Clinical Biochemistry of Domestic Animals (Sixth Edition) - UMK ...

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Chapter | 4 Lipids and Ketones
2 new carbons at the carboxyl end of the existing LCFA.
Fatty acid elongase uses the same substrates (malonyl-
CoA and NADPH) as fatty acid synthase, but it is located
in a different part of the cell and prefers palmityl-CoA as
its substrate. However, fatty acid elongase can use longer
LCFA-CoA as substrates to a limited degree to produce
LCFA-CoA with a length of as great as 24 carbons ( Cook
and McMaster, 2002 ).
Nonruminant mammals synthesize LCFA in liver, adipose,
and mammary tissue. Ruminants synthesize LCFA
primarily in adipose and mammary tissue with acetate
being the most important precursor. Ruminants generally
have a low capacity for LCFA synthesis in liver, but after
eating large amounts of high-starch diets, they may synthesize
some LCFA in the liver from acetate and propionate
( Hanson and Ballard, 1967 ; Ingle, 1972a, 1972b; Liepa
1978).
C. Catabolism of Long Chain Fatty Acids
1. Desaturation
Most animals are capable of desaturating LCFA only at
the Δ 4 , Δ 5 , Δ 6 , and Δ 9 positions (counting from the carboxyl
end). Animals are able to desaturate palmityl-CoA
and stearyl-CoA between C 9 and C 10 by means of Δ 9
desaturase system located in the endoplasmic reticulum
to produce palmitoleyl-CoA and oleyl-CoA, respectively.
However, animals are not able to create additional double
bonds beyond C 9 in these products to any significant extent,
so linoleic and linolenic acids must be absorbed from the
intestinal tract ( Cook and McMaster, 2002 ). By a combination
of the actions LCFA elongase and Δ 4 , Δ 5 , and Δ 6
desaturase systems, the livers of most mammals can synthesize
arachidonic acid and eicosapentaenoic acid from linoleic
and linolenic acids, respectively. However, the cat has
very low levels of Δ 6 desaturase in its liver and must have
arachidonic acid in its diet ( MacDonald et al ., 1984 ).
2 . β-Oxidation
The main catabolic route for LCFA is β-oxidation. Most
tissues can perform β-oxidation (erythrocytes are an exception),
but those most adept at it are liver, skeletal muscle, and
heart. In addition, the liver can partially oxidize LCFA to
ketones, an important process that will be discussed extensively
later. Before LCFA can be subjected to β-oxidation,
they must be esterified to CoA, which is accomplished by
the following reaction:
LCFA ATP CoA ←⎯⎯
→LCFA-CoA AMP PP
The reaction is catalyzed by LCFA-CoA synthetase, an
enzyme bound to the endoplasmic reticulum and the outer
mitochondrial membrane. The pyrophosphate (PP) is rapidly
hydrolyzed, so the reaction effectively consumes two
ATP. The activation of LCFA is not rate limiting for β-
oxidation ( Pande, 1971 ).
For LCFA-CoA to be catabolized, it must pass into the
mitochondrion, which is a problem because the inner mitochondrial
membrane is impermeable to it. The CoA must
be exchanged for a carnitine moiety, a reaction catalyzed
outside the mitochondrion by carnitine acyltransferase I
( Fig. 4-2 ):
LCFA-CoA carnitine ←⎯⎯
→LCFA-carnitine CoA
LCFA-carnitine passes readily through the inner mitochondrial
membrane and is acted on by carnitine acyltransferase
II, which converts the LCFA-carnitine back to
LCFA-CoA ( Kopec and Fritz, 1973 ).
Carnitine acyltransferase I appears to be controlled by
inhibition by malonyl-CoA ( McGarry et al ., 1977 ), and it
is logical that when lipogenesis is stimulated, the LCFA
that are produced should be prevented from entering the
mitochondrion where they will be catabolized.
In the mitochondrion, the process of β-oxidation per
se cleaves the LCFA into acetyl-CoA units. The reaction
sequence is as follows:
R-CH2-CH2-CO-CoA
FAD
acyl-CoA dehydrogenase
⎯⎯⎯⎯⎯⎯⎯⎯⎯→
R-CHCH-CO-CoA
FADH2
R-CHCH-CO-CoA
H2O
Δ2
-enoyl-CoA hydratase
⎯⎯⎯⎯⎯⎯⎯⎯⎯→R-C(
OH)H-CH2CO-CoA
R-C(OH)H-CH -CO-CoA NAD
2
L( )
-3-hydroxyacyl-CoA dehydrogenase
⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯→
R-CO-CH2-CO-CoA NADH H
R-CO-CH2-CO-CoA
CoA
thiolase
⎯⎯⎯⎯⎯
→ R-CO-CoA CH -CO-CoA
The resulting acyl-CoA is two carbons shorter and can
recycle through the pathway. Each trip of an acyl-CoA
through the pathway generates one FADH 2 and one NADH
H 1 , which can generate 5 ATP via oxidative phosphorylation.
If the LCFA has an odd number of carbons, which
is rare, the final product of β-oxidation will be propionyl-
CoA. The double bond produced by the acyl-CoA dehydrogenase
reaction is of trans configuration, not the cis
configuration occurring in unsaturated LCFA found free or
esterified to glycerol.
Unsaturated LCFA can proceed through β-oxidation
to within three carbons of the double bond. As this point,
Δ 2 -enoyl-CoA hydratase cannot act because it requires a
trans, rather than a cis, configuration in its substrates, and it
requires that the double bond be between C 2 and C 3 rather
than between C 3 and C 4 . At this point, Δ 3 , Δ 2 -enoyl-CoA
isomerase will convert the Δ 3 -cis double bond to a Δ 2 -
trans double bond, which will allow β-oxidation to proceed
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