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164 Metabolism
Fatty acid degradation [4] β-Ketoacyl-CoA is now broken down by
an acyl transferase into acetyl CoA and an acyl
CoA shortened by 2 C atoms (“thioclastic
A. Fatty acid degradation: E-oxidation
cleavage”).
After uptake by the cell, fatty acids are Several cycles are required for complete
activated by conversion into their CoA deriva- degradation of long-chain fatty acids—eight
tives—acyl CoA is formed.Thisusesuptwo cycles in the case of stearyl-CoA (C18:0), for
energy-rich anhydride bonds of ATP per fatty example. The acetyl CoA formed can then
acid (see p. 162). For channeling into the mi- undergo further metabolism in the tricarbox-
tochondria, the acyl residues are first trans- ylic acid cycle (see p. 136), or can be used for
ferred to carnitine and then transported biosynthesis. When there is an excess of ace-
across the inner membrane as acyl carnitine tyl CoA, the liver can also form ketone bodies
(see B). (see p. 312).
The degradation of the fatty acids occurs in When oxidative degradation is complete,
the mitochondrial matrix through an oxida- one molecule of palmitic acid supplies around
tive cycle in which C 2 units are successively 106 molecules of ATP, corresponding to an
–1
cleaved off as acetyl CoA (activated acetic energy of 3300 kJ mol . This high energy
acid). Before the release of the acetyl groups, yield makes fats an ideal form of storage for
each CH 2 group at C-3 of the acyl residue (the metabolic energy. Hibernating animals such
β-C atom) is oxidized to the keto group— as polar bears can meet their own energy
hence the term -oxidation for this metabolic requirements for up to 6 months solely by
pathway. Both spatially and functionally, it is fat degradation,while at thesametimepro-
closely linked to the tricarboxylic acid cycle ducing the vital water they need via the res-
(see p. 136) and to the respiratory chain (see piratory chain (“respiratory water”).
p. 140).
B. Fatty acid transport
[1] The first step is dehydrogenation of acyl
CoA at C-2 and C-3. This yields an unsaturated The inner mitochondrial membrane has a
2
∆ -enoyl-CoA derivative with a trans-config- group-specific transport system for fatty
ured double bond. The two hydrogen atoms acids. In the cytoplasm, the acyl groups of
are initially transferred from FAD-containing activated fatty acids are transferred to carni-
acyl CoA dehydrogenase to the electron-trans- tine by carnitine acyltransferase [1]. They are
ferring flavoprotein (ETF). ETF dehydrogenase then channeled into the matrix by an acylcar-
[5] passes them on from ETF to ubiquinone nitine/carnitine antiport as acyl carnitine,in
(coenzyme Q), a component of the respiratory exchange for free carnitine. In the matrix, the
chain (see p. 140). Other FAD-containing mi- mitochondrial enzyme carnitine acyltransfer-
tochondrial dehydrogenases are also able to ase catalyzes the return transfer of the acyl
supply the respiratory chain with electrons in residue to CoA.
this fashion. The carnitine shuttle is the rate-determin-
There are three isoenzymes (see p. 98) of ing step in mitochondrial fatty acid degrada-
acyl CoA dehydrogenase that are specialized tion. Malonyl CoA, a precursor of fatty acid
for long-chain fatty acids (12–18 C atoms), biosynthesis, inhibits carnitine acyltransferase
medium-chain fatty acids (4–14), and short- (see p. 162), and therefore also inhibits uptake
chain fatty acids (4–8). of fatty acids into the mitochondrial matrix.
[2] The next step in fatty acid degradation The most important regulator of β-oxida-
+
+
is the addition of a water molecule to the tion is the NAD /NADH+H ratio. If the respi-
+
double bond of the enoyl CoA (hydration), ratory chain is not using any NADH+H ,then
with formation of -hydroxyacyl CoA. not only the tricarboxylic acid cycle (see
[3] In the next reaction, the OH group at C- p. 136) but also β-oxidation come to a stand-
+
3 is oxidized to a carbonyl group (dehydro- still due to the lack of NAD .
genation). This gives rise to -ketoacyl CoA,
and the reduction equivalents are transferred
+
to NAD , which also passes them on to the
respiratory chain.
Koolman, Color Atlas of Biochemistry, 2nd edition © 2005 Thieme
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