section 18.4
Synthesis of Long-Chain Saturated Fatty Acids
379
and an inhibitory activity at N-methyl-D-aspartate recep-
tors. A selective antagonist of serotonin receptor 5-HT3,
ondansetron, reduces alcohol consumption in patients with
early onset alcoholism. The 5-HT3 receptors are densely
distributed in mesocorticolimbic neuronal terminals and
regulate dopamine release. Attenuation of dopamine re-
lease reduces alcohol consumption.
In chronic alcoholics, heavy drinking and decreased
food intake lead to ketoacidosis. Accelerated lipolysis aris-
ing from reduced insulin and increased glucagon secretion
caused by hypoglycemia leads to ketosis with a high
[j3-
hydroxybutyrate]/[acetoacetate] ratio. Treatment requires
normalization of fluid and electrolyte balance (Chapter 39)
and of glucose level. Administration of glucose provokes
insulin release and depresses glucagon release, thus sup-
pressing the stimuli for ketogenesis. The distinction be-
tween diabetic ketoacidosis and alcoholic ketoacidosis
may be difficult to determine, and in some patients plasma
glucose levels may not discriminate between the two en-
tities (although in diabetic ketoacidosis plasma glucose
levels are usually high, whereas in alcoholic ketoacidosis
these levels may be low, normal, or marginally elevated).
Fluid and electrolyte replacement and glucose administra-
tion in ketoacidosis are essential regardless of etiology.
Ethanol is a teratogen partly because it inhibits embry-
onic cellular proliferation. Maternal alcoholism causes fe-
tal alcohol syndrome, which is characterized by abnormal
function of the central nervous system, microcephaly, cleft
palate, and micrognathia.
18.4 Synthesis of Long-Chain Saturated
Fatty Acids
The reactions of
de novo
fatty acid biosynthesis are shown
in Figure 18-10. They are carried out by two multienzyme
systems functioning in sequence. The first is acetyl-CoA
carboxylase, which converts acetyl-CoA to malonyl-CoA.
The second is fatty acid synthase, which sequentially joins
two-carbon units of malonyl-CoA, eventually producing
palmitic acid. Both complexes consist of multifunctional
subunits. The various catalytic functions can be readily
separated in plant cells and prokaryotes, but in yeasts,
birds, and mammals, attempts to subdivide catalytic func-
tions lead to loss of activity. Important features of this
system are as follows: 1
2
1.
De novo
synthesis takes place in the cytosol (whereas
fatty acid oxidation occurs in mitochondria).
2. All carbon atoms are derived from acetyl-CoA
(obtained from carbohydrates or amino acids), and
palmitate (Cig) is the predominant fatty acid
produced. Fatty acids longer than 16 carbons, those
that are unsaturated, and hydroxy fatty acids are
obtained by separate processes of chain elongation,
desaturation, or a-hydroxylation, respectively.
3. The committed (rate-controlling) step is the
biotin-dependent carboxylation of acetyl-CoA by
acetyl-CoA carboxylase. Important allosteric
effectors are citrate (positive) and long-chain
acyl-CoA derivatives (negative).
4. Although the initial step requires C 02 fixation, C 02 is
not incorporated into fatty acids. The labeled carbon
in 14C 02 (as Hl4COf) is not incorporated into the
carbons of fatty acids synthesized.
5. Synthesis is initiated by a molecule of acetyl-CoA
that functions as a primer. Its two carbons become Cu
and Ci6 of palmitate. The acetyl group is extended by
successive addition of the two carbons of malonate
originally derived from acetyl-CoA, the unesterified
carboxylic acid group being removed as C 02. In
mammalian liver and mammary gland, butyryl-CoA
is a more active primer than acetyl-CoA.
Odd-chain-length fatty acids found in some
organisms are synthesized by priming the reaction
with propionyl-CoA instead of acetyl-CoA.
6. Release of the finished fatty acid occurs when the
chain length reaches Ci6 by action of thioester
hydrolase, which is specific for long-chain acyl-CoA
derivatives. A thioester hydrolase of mammary gland
is specific for acyl residues of Cg, Cio, or Q 2.
The overall reaction for palmitate synthesis from acetyl-
CoA is
8
Acetyl-CoA + 14NADPH + 14H+ + 7ATP + H20 ->
palmitate +
8
C
0
ASH + 14NADP+ + 7ADP + 7P,
The reducing equivalents of NADPH are derived largely
from the pentose phosphate pathway.
Acetyl-CoA carboxylase is a biotin-dependent enzyme.
It has been purified from microorganisms, yeast, plants,
and animals. In animal cells, it exists as an inactive pro-
tomer (M.W. ~400,000) and as an active polymer (M.W.
4-8 million). The protomer contains the activity of biotin
carboxylase, biotin carboxyl carrier protein (BCCP), tran-
scarboxylase, and a regulatory allosteric site. Each pro-
tomer contains a biotinyl group bound in amide linkage to
the e-amino group of a lysyl residue.
Citrate shifts the equilibrium from inactive protomer
to active polymer. The polymeric form appears as long
filaments in electron micrographs.
