Download 25,8 Ketone bodies

776
CHAPTER
25 Lipid Metabolism
25,8 Ketonebodies
AIM: To list the three ketone bodiesond the conditionsthot
cousetheir production.
Liver cells produce ketone
bodies when glucose is in short
supply.
Under certain circumstances,body cells do not have enough glucose even
for brain cells to use as an energysource.This happens most often in starvation or in untreated diabetes.In starvation, no supply of glucose is available; in diabetes, glucose is present in the blood, but it cannot penetrate
cell membranes.
A lack of glucosecausesthe cells of many organs to step up the beta oxidation of fatty acids. However, when glucose levels are lor,r4there is not
enough oxaloacetateavailable to condense with acetyl CoA in the first step
of the citric acid cycle.This is so becauseoxaloacetatecomes from the carboxylation of pyruvate, and pyruvate comes from the breakdo',nmof glucose
in glycolysis.At low glucose levels, therefore, the concentration of acetyl
CoA produced by the beta oxidation of fatty acids builds up. Under these
conditions, the liver manufactures three special compounds from the
excessaceryl CoA-the ketone bodies. Ketone bodies may be oxidized by
many tissuesto meet energy needs.
Th,eketonebodies are acetoaceticacid, B-hydroxybutyric acid, and acetone.We can see from their structural formulas that one of these compounds, p-hydroxybutyric acid, is inaccurately named as a ketone body,
since it does not contain a ketone group.
oo
iltl
ooHo
rrlll
cH.-c-cH.,
cH3-c-cH2-c-oH
cH.-c-cH2-c-oH
H
Acetoaceticacid
Acetone
B-Hydroxybuty'ric acid
(not a ketone)
The liver does not use ketone bodies for energy production but releases
them into the bloodstream. From the bloodstream, the ketone bodies reach
other tissues-mainlythe brain, the heart, and skeletal muscle.
The only ketone body that is in a form that can be used directly to produce energy is acetoaceticacid. The acetoaceticacid is converted to its
thioesterwith CoA.
o
o
o
tl
CH3-C-CH2-C-OH
+ HS-CoA
-+
o
CH:-C-CH2-C-S-CoA
Acetoaceticacid
+ H2O
AcetoacetylCoA
The thioester that is formed, acetoacetylCoA, may look familiar. If you
recall our discussion of beta oxidation, you will see that acetoacetyl CoA is
the same compound that is formed at the end of the fatty acid spiral. Tissue
cells can cleavethe acetoacewl CoA back to two molecules of acewl CoA.
oo
iltl
CH3-C-CH2-C-S-CoA
Acetoacetyl
CoA
o
+ HS-CoA
-
2CHt-C-S-CoA
25.9 Ketosis
777
The acetyl CoA is then oxidized to carbon dioxide in the citric acid cycle,
thereby providing NADH and FADH2for ATP production by cellular respiration. The thioester of the ketone body B-hydroxybutyric acid is also
formed in cells, but the hydroxyl group of the acid portion of the ester must
be oxidized to a ketone. Acetoacetyl CoA, useful for energy production, is
formed as a result of this oxidation.
oHo
ttl
CH3-C-CH2-C-S-CoA
I
--Z----+
CH3-C-CH2-C-S-CoA
NADH- H-
NAD*
H
oo
lttl
p-HydroxybutyrylCoA
Acetoacetyl CoA
Acetone, the third ketone body, is not used as an energy source.
25.9 Ketosis
AIMS: To characterizethe following ospectsof ketosis:
ketonemio,ketonurio, acetonebreath, ond ketoocidosis.
To describehow the effectsof ketosisare counteroctedby
mechonismswithin the body ond by the odministrotionof
externologents.
Prolonged ketosis stawes cells
for oxygen.
In normal metabolism,someketonebodiesare continuouslyproducedand
broken dor,rrnin energy production. The normal blood level of ketone bodies seldom exceeds3 mg/100 mL of blood. In diabetes,however,the liver
produces large quantities of ketone bodies, releasing them into the bloodstream for delivery to other tissues.This causesa substantial increasein the
level of ketone bodies in the blood of untreated diabetics. A leuel of ketone
bodies greater than about 20 mg/100 mL of blood is called ketonemia
("ketonesin the blood").
Tissue cells cannot use all the ketone bodies produced. But the liver
does not stop production, and eventually, a surplus builds up. At a leuel of
about 70 mg/100 mL of blood, ketone bodies are excretedin the urine. This
condition is ketonuria ("ketonesin the urine'). At high levels of ketone bodies in the blood, acetone is excretedby the lungs. The sweet, minty smell of
acetone breath b ecomesapparent.
The conditions of ketonuria, ketonemia, and acetone breath together
are symptoms of ketosis (also calledketoacidosis)-blood acidosis caused
by an excessofthe ketonebody acids,acetoaceticacid, and B-hydroxybutyric
acid. Diabetic ketosis involves the same problem as respiratory acidosis
and lactic acidosis.This is the problem: The ketone body acids in the blood
will lower the blood pH unless enough bicarbonate ions are presentto act
as buffers (proton sponges).
/..---->Hfrom ketone Proton
bodr acid
+
HCo3-
:-
Bicarbonate
ion
H2CO3
Carbonic
acid
The pH of the blood is maintained at 7.40 as long as the kidneys can
regeneratenew bicarbonate ions. In severecasesof diabetic ketosis, how-
778
CHAPTER
25 LipidMetabolism
ever, the kidne.vscannot supply enough bicarbonate ions to keep up with
the production of ketone bodies.More ketone bodiesare produced,insufficient bicarbonate ions are available, and the blood pH drops. This
sequencehas a disastrouseffect. Hemoglobin can pick up oxygenonly in
an environment with a low concentration of protons. The lower the pH of
the blood, the higher is the concentration of protons, and the less oxygen
can be transportedby hemoglobin. Brain cells become starvedfor oxygen.
If this lack of oxygen continues, coma and death will follow.
The first step in the treatment of patients with diabeteswho are exhibiting ketosis is usually the administration of insulin. This should restore normal glucosemetabolism and reduce the formation of ketone bodies. Like
glycosuria, ketonuria results in the loss of a large volume of body water,
often causing dehydration. In diabetic patients with severe dehydration
and ketosis, fluids and buffering power are restored by intravenous administration of solutions containing sodium bicarbonate.
25,10Cholesterol
synthesis
AIM: Toshowhow the synthesisof cholesterolond ketone
bodies illustrotesthe comportmentolization
sf cellulor
Processes.
The carbon skeleton ofcholesterol is formed from acetvl CoA.
Cholesterol is formed in the cytoplasm of liver cells. Biochemists have
sho'nmthat the 27 carbons of the carbon skeleton of this important steroid
come entirely from acetylCoA (Fig.25.5).The total biosynthesisof I molecule of cholesterolusesup 15 moleculesof acetylCoA and involvesat least
13 separatechemical reactions.A few of the main stepsin cholesterolsgrthesisare shovrmin Figure25.6.
The synthesis of cholesterol in the cl.toplasm and the synthesis of
ketone bodies in mitochondria are excellentexamplesof the compartmentalization of cellular processes.The cytoplasm lacks the enzl'rnesneeessary
to synthesizeketone bodies from acetyl CoA; the mitochondrion lacks the
enzyrnes necessary to synthesize cholesterol from acetyl CoA. Compartmentalization is often important in balancing the s1'nthetic and energy
needsof cells.\Mhena cell needsenergy,most of the acerylCoAproduced in
its mitochondria is oxidized in the citric acid cycle.\Mhen large amounts of
acetyl CoA are being oxidized, lesseramounts can be furnished to the cltoplasm. The decreasedlevel of acetyl CoA in the cltoplasm slows dornmor
c'-a-tc'-a
Figure25.5
The incorporationof the acetyl
carbonsof acetylCoA into the
carbonskeletonof cholesterol.
The carbonsof cholesterol
shown in colorcome from the
methyl group of acetylCoA.The
remainderof the carbonscome
from the carbonylgroup (-C=O).
ct
a- c- - j- c' - a
CH3-C-S-CoACl
1
5Y
1
lll
-".c''frc--.-c-c
-===-->a
-L'-a-C--a'-C
I
t- a- '
c