section 18.1
Oxidation of Fatty Acids
371
The latter reaction occurs in the oxidation of natural
unsaturated fatty acids, and an epimerase converts the
product to the L-isomer, which is the substrate of the
next enzyme.
3. /3-HydroxyacyI-CoA dehydrogenase oxidizes
/3-hydroxyacyl-CoA by an NAD+-linked reaction that
is absolutely specific for the L-stereoisomer. The
electrons from the NADH generated are passed on to
NADH dehydrogenase of the respiratory chain.
4. 3-Ketoacyl-CoA thiolase f/3-keto thiolase) catalyzes a
thiolytic cleavage, has broad specificity, and yields
acetyl-CoA and acyl-CoA shortened by two carbon
atoms. The reaction is highly exergonic
(AG0'
= —6.7 kcal/mol) and favors thiolysis. The
enzyme has a reactive —SH group on a cysteinyl
residue, which participates as follows (E = enzyme):
o
o
o
o
II
II
II
II
R _ C — C H
2
— C — S C oA + H S — E < = ± R C — S — E + C H
3
— C — SC oA
0 -K eto acy l-C o A
A cetyl-C oA
0
0
II
I
R— C — S — E + H S— C oA « = f R— C — S C oA + H S — E
A cyl-C oA
(R e g e n e ra te d
(w ith tw o
en zy m e)
le ss c a rb o n
ato m s)
Three
enzyme
activities—long-chain
enoyl-CoA
hydratase,
/3-hydroxyacyl-CoA
dehydrogenase,
and
long-chain /3-ketoacyl-CoA thiolase (reactions 2-4, Fig-
ure 18-3)—are associated with a trifunctional protein
complex consisting of four
a-
and four /3-subunits
bound to inner mitochondrial membrane. Each of the
four a-subunits possesses hydratase and dehydrogenase
enzyme
activities
at the N-terminal and C-terminal
domains, respectively. The active site for the thiolase
activity resides in the four /3-subunits of the protein
complex. Deficiencies of the dehydrogenase activity or all
of the three enzyme activities for oxidation of long-chain
fatty acids have been described. These deficiencies can
cause nonketotic hypoglycemia during fasting, hepatic
encephalopathy, and cardiac and skeletal myopathy. In
some instances, women carrying fetuses with a deficiency
of long-chain /3-hydroxyacyl-CoA dehydrogenase may
themselves develop acute liver disease, hemolysis, and
a low platelet count. This clinical disorder is associated
with a high risk of maternal and neonatal morbidity
and mortality, and is known as HELLP (hemolysis,
elevated liver enzyme levels and low platelet count). A
change of Glu 474 to Gin (E474Q) in the a-subunits
of the trifunctional protein has been identified in three
unrelated children whose mothers had an acute fatty
liver episode or HELLP syndrome during pregnancy.
The fetal-maternal interaction that leads to toxic effects
in women during pregnancy may be due to transport of
long-chain /3-hydroxyacyl metabolites produced by the
fetus and placenta to the maternal liver.
Other inborn errors of fatty acid oxidation include de-
fects in short-chain /3-hydroxy acyl-CoA dehydrogenase
and medium-chain /3-ketoacyl-CoA thiolase. The spec-
trum of clinical findings in these and other fatty acid
oxidation defects are variable; typical symptoms include
fasting intolerance, cardiomyopathy, and sudden death.
Children with long-chain fatty acid oxidation disorders
are treated with frequent feeding of a low-fat diet consist-
ing of medium-chain triglycerides. This dietary regimen
can prevent hypoketotic hypoglycemic liver dysfunction.
Energetics of /3-Oxidation
Palmitoyl-CoA yields
8
acetyl-CoA molecules and 14
pairs of hydrogen atoms, by seven cycles through the
/3-oxidation system. Acetyl-CoA can be oxidized in the
TCA cycle, used for the synthesis of fatty acid or choles-
terol, or used for the formation of ketone bodies in liver.
/3-Oxidation of an acyl-CoA with an uneven number of
carbon atoms also yields a propionyl-CoA during the
acetyl-CoA acyltransferase reaction of the last cycle.
Two high-energy bonds are consumed in the activation
of a fatty acid molecule. Every mole of fatty acyl-CoA that
cycles through reactions 1-4 produces 1 mol of FADH
2
,
1 mol of NADH, and 1 mol of acetyl-CoA. On the last
pass of an even-chain-length fatty acid,
2
mol of acetyl-
CoA are formed; and the final pass of an odd-chain-length
molecule releases 1 mol of propionyl-CoA. The amount of
ATP formed from complete oxidation of a hexanoic acid
is calculated as shown in Table 18-2.
Fatty acid oxidation produces more moles of ATP per
mole of CO
2
formed than does carbohydrate oxidation. In
this case, oxidation of
1
mol of hexose produces at most
(assuming malate shuttle operation exclusively) 38 mol of
ATP.
Complete oxidation of one molecule of palmitic acid
yields 129 ATP molecules:
C
1 5
H
3 1
COOH +
8
C
0
ASH + ATP + 7FAD +
7NAD+ + 7H20 —
8
CH
3
COSC
0
A + AMP +
PPi + 7FADH
2
+ 7NADH + 7H+
Each molecule of acetyl-CoA yields 12 ATP (12 x
8
=
96); FADH
2
yields 2 ATP (7x2=14); NADH yields
3ATP (7x3 = 21); and two high-energy bonds are con-
sumed (—2; ATP -> AMP + PPj). Thus, net ATP pro-
duction is 129. The energy yield from total combustion
of palmitic acid in a bomb calorimeter (Chapter 5) is
