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chapter 18
Lipids I: Fatty Acids and Eicosanoids
TABLE 18-2
Reaction
Direct Consequences of the Reaction
Moles of ATP Gained or Lost
per Mole of Hexanoic Acid
Activation reaction
Hexanoic acid —> Hexanoyl-CoA
- 2
First dehydrogenation
Dehydrogenation of acyl-CoA;
2 (FAD —» FADH2)
+ 4
Hydration
Hydration of
a,
/3-unsaturated fatty acyl-CoA
0
Second dehydrogenation
Dehydrogenation of /3-hydroxy-acyI-CoA;
2(NAD+—>NADH+H+)
+ 6
Oxidation of acetyl-CoA
Formation of 3 mol of acetyl-CoA,
and their oxidation in the TCA cycle and electron
transport system
+(3x12) =+36
Total
ATP =+44
—2380 kcal/mol:
C
1 6
H
3 2
O
2
+ 2302 -* I
6
CO
2
+ 16H20 at 20°C,
AH° = -2380 kcal/mol
In biological oxidation, the energy conserved as ATP
is about 942 kcal/mol (129 x 7.3). Thus, the percent-
age of standard free energy of oxidation of palmitic
acid conserved as high-energy phosphate is about 40%
(942/2380 x 100).
Regulation of Fatty Acid Oxidation
Regulation of fatty acid oxidation involves diet, cofactors,
competing substrates and hormones of fatty acid mobi-
lization. Adipose tissue triacylglycerol lipolysis is one of
the major sites of regulation. The other site is CPTI. The
latter is inhibited by malonyl-CoA which is involved in
fatty acid biosynthesis (discussed later). Thus, fatty acid
oxidation and synthesis do not occur simultaneously. In-
sulin inhibits fatty acid oxidation by blocking lipolysis
in adipose tissue, and it stimulates lipogenesis and syn-
thesis of malonyl-CoA. Glucagon stimulates fatty acid
oxidation by inhibiting synthesis of acetyl-CoA carboxy-
lase which leads to decreased synthesis of malonyl-CoA.
This causes enhanced activity of CPTI, and promotion of
fatty acid oxidation. In the fed state, the glucagon/insulin
ratio is low, and fatty acid synthesis is promoted in
the liver. In the fasting state, the glucagon/insulin ratio
is high and mobilization of free fatty acids from adi-
pose tissue and mitochondrial fatty acid oxidation are
augmented.
Peroxisomal Fatty Acid Oxidation
Peroxisomes have a single membrane and contain a fairly
homogeneous, moderately electron-dense matrix. They
are present in many mammalian cells and are particularly
abundant in liver and kidney. A normal hepatocyte con-
tains about a thousand peroxisomes, whose proliferation
is inducible by hypolipidemic drugs such as clofibrate
(Chapter
20).
Peroxisomes
contain
H
2
0 2-producing
oxidases and also H
2 0 2
-inactivating catalase. Oxidation
of very long-chain, saturated, unbranched fatty acids
(C
2 4
-C
2 6
) appears to take place mainly, if not exclu-
sively, in peroxisomes after the acyl-CoA derivatives are
transported across the membrane without involvement
of carnitine.
Oxidation
is
mediated by
flavoprotein
dehydrogenases that yield H
2
O
2
and acetyl-CoA and
terminates with octanoyl-CoA. Octanoyl- and acetyl-CoA
are transferred to mitochondria for further oxidation. Phy-
tinic acid monooxygenase, which initiates the catabolism
of phytinic acid (a
2 0
-carbon branched chain fatty acid
of dietary origin), is probably a peroxisomal enzyme.
Peroxisomal oxidation does not yield ATP. All the energy
produced appears as heat.
Three genetic disorders (
Zellweger’s syndrome, neona-
tal adrenoleukodystrophy,
and
childhood adrenoleukodys-
trophy)
exhibit defective formation of peroxisomes (in
Zellweger’s syndrome no morphologically detectable per-
oxisomes are present) or deficiency of one or more con-
stituent enzymes. All three disorders are characterized
by a marked accumulation of very long chain, saturated,
unbranched fatty acids (tetracosanoic and hexacosanoic
acids) in liver and central nervous system tissues, severe
neurological symptoms, and early death.
Peroxisomes contain dihydroxyacetone phosphate acyl-
transferase and alkyldihydroxyacetone phosphate syn-
thase, which are involved in synthesis of the plasmalogens
(Chapter 19). Peroxisomes may also participate in the
biosynthesis of bile acids. The conversion of trihydrox-
ycholestanoic acid to cholic acid (Chapter 19) has been
localized to peroxisomes.
