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chapter 18
Lipids I: Fatty Acids and Eicosanoids
kinases act at different sites. Insulin suppresses cAMP
levels and promotes activity of acetyl-CoA carboxylase.
Insulin may also increase the activity of acetyl-CoA car-
boxylase phosphatase, which is complexed with the car-
boxylase. This phosphatase also dephosphorylates glyco-
gen synthase, phosphorylase a, and HMG-CoA reductase.
Thus, common mediators (e.g., insulin, glucagon, and cat-
echolamines) regulate fatty acid synthesis and carbohy-
drate metabolism.
Long-term regulation of acetyl-CoA carboxylase in-
volves nutritional, hormonal (e.g., insulin, thyroxine), and
other factors. In animals on high-carbohydrate diets, fat-
free diets, choline deprivation, or vitamin Bi2 deprivation,
the activity is enhanced. However, fasting, high intake of
fat or of polyunsaturated fatty acids, and prolonged bi-
otin deficiency leads to decreased activity. In diabetes, the
enzyme activity is low, but insulin administration raises
it to normal levels.
Fatty acid synthesis is also carried out by a multienzyme
complex and leads from acetyl-CoA, malonyl-CoA, and
NADPH to palmitic acid. The overall process is as follows:
0
o
II
»
C H
3
C — S C o A + 7 H O O C — C H
2
C — S C o A + 1 4 N A D P H + 1 4 H + ------- ►
A c e ty l-C o A
M a lo n y l-C o A
C H
3
C H
2
(C H
2
C H
2
)
6
C H 2C O O H + 7 C 0
2
+ 1 4 N A D P + +
8
C
0
A S H + 6 H 20
P a lm itic a c id
The fatty acid synthesis complex contains seven catalytic
sites.
Acetyl transacylase catalyzes the reaction
O
II
C H
3
C — S C o A + A C P — S H ------ ►
O
II
C H
3
C — S — A C P + C o A S H
and malonyl transacylase catalyzes the reaction
O
O
II
II
H O — C — C H
2
— C — S C o A + A C P — S H -►
O
O
II
II
H O — C — C H
2
— C — S — A C P
(ACP-SH is the 4'-phosphopantetheine-SH of the acyl
carrier domain.)
These two priming reactions load a cysteinyl-SH of
one subunit with acetyl-CoA, and the -SH of the 4'-
phosphopantetheine arm of the acyl carrier site on the other
subunit with malonyl-CoA.
yS-Ketoacyl-ACP synthase (condensing enzyme) has an
active cysteine-SH group that forms an acetyl-S (or acyl-
S) intermediate (E = enzyme).
O
C H
3
C — S — A C P +
E —
S H r —
t
O
II
C H
3
C — S — E + A C P — SH
The condensation occurs with release of C 02:
O
O
O
II
II
II
C H
3
C — S — E + H O — C — C H
2
— C — S — A C P —
►
O
O
II
II
C H 3C C H 2C — S — A C P + C 0 2 + E — SH
/6-Ketoacyl-ACP reductase catalyzes the first reduction
reaction:
O
O
II
II
CH3C—CH2C—S—ACP + NADPH + + H + ;----►
O H
O
I
II
C H
3
— C H C H
2
C — S — A C P + N A D P +
It is stereospecific, and the product formed is
D(—)-/?-
hydroxybutyryl-ACP (or
D(—
)-/3-hydroxyacyl-ACP, in
subsequent reactions).
/LHydroxyacyl-ACP dehydratase catalyzes the reac-
tion:
O H
O
I
II
C H
3
C H C H
2
C — S — A C P « = ♦
O
II
f r a n s - C H
3
C H = C H C — S — A C P + H 20
In this stereospecific reaction, the
D(—
) isomer is converted
to a mms'-a,/?-unsaturated acyl-ACP derivative.
Enoyl-ACP reductase catalyzes the second reduction
with NADPH.
O
II
C H
3
C H = C H C — S — A C P + N A D P H + H + ; = ♦
O
II
+
C H
3
C H
2
C H
2
C — S — A C P + N A D P
The product formed is a saturated acyl-thioester of ACP.
