Beruflich Dokumente
Kultur Dokumente
M 29
Concept: Fatty Acid Synthesis, Origin of Acetyl-CoA for Fat Synthesis , Regulation of Fatty Acid Synthesis ,
Elongation and Desaturation of Fatty Acids , Triacylglyceride Synthesis , Phospholipid Structures , Phospholipid
Metabolism , Plasmalogen Synthesis , Sphingolipid Metabolism , Clinical Significance of Sphingolipids , Eicosanoid
Metabolism , Cholesterol and Bile Acid Synthesis , Fatty Acid Oxidation and Ketogenesis
One might predict that the pathway for the synthesis of fatty acids would be the reversal of the oxidation
pathway. However, this would not allow distinct regulation of the two pathways to occur even given the fact
that the pathways are separated within different cellular compartments.
The pathway for fatty acid synthesis occurs in the cytoplasm, whereas, oxidation occurs in the mitochondria.
The other major difference is the use of nucleotide co-factors. Oxidation of fats involves the reduction of
FADH+ and NAD+. Synthesis of fats involves the oxidation of NADPH. However, the essential chemistry of
the two processes are reversals of each other. Both oxidation and synthesis of fats utilize an activated two
carbon intermediate, acetyl-CoA. However, the acetyl-CoA in fat synthesis exists temporarily bound to the
enzyme complex as malonyl-CoA.
The synthesis of malonyl-CoA is the first committed step of fatty acid synthesis and the enzyme that
catalyzes this reaction, acetyl-CoA carboxylase (ACC), is the major site of regulation of fatty acid synthesis.
Like other enzymes that transfer CO2 to substrates, ACC requires a biotin co-factor.
The rate of fatty acid synthesis is controlled by the equilibrium between monomeric ACC and polymeric
ACC. The activity of ACC requires polymerization. This conformational change is enhanced by citrate and
inhibited by long-chain fatty acids. ACC is also controlled through hormone mediated phosphorylation (see
below).
The acetyl groups that are the products of fatty acid
oxidation are linked to CoASH. As you should recall, CoA
contains a phosphopantetheine group coupled to AMP. The
carrier of acetyl groups (and elongating acyl groups) during
fatty acid synthesis is also a phosphopantetheine prosthetic
group, however, it is attached a serine hydroxyl in the
synthetic enzyme complex. The carrier portion of the
synthetic complex is called acyl carrier protein, ACP. This is
somewhat of a misnomer in eukaryotic fatty acid synthesis
since the ACP portion of the synthetic complex is simply one
of many domains of a single polypeptide. The acetyl-CoA
and malonyl-CoA are transferred to ACP by the action of
acetyl-CoA transacylase and malonyl-CoA transacylase,
respectively.
All of the reactions of fatty acid synthesis are carried out by the multiple enzymatic activities of FAS. Like
fat oxidation, fat synthesis involves 4 enzymatic activities. These are, b-keto-ACP synthase (condensing
enzyme), b-keto-ACP reductase, 3-OH acyl-ACP dehydratase and enoyl-ACP reductase(give a look to the
FAS reaction mechanism). The two reduction reactions require NADPH oxidation to NADP+.
The primary fatty acid synthesized by FAS is palmitate. Palmitate is then released from the enzyme by
thioesterase reaction and can then undergo separate elongation and/or unsaturation to yield other fatty acid
molecules.
The fatty acid product released from FAS is palmitate (via the action of palmitoyl thioesterase) which is a
16:0 fatty acid, i.e. 16 carbons and no sites of unsaturation. Elongation and unsaturation of fatty acids occurs
in both the mitochondria and endoplasmic reticulum (microsomal membranes). The predominant site of
these processes is in the ER membranes. Elongation involves condensation of acyl-CoA groups with
malonyl-CoA. The resultant product is two carbons longer (CO2 is released from malonyl-CoA as in the
FAS reaction) which undergoes reduction, dehydration and reduction yielding a saturated fatty acid. The
reduction reactions of elongation require NADPH as co-factor just as for the similar reactions catalyzed by
FAS. Mitochondrial elongation involves acetyl-CoA units and is a reversal of oxidation except that the final
reduction utilizes NADPH instead of FADH2 as co-factor.
Desaturation occurs in the ER membranes as well and in mammalian cells involves 4 broad specificity fatty
acyl-CoA desaturases (non-heme iron containing enzymes). These enzymes introduce unsaturation at C4,
C5, C6 or C9.
The electrons from the reduced fatty acid (saturated) and from the desaturase are transferred to molecular
oxygen to form water and oxydized fatty acid (unsaturated). NADH is the donor of two electrons which
keep the desaturase in the reduced form through the action of the enzyme NADH-cytochrome b5 reductase
. These electrons are un-coupled from mitochondrial oxidative-phosphorylation and, therefore, do not yield
ATP.
Since these enzymes cannot introduce sites of unsaturation beyond C9 they cannot synthesize either
linoleate (18:2D9, 12) or linolenate (18:3D9, 12, 15). These fatty acids must be acquired from the diet and are,
therefore, referred to as essential fatty acids. Linoleic is especially important in that it required for the
synthesis of arachidonic acid. As we shall encounter later, arachindonate is a precursor for the eicosanoids
(the prostaglandins and thromboxanes). It is this role of fatty acids in eicosanoid synthesis that leads to poor
growth, wound healing and dermatitis in persons on fat free diets. Also, linoleic acid is a constituent of
epidermal cell sphingolipids that function as the skins water permeability barrier.
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Synthesis of Triglycerides
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Long chain acyl-CoA dehydrogenase: removes two hydrogens by the reduction of FAD
to FADH2 converting the single C C bond to a double C C bond. The FADH2 reacts with the
Respiratory Chain allowing oxidative
phosphorylation to generate ATP.
Hydration: H and OH of water is added
across the double bond formed by the
removal (above) of two hydrogens to FADH2.
Dehydrogenation #2 : here again two
hydrogens are removed and added to NAD+
to form H+ and NADH which reacts with the
Respiratory Chain allowing oxidative
phosphorylation to generate ATP.
Thiolysis: Coenzyme A (SCoA) cleaves the
fatty acyl-CoA between the beta and alpha
carbons, splitting the two-carbon acetyl-
CoA and the fatty acyl-CoA shorted by two
carbons.
Repeat of the cycle shortens the fatty
acyl-CoA two carbons known as the "Beta
oxidation spiral".
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