chapter 18
Lipids I: Fatty Acids and Eicosanoids
a -K e to g lu ta ra te
S u c c in a te
+ $
,+ c o *
N H .
i y
( C ^ — N - [ C H J — C H — C O O H
As^>7b a te
' (CHJj,— N - [ C H J — C H — C H — C O O H
F e 2+ ’
e-N -T rim eth y lly sin e
S u c c in a te
a -K e to g lu ta ra te
+ C Q ,
+ Q ,
ß-H y d ro x y -e-N -trim eth y ily sin e
\ 2
g ly c in e ^ \
P y rid o x al
NAD H + H+
p h o s p h a te
C H — C O O H - A^
a , e
N [ C H J - C O O H
( C H ^ - N - [ C H J - C H O
F e J+ ’
C arn itin e
Y -B u ty ro b etain e
Y -B u ty ro b e ta in e a ld e h y d e
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.
The major pathway for fatty acid oxidation, /1-oxidation
(Figure 18-3), involves oxidation of acyl-CoA at the
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
-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
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
previous page 400 Bhagavan Medical Biochemistry 2001 read online next page 402 Bhagavan Medical Biochemistry 2001 read online Home Toggle text on/off