI
CHr
t-
HO-C-COO
I
9H,
l
coo-
t-
HO-C-COO
+ HS-CoA + H*
I
CH,
t-
coocitrate
coo-
Hzo
H-
citrate
cooI
C-H
I
c-cootl
C-H
I
coo-
cls-aconitateintermediate
H-C
cooI-H
I
H-C -COO-
I
HO-C -H
I
coo
isocitrate
STEP3
ln the first of
f o u r o x i d a t i o ns t e p si n t h e
cycle,the carbon carrying
the hydroxyl group is
convertedto a carbonyl
g r o u p .T h e i m m e d i a t e
p r o d u c ti s u n s t a b l e l,o s i n g
C O ,w h i l e s t i l l b o u n d t o
the enzyme.
cooI
H-C -H
I
H-C -H
I
a-i
I
coo
cooI-H
H-C
H_C
I
HO-c-H
I
coo-
(x-ketogIutarate
isocitrate
STEP4
The o-ketog/utarate
dehyd ro gen asecomplex closely
r e s e m b l etsh e l a r g ee n z y m e
complexthat convertspyruvate
to acetyl co{(pyruvate
dehydrogenase).lt likewise
catalyzesan oxidation that
producesNADH,CO2,and a
h i g h - e n e r g yt h i o e s t e rb o n d t o
coenzymeA (CoA).
STEP5
A phosphate
m o l e c u l ef r o m s o l u t i o n
d i s p l a c etsh e C o A ,f o r m i n g a
h i g h - e n e r g yp h o s p h a t e
l i n k a g et o s u c c i n a t eT. h i s
p h o s p h a t ei s t h e n p a s s e dt o
G D Pt o f o r m G T P .( l n b a c t e r i a
and plants,ATP is formed
instead.)
cooI
H-C-H
I-H
cooI
H-C -H
I
H-C-H
I
c:o
I
coo-
H-C
S
succinyl-CoA
(x-ketoglutarate
cooH-C
-H
H-C
I
S-CoA
H-C
coo
I-H
I
H-C-H
s u c cni a t e
cooI
C-H
H-C
I
coo
f u marate
S T E P8
l n t h e l a s to f J o u r
o x i d a t i o ns t e p si n t h e c y c l et,h e
c a r b o nc a r r y i n gt h e h y d r o x y l
group is converted
t o a c a r b o n y lg r o u p ,
regeneratingthe oxaloacetate
n e e d e df o r s t e p 1 .
,,
I
coo-
I
coo
S T E P7
T h e a d d i t i o no f
water to fumarate placesa
hydroxyl group next to a
c a r b o n y lc a r b o n .
coo
I-H
I
,,
)
n-L-r
I
H-C-H
I
s u c c ln a r e
succinyl-CoA
S T E P6
ln the third
oxidation step in the cycle,FAD
removestwo hydrogen atoms
from succinate.
cooI
HO-C -H
I
H-C-H
I
coomalate
I
I-CoA
succinatedehydrogenase
-
cooI
C-H
/\
rl
H-C
I
coo-
f umarate
cooI
HO-C -H
I
H-C-H
I
coo
malate
cooI
c:o
I
CH,
I
coo
oxa loacetate
+ HS-CoA
124
Chapter2: CellChemistryand Biosynthesis
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