Download 25., Fatty ocid oxidation

25.3 FattyAcid Oxidation
Stimulus
(lowblood glucose)
+
Fat cell
Epinephrine
Fatty acids
Figute25.2
Mobilizationof fatty acidsfrom
adiposetissue.
streanl. Fat mobilization is shor,rrnin Figure 25.2.The mobilized fatty acids
become tightly attached to a plasma protein, serum albumin. The serum
albumin transpofis the fatty acids to tissues where they are taken up by
cells that need them. The glycerol produced by the hydrolysis of the
triglyceride also enters these cells.
25., Fattyocid oxidation
AIMS: Tonomeand describethe processof the cotobolismof
fatty ocids,indicoting the end products.Topredict the
hydrolysisproductsof typicol lipid molecules.Todetermine
the number of moleculesof ocetylCoA,NADH,ond FADH,
thot resultfrom the beto oxidotion of o given fotty ocid.
Fatty acids are degraded to
acetyl coenzymeA.
Fatty acids enter tissue cells that need energy.Before a fatty acid molecule
can be oxidized to produce energy,however,it must be converted to a fatty
acyl CoA-a thiol esterformed from a fatty acid and CoA.
o
R-C
o
OH + I',S-CoA ------ R-C-S-CoA
Fatty acid
Fattyacyl CoA
+ H,O
25 Lioid Metabolism
CHAPTER
Lipid StorageDiseases
Inborn errors associatedwith lipid metabolism
include Tay-Sachsdisease,Gaucher's disease,
and Niemann-Pick disease.All three conditions
are lipid storage diseases. Normally, both
triglycerides and complex lipids are constantly
being broken down and synthesizedin the body.
The lipid storage diseases seem to occur
requiredto catbecausethe body lacksenzy.rnes
lipids.
complex
alyze the breakdown of certain
to
accumulation
This enzyme deficiency leads
of abnormally high levels of complex lipids in
specific tissues, particularly the brain, spleen,
and liver. In all lipid storage diseases,there
is retardation of mental and physical development for reasons that are not well understood.
disease,in which lipids primarily
Tay-Sachs
accumulate in the brain, is characterized by
paralysis, a deteriorated mental state, and
the storedlipids are priblindness.In Tay-Sachs,
marily gangliosides,the most complexmembers
of the lipids containing sphingosine isee figure,
part a). As shown in the figure, the gangliosides
contain four different sugar units.
Gaucher'sdiseasehas many variants with
certain clinical features,including elevated concentrations of serum acid phosphatase. The
structure of a typical cerebroside that accumulates in this disease is shown in part (b) of the
figure. The spleen becomes enlarged because
spleen cells accumulate cerebrosides(see Sec.
16.3). Gaucher's disease may progress rapidly
and be fatal in infancy, but some patients live
fairly norrnal life spans. This suggests that
Gaucher's disease is a group of inheritable diseases.The inherited mutation may be different
in each form of the disease,but all these mutations affect cerebroside metabolism.
The chemical abnormality found in Niemann-Pick disease is an increased content
of sphingolipids (see Sec. 16.3) in the organs,
but especially the spleen (see figure, part c). As
in Gaucher'sdisease,lhere are many variants
of Niemann-Pick disease,indicating a variety of
mutations affecting sphingolipid metabolism.
At right: The three lipids whose excessivestorage
disease,Caucher'sdisease,and
causesTay-Sachs
disease,the
disease.ln Tay-Sachs
Niemann-Pick
the most complex
storedlipidsare gangliosides,
membersof the lipidscontainingsphingosine(a). The
containglucose(CIu),
sugarunits of the gangliosides
galactose(Cal), and two unusual sugarstN-acetyl(Naga)and ff-acetylneurominic acid
galactosamine
(Nana).ln Gaucher'sand Niemann-Pick
the
diseases,
lipids that cannot be broken down are the cerebrosides (b) and the sphingomyelins(c), respectively.
The conversion of fatty acids to fatty acyl CoA occurs in the cytoplasm
of cells, but the subsequent oxidation of fatty acyl CoA occurs in the
mitochondria. This presentsa problem, since fatty acyl CoA molecules
cannot passthrough the mitochondrial membrane.The passageof fatty
acyl CoA from the cytoplasm into the mitochondria is done indirectly.
The fatty acyl CoA is flrst converted into an ester of the amino alcohol
carnitine.
.l
o
tl
--'-la- li:rr,-l
ooH
t-l
R-C-SCoA
Fatty acyl CoA
R-C-O
-l
+ (H3C)3N-CH2-CH-CO2H
Carnitine
----- (H3C)gN-CH2-CH-CO2H
Fatty acyl carnitine
+ H-SCoA
25.5 Fatty Acid Oxidation
767
cH2oH
o
OH
CJI,OH
I
CHOH
ul
K*""')
|,o---\Cnon
HOOC\t
t/
l---1
NHCCH3
o
(a) A ganglioside(accumulatesin Tay-Sachsdisease)
CH2OH
OH
l-o -\Q-CHz-QH-CH-CH:CH(CHz)rzCHs
. /t
'l
/
\
\os/lo
HO\
l/
|
OH
l_{
|
|
rtl l
|
NH-C-R
(b) A cerebroside(accumulatesin Gaucher'sdisease)
9H.
* t l- l l
CH3 - N
CH2CH2-
|
cHro-lo
o
oH
O- P-
|
O-
CH2' l-
CH -
CH -
CH :
CH(CHz) rzCHe
,l'"-8-,.
(c) A sphingomyelin(accumulatesin Niemann-Pick disease)
The fatty acyl carnitine passes through the mitochondrial membrane,
where reaction with CoA converts it back to fatty aryl CoA. .- _
In mitochondrion
o
tl
,l
R-C-O
(H3C)3N-CHr-CH-CO2H
Fattyaryl carnitine
+ H-SCoA
+
o
tl
R-C-SCoA
Fattyacy|CoA
OH
*l
+ (H3C)3N-CH2-CH-CO2H
iu*ititt"
The fattyacyl camitine ls so important in the metabolism of fatty acids that
a carnitine deficiency can be life-threatening. Clarence, the sick baby in the
Casein Point earlier in this chapter, is an example.
758
2s LipidMetabolism
CHAPTER
ro rHECnsrlx Ponrr:Carnitinedeficiency
Folr.ow-up
Clarence was found to be suffering from a potentially fatal carnitine deflciency. This deficiency was
the result of a defect in the genes responsible for
fatty acid metabolism. Clarence's symptoms-vomlting, slow heart rate, and breathlng problemswere generai, and the condition ls rare. He was fortunate that his carnitine deficiency was diagnosed
before it took its fatal course. Most of the symptoms
of his disease disappeared when carnitine was
added to his formula three times a day. Since his
carnitine deficiency was accompanied by other
defects in his fatty acid metabolism, Clarence also
was placed on a low-fat diet. Clarence, whose prognosis was poor, seems to be thriving on his carnitine supplement and low-fat diet.
Carnitinesupplements
help in the oxidationof
long-chainfatty acids.
Fatty acid activation
Formation of fatty acyl CoA molecules shows how the energy stored in the
phosphatebonds of AIP can be used to drive chemical processesthat normally could not occur. Neither the fatty acid nor the CoA is sufficiently
energetic to form the fatty acyl CoA directly, so the cell boosts the chemical
' reactivity of the fatty acid carboxyl group by investing ATP The triphosphate group of the AIP molecule is cleaved to give p1'rophosphate (PPi)'
and the remaining adenosinemonophosphate (AMP)forms a high-energy
anhydride bond with the fatty acid.
LIioh-cnclq-
an1'rt-dricie
linkage
oo
tl
o
R-C-OH
l
r---tj-?
a
+
P-C
+ PPr
R-C-O-P-O
o
-,rll
Mixed anhydride
Fatty acid
The anhydride linkage formed between the fatty acid and AMP in this reaction is energeticenough to be broken by reaction with the thiol group of CoA'
o:.
fil*l
R-C-O-:--
O I Adenosine
I
o
+ HS_CoA ->
R_C_S_CoA +
oPo
o
Mixed anhydride
CoA
Eethz
acyl CoA
Adenosine
monophosphate
(AMP)
25.5 FattyAcid Oxidation
759
The thioester bond of the fatty acyl CoA is a high-energy bond, just as it
is in acetyl CoA.Therefore,some of the energyinvested in the breakdor,mof
ATP to AMP has been conserved in the thioester bond of the fatty acyl CoA.
The cost to the cell of activating one molecule of fatty acid is the loss of two
high-energy phosphoric acid anhydride bonds: one in the formation of the
anhydride between the fatty acid and AMP and one when PP;is hydrolyzed
to2P;.
Beta oddation
The formation of fatty acyl CoA molecules prepares fatty acids for entry
into the mitochondria. In the mitochondria, fatty acyl CoA molecules are
degraded to acetyl CoA in the catabolic processcalledbetaoxidation. During beta oxidation, the third (beta) carbon of the saturated fatty acid chain
of the fatty acyl CoA molecule is oxidized to a ketone.
H/
P
q
tt
oo
/O
/ /tl
oxidarion
C-C-C-C-C-C-S-CoA
6 5 4ls
2 r
H
|
^
ll
o
Fatty acyl CoA
There are four reactions involved in beta oxidation. An example is the
fatty acyl CoA formed from a 16-carbon acid, palmitic acid. Any NADH or
FADH2produced in thesereactionsmust be'accountedfor, sincethe reducing power of thesemoleculesmay be used to produceATPin respiration.As
in all the metabolic reactions we have discussed,every step of beta oxidation is catalyzedby enzymes.
Step1:Dehydrogenation. A carbon-carbon double bond is formed between
the second and third carbons of the palmitic acid chain. One molecule of
FADH2is produced.
o
HHO
IIil
CH"
- - l t ' : " C-C - S-CoA
"+ CH,- +-C^-
-,-=-_=
tsAD
HH
tl
CH3+CH2+zCH:CH-C-S
a
B
FADrr,
-CoA
As we have seen, FAD is often the coen4/rne for en4rmes that catalyze the
removal of hydrogen from saturated carbon compounds. This is the case
here, and one FADH, molecule is producec.
Step2: Hydration. A molecule of water is added to the double bond of the
fatty acyl CoA.This step is the hydration reaction of beta oxidation.
o
CH3+CH,+'CH:CH-C-S-CoA
OHHO
+ Ho-H
-*
CHr_FCrrb?B
ttl
?;C-S-CoA
HH
Step3: Oxidation. The hydroxyl group is now oxidized to a ketone. NAD+
is the coenzyme that acts as the oxidizing agent in this second oxidation
770
25 Lipid Metabolism
CHAPTER
reaction of beta oxidation. Thus beta oxidation has now produced one molecule of FADH2and one molecule of NADH.
oHo
i l-t t l -
OHHO
llll
CH3+ CH2Jrz- C6-
l'
HHH
Ca C- S- CoA --Z---I
NAD
CH3+ CH2JrT C
C
C- S- CoA
I
-\ADH-H
Step 4: Carbon-carbon bond cleauage. The carbon-carbon bond between
the second and third carbons is cleaved to give acetyl CoA and a new fatty
acyl CoA that is two carbons shorter than the starting thioester: This reaction involves another molecule of CoA, but no AIP is expended.
o
o
oHo
illll
+ HS-CoA
CH"+CH,JlrC-C-C-S-CoA
------CHs-FCH2-lrrC-S-CoA
I
+ CH3C-S-CoA
2carbons
14carbons
H
l6 carbons
The fragmentation of fatty acyl CoA molecules into molecules of acetyl
CoA is similar to other metabolic cycles.The steps of beta oxidation repeat
over and over again until the fatty acyl CoA is completely degradedto aceryl
CoA. Look at Figure 25.3. The fatty acyl CoA that starts each round of the
o
R-CH2-CH2-C-OH
Activation
AMP + 2P1
o
il
R-CH2-CH2-C-S-CoA
FADH2
Cycle repeatswith
fatty acyl CoA that is
two carbons shorter
than in previous round
Dehydrogenation (oxidation)
o
tl
R- CH: CH-C-
S-CoA
t
-Hzo
V
$
R-C-
To citric
S-CoA
acidcvcre
OH
o
I
R-CH-CHr-C-S-CoA
n ,/
S-CoA
CH.-CAcetyl CoA
o
25.5
Figure
Thefattyacidspiral.
o
il
R-C-CH2-C-S-CoA
Hydration
lElq.
25.4ATPYield
771
beta-oxidation cycle is two carbons shorter than in the previous round. For
this reason,the pathway for the degradation of fatty acids to acetyl CoA is
ofien called thefatty acid spiral.
Every round of the spiral produces one molecule each of acetyl CoA,
NADH, and FADH2 until the fatty acyl CoA molecule is only four carbons
long. At this point, the first three steps of the final round of beta oxidation
produce the compound acetoacetyl CoA. The fourth step, the reaction of
acetoacetyl CoA with CoA, produces an extra molecule of aceryl CoA from
the tail end of the fatry acid without formation of NADH and FADHz.
o
o
il
CH3-C-CH2-C-S-CoA
+ HS-Cofi +
Acetoaceryl
CoA
Studies have sholvn that exercising lessfrequently but for a longer
duration is a good approach to
burning body fat. After 40 minutes
of exercising,the percentageof
energy supplied by fat is greater
than that supplied by carbohydrates.Still longer exerciseperiods
lead to an even higher percentage
of energybeing supplied by body
fat.
oo
CH3-C-S-CoA + CH.-C-S-CoA
In other words, the complete conversion of a fatty acyl CoA to two-carbon
fragments of acetyl CoA always produces one more molecule of acetyl CoA
than of NADH or FADHT.To summarize, the breakdo'vrrnof palmitic acid
gives eight molecules of acetyl CoA,but only sevenmolecules of NADH and
sevenmoleculesof FADH2are produced.
PRACTICE
EXERCISE
25.I
Lauric acid is converted to acetyl CoA in beta oxidation. Determine the
yields of (a) acetyl CoA, (b) NADH, and (c) FADH2.
25.4ATPyield
AIM: To calculotethe numberof ATPmoleculesformedby the
oxidotion of o fotty ocid molecule.
Focus
The complete oxidation of 1
molecule of palmitic acidyields
129 molecules ofATP.
In Chapter 24 we saw that the carbons of the aceryl CoA produced by the
catabolism of glucose can be completely oxidized to carbon dioxide in the
citric acid cycle. Each molecule of acetyl CoA oxidized in this fashion yields
enough energy to make one molecule of AIB one molecule of FADH2,and
three molecules of NADH. The reducing power of each molecule of NADH
can make three molecules of ATP by cellular respiration; FADH2produces
two molecules of AIP in the same way. It was shor,rmthat 38 AIP molecules
is the total useful energyyield of aerobic glucosecatabolism.
Molecules of acetyl CoA are the same, regardlessof their source. Like
acetyl CoA molecules produced from glucose,the acetyl CoA molecules
formed in the fatty acid spiral can be oxidized in the citric acid cycle. Since
we can find the yield of NADH, FADH2, and AIP from the beta-oxidation
reactions of the fatty acid spiral and from the citric acid cycle, we can calculate how many molecules of AIP are produced by the total oxidation of
one molecule of any fatty acid to carbon dioxide and water. Table 25.1
shows a calculation of this kind for palmitic acid.
In calculating the totalAIP yield obtained from the complete oxidation
of the fatty acid, we can count the investment of two high-energy phos-