Download Fatty Acids :biosynthesis

Section 7.
Lipid Metabolism
Fats: fatty acid biosynthesis
11/04/05
Oxidation of Fatty Acids Other Than Palmitate
O
CH2 CH CH CH CH CH CH CH CH CH2 C
–
O
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH3
Arachidonate
(eicosatetraenoate) 20:4 all cis-5,8,11,14
• Any even number of saturated carbons does not require any
additional enzymes. Products are as for palmitate.
• An odd number of saturated carbons does not require any
additional enzymes. Same products plus one propionyl CoA.
• Unsaturated fatty acids require additional enzymes. Same
products, but less energy, compared to
O
saturated fatty acid the same length.
CH3 CH2 C SCoA
• See table 12.1 for a list of common
propionyl CoA
fatty acids.
1
Double Bonds in Odd-Numbered Positions
• As acetyl CoA’s are removed
from an unsaturated fatty acid,
double bonds move into or near
the active sites of the oxidation cycle enzymes.
• An odd-numbered double bond
moves into the 3-position, which
is not a substrate for the principal
enzymes of the cycle.
• An isomerase moves it to the 2position.
• Moving the double bond is
energy neutral, but one less
FADH2 is made because one
acyl CoA dehydrogenase step is
2 “skipped.”
16:1 cis-9
(p 610)
Double Bonds in Even- Numbered Positions.
• An even-numbered double bond
moves to the 4-position.
• Acyl CoA dehydrogenase oxidizes
it producing FADH2 and the nonsubstrate dienoyl CoA.
• The additional enzyme 2,4-dienoyl
CoA reductase uses NADPH to
produce a position double bond.
• The additional enzyme cis 3-enoyl
CoA isomerase (see above) moves
the double bond from the 3- to the
2-position.
• NADH is produced after hydration,
and then acetyl CoA, as usual (not
shown).
• The net effect for the cycle is the
equivalent of one less NADH.
3
O
R CH CH CH2 CH2 C S
CoA
acyl CoA
4
FAD
FADH2
acyl CoA
dehydrogenase
O
R CH CH CH CH C S CoA
2,4-dienoyl CoA
NADPH + H+
NADP+
2,4-dienoyl
CoA reductase
O
R CH2 CH CH CH2 C S CoA
cis -enoyl CoA
cis 3-enoyl CoA
isomerase
R CH2 CH2 CH
O
CH C S CoA
Fig. 22.10
modified
+ 3 acetyl CoA
+ 3 FADH2
+ 3 NADH
Example:
Linoleoyl CoA
C18:2 cis-9,cis-12
+ acetyl CoA
+ NADH (no FADH2)
4
Ketone
Bodies
CoA
•
O
C
2 CH3 C S CoA
acetyl CoA
CH2
acetyl CoA
+ H2O
CoA
CH3
C
O
C
O
–
3-hydroxy-3-methyl
glutaryl CoA
acetyl CoA
CH3
HO
O
CH
NAD+
H+ +
NADH
CH3
O C
CH2
C
C
–
O
O
O
CH3
C
CH2
3-D-hydroxybutyrate
5
HO
CH2
acetoacetyl CoA
See fig. 22.19
•
•
CH2
CH3
The liver normally
converts acetyl CoA to
ketone bodies that are
used by peripheral
tissues.
•
CoA
C S
C S CoA
O
•
O
O
O–
CH3
+ CO2
acetone
acetoacetate
Production is enhanced by low carbohydrate (diabetes, starvation) and/or
low O2 (hypoventilation)
General anesthesia: CO2 up, pH down, ketone bodies up.
Volatile acetone formation is non-enzymatic.
Acetoacetate
Utilization
• In peripheral tissues,
the ketone body
acetoacetate is
activated, and
converted back to
acetyl CoA.
• 3-hydroxybutyrate
and acetoacetate are
favored over
glucose by the renal
cortex and cardiac
muscle.
6
Fig. 22.20
Summary of Fatty Acid Biosynthesis
• When the cell energy level is high, rather than
being used by the Krebs cycle, acetyl CoA is
transferred from the mitochondrial matrix to the
cytosol.
• In the cytosol, acetyl CoA is converted to malonyl
CoA, which is used by fatty acyl synthase (FAS)
for the synthesis of palmitate.
• Palmitate is transported to adipose tissue and
used to synthesize triacylglycerol.
• The palmitate synthetic reactions are reversals of
the degradative reactions, but the enzymes,
cofactors and locations are different.
7
Reactions
on the
right are
catalyzed
by FAS
in the
cytosol.
Fig. 22.2
8
Compare
degradation
and
synthesis
structures.
Citrate Shuttle Transfers Acetyls to Cytosol
ATP
+ CO2
Fig. 22.25
9
+CO2
• High [ATP] inhibits the Krebs cycle; [citrate] increases.
• Citrate translocase enables citrate and pyruvate to cross the
mitochondrial inner membrane. CoA does not cross (remember
acyl CoA / acyl carnitine).
• NADPH is made at the expense of NADH in the cytosol.
Activation by Acetyl CoA Carboxylase
O
–
+
ATP
+
HCO
CH3 C S CoA
3
acetyl CoA
O
–
C
O
O
CH2 C S CoA + ADP + Pi
malonyl CoA
(p 617)
• In the cytosol, acetyl CoA is carboxylated to make the activated precursor,
malonyl CoA.
• This is the committed step in fatty acid biosynthesis.
• ATP provides energy.
• Biotin is a cofactor.
• Two sequential reactions occur in the active site.
(p 618)
biotin-Enz + ATP + HCO3-  CO2~biotin-Enz + ADP + Pi
CO2~biotin-Enz + acetyl CoA  malonyl CoA + biotin-Enz
10
• ATP reacts first
providing energy
to bind and
activate HCO3-.
• Next acetyl CoA
binds and the
activated CO2- is
transferred to the
acetyl group.
Biotin: a CO2 Carrier
Figs. 24-10 and 24-11 (Stryer 4th)
11
Fatty Acid Synthase Reactions
CE
(KR)
CE +
Fig. 22.22
Condensation forms 4 carbon unit on acyl carrier protein (ACP).
Reduction of ketone to hydroxyl by NADPH.
12
Fatty Acid Synthase Reactions, con’t
(DH)
(ER)
Fig. 22.22
13
• Dehydration produces a double bond.
• Reduction to a saturated 4 carbon fatty acid chain.
FAS is
a
Dimer
Fig. 22.23
14
• Malonyl transfer (MT), acetyl transfer (ATP and condensation
(CE) on one subunit.
• Reduction (KR), dehydration (DH), reduction (ER) and
thiolysis (TE) on the other subunit.
• The growing FA chain is passed between subunits by ACP.
Acyl carrier protein (ACP)
Fig. 22.21
• ACP has a long flexible chain, derived from pantothenic
acid, to which the growing fatty acid is attached.
15
Condensation
Fig. 22.24
16
• Both subunits of FAS are involved.
• Condensation is catalyzed by CE on upper subunit.
Reduction
Fig. 22.24
17
• 2 NADPH are used.
• Reduction (reduction, dehydration, reduction see slides 12
&13) occur on lower subunit of the dimer.
Translocation and binding of a new
malonyl CoA
Fig. 22.24
18
< The 4 carbon chain is transferred to CE.
^ A new malonyl CoA binds ACP on other subunit.
• The cycle (condendation, reduction,
dehydration, reduction) repeats until 16 carbon
palmitate is formed (not shown).
• Palmitate is released by TE (see slide 14).
Net Reaction for Palmitate Synthesis
8 acetyl CoA + 7 ATP + 14 NADPH + 6 H+

palmitate + 14 NADP+ + 8 CoA + 6 H2O + 7 ADP + 7Pi
(p 622)
For this reaction, there are 7 (for 7 ATP) + 35 (for 14
NADPH) = 42 ~P equivalents used.
Compare to 26 obtained from the palmitate conversion
to acetyl CoA by fatty acyl CoA synthetase and the
-oxidation cycle.
19
Control of Fatty Acid
Synthesis is at the
Committed Step
20
• Fig. 24-18
Styer 4th
Control of Acetyl CoA Carboxylase Activity
Fig. 22.26
• Phosphorylation by kinase inhibits carboxylase (+AMP, -ATP).
• Phosphatase activates carboxylase (+insulin, -glucagon, &
epinephrine).
• Citrate partially activates the inactive phosphorylated acetyl
Co A carboxylase allosterically.
• Palmitoyl CoA inhibits carboxylase and citrate translocase.
21
Web links
Odd Chain Fatty Acids. The fate of propionyl CoA.
Unsaturated Fatty Acid Oxidation. The role of isomerase.
Next Topic: Membrane lipids.