Page 177 - Color Atlas of Biochemistry
P. 177
168 Metabolism
Fatty acid synthesis ductase [6]. Finally, domain 3 serves to release
the finished product by acyl-[ACP]-hydrolase
In the vertebrates, biosynthesis of fatty acids [7] after sevensteps of chainelongation.
is catalyzed by fatty acid synthase, amulti-
functional enzyme. Located in the cytoplasm,
the enzyme requires acetyl CoA as a starter B. Reactions of fatty acid synthase
molecule. In a cyclic reaction, the acetyl resi- The key enzyme in fatty acid synthesis is ace-
dueis elongated by oneC 2 unit at a time for tyl CoA carboxylase (see p. 162), which pre-
+
seven cycles. NADPH+H is used as a reducing cedes the synthase and supplies the malonyl-
agent in the process. The end product of the CoA required for elongation. Like all carbox-
reaction is the saturated C 16 acid, palmitic ylases, the enzyme contains covalently bound
acid. biotin as a prosthetic group and is hormone-
dependently inactivated by phosphorylation
or activated by dephosphorylation (see
A. Fatty acid synthase
p. 120). The precursor citrate (see p. 138) is
Fatty acid synthase in vertebrates consists of an allosteric activator, while palmitoyl-CoA
two identical peptide chains—i. e., it is a ho- inhibits the end product of the synthesis
modimer. Each of the two peptide chains, pathway.
which are shown here as hemispheres, cata- [1] The first cycle (n = 1) starts with the
lyzes all seven of the partial reactions re- transfer of an acetyl residue from acetyl CoA
quired to synthesize palmitate. The spatial to the peripheral cysteine residue (Cys-SH). At
compression of several successive reactions thesametime,
into a single multifunctional enzyme has ad- [2] a malonyl residue is transferred from
vantages in comparison with separate en- malonyl CoA to 4-phosphopantetheine (Pan-
zymes. Competing reactions are prevented, SH).
the individual reactions proceed in a coordi- [3] By condensation of the acetyl resi-
nated way as if on a production line, and due due—or (in later cycles) the acyl residue—with
to low diffusion losses they are particularly the malonyl group, with simultaneous decar-
ef cient. boxylation, the chain is elongated.
Each subunit of the enzyme binds acetyl [4]–[6] The following three reactions (re-
residues as thioesters at two different SH duction of the 3-oxo group, dehydrogenation
groups: at one peripheral cysteine residue of the 3-hydroxyl derivative, and renewed
(CysSH) and one central 4 -phosphopante- reduction of it) correspond in principle to a
theine group (Pan-SH). Pan-SH, which is very reversal of β-oxidation, but they are catalyzed
+
similar to coenzyme A (see p. 12), is cova- by other enzymes and use NADPH+H instead
+
lently bound to a protein segment of the syn- of NADH+H for reduction. They lead to an
thase known as the acyl-carrier protein (ACP). acyl residue bound at Pan-SH with 2n + 2 C
This part functions like a long arm that passes atoms (n = the number of the cycle). Finally,
the substrate from one reaction center to the depending on the length of the product,
next. The two subunits of fatty acid synthase [1 ] The acyl residue is transferred back to
cooperate in this process; the enzyme is the peripheral cysteine, so that the next cycle
therefore only capable of functioning as a can begin again with renewed loading of the
dimer. ACP with a malonyl residue, or:
Spatially, the enzyme activities are ar- [7] After seven cycles, the completed pal-
ranged into three different domains. mitic acid is hydrolytically released.
Domain 1 catalyzes the entry of the substrates
acetyl CoA and malonyl CoA by [ACP]-S- In all, one acetyl-CoA and seven malonyl-
acetyltransferase [1] and [ACP]-Smalonyl CoA are converted with the help of 14
transferase [2] and subsequent condensation NADPH+H + into one palmitic acid, 7 CO 2 ,
+
of the two partners by 3-oxoacyl-[ACP]- 6H 2 O, 8CoA and14NADP . Acetyl CoA car-
synthase [3]. Domain 2 catalyzes the conver- boxylase also uses up seven ATP.
sion of the 3-oxo group to a CH 2 group by 3-
oxoacyl-[ACP]-reductase [4], 3-hydroxyacyl-
[ACP]-dehydratase [5], and enoyl-[ACP]-re-
Koolman, Color Atlas of Biochemistry, 2nd edition © 2005 Thieme
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