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

56
Chapter | 3 Carbohydrate Metabolism and Its Diseases
PROTEIN CARBOHYDRATE LIPID
amino acids
glucose
fatty acids
FIGURE 3-10 Interrelationships of carbohydrate,
protein, and lipid metabolism.
alanine
serine
glycine
aspartate
glycogen
oxaloacetate
glucose-6-P
Pentose
cycle
pyruvate
TCA
acetyl-CoA
NADP
NADPH
acetoacetate
citrate
acetyl-CoA
acetoacetyl-CoA
b-hydroxy-b-methyl
glutaryl-CoA
(HMG)
cholesterol
glutamate
-ketoglutarate
acetone
b-OH-butyrate
The relationship between carbohydrate and lipid metabolism
deserves special mention for the carbohydrate economy,
and the status of glucose oxidation strongly influences
lipid metabolism. A brief description of lipid metabolism
follows, and greater detail may be found in the chapter on
lipid metabolism.
A . Lipid Metabolism
1 . Oxidation of Fatty Acids
Intracellular fatty acids are either synthesized in the cytoplasm
or taken up as free fatty acids. Fatty acid oxidation
begins in the cytoplasm with the activation of fatty acids to
form fatty acyl-CoA. The activated fatty acyl-CoA is bound
to carnitine for transport into the mitochondria where fatty
acyl-CoA is released for intramitochondrial oxidation.
The classical β -oxidation scheme for the breakdown
of fatty acids whereby two-carbon units are successively
removed is a repetitive process involving four successive
reactions. After the initial activation to form a CoA derivative,
there is (1) a dehydrogenation, (2) a hydration, (3) a
second dehydrogenation, and (4) a cleavage of a two-carbon
unit. The result is the formation of AcCoA and a fatty
acid residue shorter by two carbon atoms. The residue can
then recycle to form successive AcCoA molecules until
final breakdown is achieved. In the case of odd-chain fatty
acids, propionyl-CoA is formed in the final cleavage reaction.
The hydrogen acceptors in the oxidative steps are
NAD and FAD. The further oxidation of AcCoA to CO 2
and water proceeds in the common pathway of the TCA
cycle. In the process, 2 moles of CO 2 are evolved per mole
of AcCoA entering the cycle. Therefore, fatty acids could
not theoretically lead to a net synthesis of carbohydrate.
Net synthesis of carbohydrate from fatty acids would
require the direct conversion of AcCoA into some glucose
precursor (i.e., pyruvate). The reaction
pyruvate → acety1 CoA CO2
however, is irreversible and the only route by which fatty
acid carbon could theoretically appear in carbohydrate is
through the TCA cycle intermediates, and this occurs without
a net synthesis.
2 . Synthesis of Fatty Acids
The pathway for fatty acid synthesis is separate from that
of the β -oxidation mechanism for fatty acid breakdown.
Malonyl-CoA is first formed by the addition of CO 2 .
Subsequently, two carbon units from malonyl-CoA are
sequentially added to the growing chain with a loss of CO 2
at each addition. At each step, there is also a reduction,
dehydration, and a final reduction to form a fatty acid that
is two carbons longer than the previous one.
The synthesis of fatty acids also requires NADPH as the
hydrogen donor rather than NADH or FADH. The major
source of NADPH is during the oxidation of glucose in the
HMP shunt pathway. NADPH concentration is also high
in the cytoplasm of liver and adipose cells where HMP
shunt activity is also high. The availability of this NADPH
is the basis for the linkage of carbohydrate oxidation
to lipid synthesis.
3 . Synthesis of Cholesterol and Ketone Bodies
AcCoA is also the precursor of cholesterol and the ketone
bodies: AcAc, 3-OH-B, and acetone. The synthesis of cholesterol
proceeds through a series of reactions beginning
with the stepwise condensation of 3 moles of AcCoA to