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chapter 18
Lipids I: Fatty Acids and Eicosanoids
4,-phosphopantetheine (20 nm long) derived from coen-
zyme A is bound as a phosphodiester through the hydroxyl
group of a specific seryl residue. The acyl intermediates are
in thioester linkage with the -SH of the prosthetic group,
which serves as a swinging arm to carry acyl groups from
one catalytic site to the next.
The structure of 4'-phosphopantetheine attached to the
serine residue of ACP is
O
CH3
0
o
Servi
}
»
I
il
I
residue f —0 — P— '° — 1CH2— 1
c — C H — C — N— C H 2— CH 2— C — N— C H 2— CH 3— SH
OH
I
OH
CH3
Sources of NADPH for Fatty Acid Synthesis
The reducing agent for fatty acid synthesis is NADPH.
It is mostly supplied by the pentose phosphate pathway
(Chapter 15) in the reactions
Giucose-6-phosphate
G lu c o s e
6
-p h o s p h a te --------- phyarogenase------- (
6
-P h o s p h a te -g lu c o n o la c to n e
NADP‘
NADPH+ H ’
and
6
-P h o s p h o g lu c o n a te
6
-Phosphogiuconate
dehydrogenase
NADP*
CO?
NADPH + H*
R ib u lo se 5 -p h o s p h a te
Oxidation of malate also provides NADPH:
M alate
Malic enzyme
NADP*
C02
NADPH+ H*
P yru vate
These three enzymes, like the fatty acid synthase complex,
are located in the cytosol. Active lipogenesis occurs in
liver, adipose tissue, and lactating mammary glands, which
contain a correspondingly high activity of the pentose
phosphate pathway. Thus, lipogenesis is closely linked to
carbohydrate oxidation. The rate of lipogenesis is high in
humans on carbohydrate-rich diets. Restricted energy in-
take, a high-fat diet, and insulin deficiency decrease fatty
acid synthesis.
Source and Transport of Acetyl-CoA
Acetyl-CoA is synthesized in mitochondria by a num-
ber of reactions: oxidative decarboxylation of pyruvate,
catabolism of some amino acids (e.g., phenylalanine, ty-
rosine, leucine, lysine, and tryptophan; see Chapter 17),
and /1-oxidation of fatty acids (see above). Since acetyl-
CoA cannot be transported directly across the inner
mitochondrial membrane to the cytosol, its carbon atoms
are transferred by two transport mechanisms.
1. Transport dependent upon carnitine: Carnitine
participates in the transport of long-chain acyl-CoA
into the mitochondria and plays a similar role in the
transport of acetyl-CoA out of mitochondria.
However, carnitine acetyl transferases have a minor
role in acetyl-CoA transport.
2. Cytosolic generation of acetyl-CoA (“citrate
shuttle”): This pathway is shown in Figure 18-13.
Citrate synthesized from oxaloacetate and acetyl-CoA
is transported to the cytosol via the tricarboxylate
anion carrier system and cleaved to yield acetyl-CoA
and oxaloacetate.
ATF citrate-lyase
Citrate3“ + ATP4“ + CoA----------------------- ►
(or citrate cleavage enzyme)
acetyl-CoA + oxaloacetate2- + ADP3- + P2-
Thus, citrate not only modulates the rate of fatty acid
synthesis but also provides carbon atoms for the synthe-
sis. The oxaloacetate formed from pyruvate may eventu-
ally be converted (via malate) to glucose by the gluco-
neogenic pathway. The glucose oxidized via the pentose
phosphate pathway augments fatty acid synthesis by pro-
viding NADPH. Pyruvate generated from oxaloacetate
can enter mitochondria and be converted to oxaloacetate,
which is required for the formation of citrate.
Regulation of Fatty Acid Synthase
Like acetyl-CoA carboxylase, FAS is under short- and
long-term control. The former is due to negative or positive
allosteric modulation or to changes in the concentrations of
substrate, cofactor, and product. The latter usually consists
of changes in enzyme content as a result of protein synthe-
sis or decreased protein degradation. Variation in levels
of hormones (e.g., insulin, glucagon, epinephrine, thyroid
hormone, and prolactin) and in the nutritional state affect
fatty acid synthesis through short- and long-term mech-
anisms. In the diabetic state, hepatic fatty acid synthesis
is severely impaired but is corrected by administration of
insulin. The impairment may be due to defects in glucose
metabolism that lead to a reduced level of an inducer or
increased level of a repressor of transcription of the FAS
gene, or both. Glucagon and epinephrine raise intracellu-
lar levels of cAMP, and their inhibitory effect on fatty acid
synthesis may be due to phosphorylation or déphospho-
rylation of acetyl-CoA carboxylase. They also stimulate
the action of hormone-sensitive triacylglycerol lipase
and raise intracellular levels of long-chain acyl-CoA.
