368
chapter 18
Lipids I: Fatty Acids and Eicosanoids
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F I G U R E 1 8 -2
Carnitine biosynthesis in humans. A lysyl residue is trimethylated by S-adenosylmethionine, with subsequent
proteolytic release of trimethyllysine, the starting material. The reactions are catalyzed by ( 1
) trimethyllysine
A-hydroxylase, (2) /S-hydroxy-trimethyllysine aldolase (pyridoxal phosphate), (3) /-trimethylaminobutyraldehyde
dehydrogenase, and (4) /-butyrobetaine hydroxylase.
membrane carnitine transport, carnitine palmitoyltrans-
ferase I (CPTI), carnitine palmitoyltransferase II (CPTII),
and camitine-acylcarnitine translocase. Clinical manifes-
tations of disorders of carnitine metabolism and fatty acid
oxidation disorders (discussed later) span a wide spec-
trum and can be affected by the severity and site of the
defect (e.g., muscle, liver, and kidney). The disorders may
be characterized by hypoketotic hypoglycemia, hyperam-
monemia, liver disease, skeletal muscle weakness, and
cardiomyopathy. In some instances, dietary intervention
brings about marked improvement in the clinical mani-
festations; for example, patients with carnitine transport
defect respond well to carnitine therapy.
/3-Oxidation
The major pathway for fatty acid oxidation, /1-oxidation
(Figure 18-3), involves oxidation of acyl-CoA at the
fi-
carbon and removal of two carbon fragments as acetyl-
CoA and takes place entirely in the mitochondrial matrix.
Oxidation of a saturated acyl-CoA with an even number
of carbon atoms to acetyl-CoA requires repeated sequen-
tial action of four enzymes.
1. Acyl-CoA dehydrogenase dehydrogenates acyl-CoA
at the
a-
and
fi
-carbon atoms to yield the
oq/l-unsaturated acyl-CoA (or A2-unsaturated
acyl-CoA). Each one of four distinct dehydrogenases
is specific for a given range of fatty acid chain length.
All four are flavoproteins and contain a tightly bound
molecule of flavin adenine dinucleotide (FAD). The
electrons from the acyl-CoA dehydrogenase are
transferred to the main respiratory chain (Chapter 14)
through mitochondrial electron transfer flavoprotein
(ETF) and ETF-ubiquinone oxidoreductase
(ETF-QO) (Figure 18-4). Both ETF and
ETF-ubiquinone oxidoreductase are nuclear encoded
proteins. They also mediate transfer of electrons from
dimethylglycine dehydrogenase and sarcosine
dehydrogenase. Inherited defects in ETF and
ETF-QO cause accumulation of organic acids
(acidemia) and their excretion in the urine (acidurias)
Examples of these disorders are glutaric acidemia
type I and type II which are inherited as autosomal
recessive traits. Glutaric acid is an intermediate in the
metabolism of lysine, hydroxy lysine, and tryptophan.
Glutaric acidemia type I
is caused by deficiency of
glutaryl-CoA dehydrogenase which catalyzes the
conversion of glutaryl-CoA to crotonyl-CoA.
Glutaric acidemia type II
is caused by defects in the
ETF/ETF-QO proteins. The clinical manifestations of
these disorders are similar to medium-chain acyl-CoA
dehydrogenase deficiency (discussed later). The A1
2
double bond formed by the acyl-CoA dehydrogenase
has a trans configuration. The double bonds in
naturally occurring fatty acids are generally in the cis
configuration. The oxidation of unsaturated c/s-fatty
acids requires two auxiliary enzymes, enoyl-CoA
isomerase and 2,4-dienoyl-CoA reductase.
Acyl-CoA dehydrogenase (especially butyryl-CoA
dehydrogenase) is irreversibly inactivated by
methylene cyclopropylacetyl-CoA through the
formation of covalent adduct with the FAD of the
enzyme. The inhibitor is derived by transamination
